Genome-wide association study of pathological gambling.

BACKGROUND: Pathological gambling is a behavioural addiction with negative economic, social, and psychological consequences. Identification of contributing genes and pathways may improve understanding of aetiology and facilitate therapy and prevention. Here, we report the first genome-wide association study of pathological gambling. Our aims were to identify pathways involved in pathological gambling, and examine whether there is a genetic overlap between pathological gambling and alcohol dependence. METHODS: Four hundred and forty-five individuals with a diagnosis of pathological gambling according to the Diagnostic and Statistical Manual of Mental Disorders were recruited in Germany, and 986 controls were drawn from a German general population sample. A genome-wide association study of pathological gambling comprising single marker, gene-based, and pathway analyses, was performed. Polygenic risk scores were generated using data from a German genome-wide association study of alcohol dependence. RESULTS: No genome-wide significant association with pathological gambling was found for single markers or genes. Pathways for Huntington's disease (P-value=6.63×10(-3)); 5'-adenosine monophosphate-activated protein kinase signalling (P-value=9.57×10(-3)); and apoptosis (P-value=1.75×10(-2)) were significant. Polygenic risk score analysis of the alcohol dependence dataset yielded a one-sided nominal significant P-value in subjects with pathological gambling, irrespective of comorbid alcohol dependence status. CONCLUSIONS: The present results accord with previous quantitative formal genetic studies which showed genetic overlap between non-substance- and substance-related addictions. Furthermore, pathway analysis suggests shared pathology between Huntington's disease and pathological gambling. This finding is consistent with previous imaging studies.

[Suicide in psychiatric hospitals : Results, risk factors and therapeutic measures]. / Suizid im psychiatrischen Krankenhaus : Ergebnisse, Risikofaktoren, therapeutische Maßnahmen.

Suicide prevention is a core responsibility of psychiatry and psychotherapy. Periods of change in psychiatric inpatient treatment concepts are usually also accompanied by an increase in psychopathological behavior and with increased suicide rates in psychiatric hospitals, as seen in the 1970s and 1980s in Germany. That this represented a real increase of inpatient suicides during those years was confirmed and subsequently the number and rate of inpatient suicides has decreased from approximately 280 out of 100,000 admissions of patients in 1980 to approximately 50 in 2014. Death can also occur in psychiatric hospitals and an absolute prevention is not possible even under optimal conditions of therapy and nursing, communication and security. The suicide rate has clearly decreased over the last two decades in relation to admissions. The group of young male schizophrenic patients newly identified as having a high clinical suicide risk has decreased among the suicide victims whereas the percentage of severely depressed patients with delusions has increased. This reduction could be associated with the comprehensive improvements in educational and training programs in the field of suicide and suicide prevention, objectification of coping methods, development of diagnostic and therapeutic strategies, improvements in therapy and relationship possibilities and a general reduction in the number of suicides in Germany.

Assessing and treating alcohol relapse risk in liver transplantation candidates.

In Europe between 30 and 50% of all liver transplantations (LTX) are done within the context of chronic end-stage alcoholic liver disease (ALD). However, post-operatively 20-25% of these patients lapse or relapse into heavy alcohol use. Thus, assessment of alcohol relapse risk before enlisting and therapeutic follow-up during and after LTX is of utmost importance. However, as yet there are enormous differences between European countries and between transplant centers, with regard to the assessment methods and criteria and the implementation of therapeutic follow-up. Only the so-called '6-month abstinence' rule is widely used. However, there are not much scientific data validating its use in predicting relapse. Thus, there is a clear need of a more homogeneous approach, which was the focus of a symposium of the European Federation of Addiction Societies during the 14th conference of the European Society for Biomedical Research on Alcoholism, 2013 (ESBRA), entitled 'Liver transplantation: A European perspective'. In a follow-up on this symposium, the authors aim to sum up the evidence of psychiatric assessment criteria and psychiatric treatment interventions relevant in the context of patient selection and patient follow-up within ALD transplantation procedures. Based upon these findings, we propose elements of a procedure that can serve as a first step toward a model of good practice regarding addiction-specialist input within the pre- and post-transplantation period.

Dimensionality and stages of severity of DSM-5 criteria in an international sample of alcohol-consuming individuals.

INTRODUCTION: The DSM-5 alcohol use disorder (AUD) criteria proposal contains 11 criteria that include most of the DSM-IV abuse and dependence criteria plus craving. The aims of the current study in a large and international alcohol-consuming sample were to confirm the dimensionality of the DSM-5 AUD criteria and to differentiate grades of severity of DSM-5 AUD in subjects who pass the proposed DSM-5 diagnostic threshold of two criteria. METHOD: We used the World Health Organization (WHO)/International Society on Biomedical Research on Alcoholism (ISBRA) Study on State and Trait Markers of Alcohol Use and Dependence dataset. Subjects included in the analyses were aged ≥ 18 years and were recruited in five countries: Australia, Brazil, Canada, Finland and Japan. Assessment of AUD and additional characteristics was conducted using an adapted version of the Alcohol Use Disorder and Associated Disabilities Interview Schedule (AUDADIS). Dimensionality of the DSM-5 criteria was evaluated using factor analysis and item response theory (IRT) models. The IRT results led to the classification of AUD patients into three severity groups. External validators were used to differentiate statistically across subgroups. RESULTS: A total of 1424 currently drinking individuals were included in the analyses. Factor and IRT analyses confirmed the dimensional structure of DSM-5 AUD criteria. More than 99% of the subjects could be allocated to one of the suggested severity subgroups. The magnitude of the external validators differed significantly across the severity groups. CONCLUSIONS: The results confirm the dimensional structure of the proposed DSM-5 AUD criteria. The suggested stages of severity (mild, moderate and severe) may be useful to clinicians by grouping individuals not only in the mild but also in the moderate to severe spectrum of DSM-5 AUD.

Prevalence of suicide attempts in pathological gamblers in a nationwide Austrian treatment sample.

BACKGROUND: For pathological gambling (PG), a 12-month prevalence rate of up to 0.66% has been reported. Multiple financial, occupational and relationship problems and losses, humiliation of the person and the environment are possible side effects and may lead to hopelessness, suicidal ideation and suicidal behavior. Suicide attempt rates among pathological gamblers of between 4% and 40% and suicidal ideation of between 12% and 92% have been reported. AIM: This study aims at assessing the prevalence of suicide attempts in PG and at elucidating differences between the patients with and without suicide attempt history (SAH) in a large nationwide Austrian sample. METHODS: Between 2002 and 2011, the Austrian Society for the Research of Non-Substance Related Addiction collected 862 questionnaires of pathological gamblers undergoing outpatient and inpatient treatment for PG in Austria. RESULTS: (a) Of all pathological gamblers, 9.7% had an SAH. (b) The SAH group suffered significantly more from a comorbid disorder and was more often in previous inpatient treatments. (c) The SAH patients had a longer time of an abstinence period in their PG career. DISCUSSION: One in 10 pathological gamblers has an SAH, demonstrating the relevance of suicidality in this population. Significant differences for several parameters were found for PG with and without SAH. However, a regression analysis only explained 15% of the variance. This suggests that suicidality must be considered in pathological gamblers in general.

Association of functional DBH genetic variants with alcohol dependence risk and related depression and suicide attempt phenotypes: results from a large multicenter association study.

OBJECTIVE: Dopamine-beta-hydroxylase (DBH) metabolizes the conversion of dopamine to noradrenaline. DBH, located on chromosome 9q34.2 has variants with potential functional consequences which may be related to alterations of neurotransmitter function and several psychiatric phenotypes, including alcohol dependence (AD), depression (MD) and suicidal behavior (SA). The aim of this association study in a large multicenter sample of alcohol-dependent individuals and controls is to investigate the role of DBH SNPs and haplotypes in AD risk and associated phenotypes (AD with MD or SA). METHOD: 1606 inpatient subjects with DSM-IV AD from four addiction treatment centers and 1866 control subjects were included. Characteristics of AD, MD and SA were obtained using standardized structured interviews. After subjects were genotyped for 4 DBH polymorphisms, single SNP case-control and haplotype analyses were conducted. RESULTS: rs1611115 (near 5') C-allele and related haplotypes were significantly associated with alcohol dependence in females. This association with female alcohol dependence also accounts for the significant relationship between this variant and comorbid conditions and traits. CONCLUSIONS: This study presents evidence for a potentially functional DBH variant influencing the risk for alcohol dependence while other comorbid conditions are not independently influenced by this SNP. However, the study also supports the possible role of the dopamine system in the etiology of female alcohol dependence.

[Direct metabolites of ethanol as biological markers of alcohol use: basic aspects and applications]. / Direkte ethanolmetaboliten als biomarker für alkoholkonsum: grundlagen und anwendungen.

In addition to self reports and questionnaires, biomarkers are of relevance in the diagnosis of and therapy for alcohol use disorders. Traditional biomarkers such as gamma-glutamyl transpeptidase or mean corpuscular volume are indirect biomarkers and are subject to the influence of age, gender and non-alcohol related diseases, among others. Direct metabolites of ethanol such as ethyl glucuronide (EtG), ethyl sulphate (EtS) and phosphatidylethanol (PEth) are direct metabolites of ethanol, that are positive after intake of ethyl alcohol. They represent useful diagnostic tools for identifying alcohol use even more accurately than traditional biomarkers. Each of these drinking indicators remains positive in serum and urine for a characteristic time spectrum after the cessation of ethanol intake - EtG and EtS in urine up to 7 days, EtG in hair for months after ethanol has left the body. Applications include clinical routine use, emergency room settings, proof of abstinence in alcohol rehabilitation programmes, driving under influence offenders, workplace testing, assessment of alcohol intake in the context of liver transplantation and foetal alcohol syndrome. Due to their properties, they open up new perspectives for prevention, interdisciplinary cooperation, diagnosis of and therapy for alcohol-related problems.

Identification of 48 homologues of phosphatidylethanol in blood by LC-ESI-MS/MS.

Phosphatidylethanol (PEth) is an abnormal phospholipid carrying two fatty acid chains. It is only formed in the presence of ethanol via the action of phospholipase D (PLD). Its use as a biomarker for alcohol consumption is currently under investigation. Previous methods for the analysis of PEth included high-performance liquid chromatography (HPLC) coupled to an evaporative light scattering detector (ELSD), which is unspecific for the different homologues--improved methods are now based on time of flight mass spectrometry (TOF-MS) and tandem mass spectrometry (MS/MS). The intention of this work was to identify as many homologues of PEth as possible. A screening procedure using multiple-reaction monitoring (MRM) for the identified homologues has subsequently been established. For our investigations, autopsy blood samples collected from heavy drinkers were used. Phosphatidylpropanol 16:0/18:1 (internal standard) was added to the blood samples prior to liquid-liquid extraction using borate buffer (pH 9), 2-propanol and n-hexane. After evaporation, the samples were redissolved in the mobile phase and injected into the LC-MS/MS system. Compounds were separated on a Luna Phenyl Hexyl column (50 mm x 2 mm, 3 microm) by gradient elution, using 2 mM ammonium acetate and methanol/acetone (95/5; v/v). A total of 48 homologues of PEth could be identified by using precursor ion and enhanced product ion scans (EPI).

Selective detection of phosphatidylethanol homologues in blood as biomarkers for alcohol consumption by LC-ESI-MS/MS.

A new validated method for the quantitation of the abnormal phospholipid phosphatidylethanol (PEth)--a biomarker for ethanol uptake--has been developed by LC-ESI-MS/MS following miniaturised organic solvent extraction and reversed phase chromatography with phosphatidylbutanol (PBut) as internal standard. PEth homologues with two fatty acid substituents-PEth 18:1/18:1, PEth 16:0/16:0-were determined in post-mortem blood collected from heavy drinkers at autopsy and also in whole blood samples from a volunteer after a single 60 g-dose of ethanol. Furthermore, PEth 18:1/16:0 or its isobaric isomer PEth-16:0/18:1 was detected. In comparison to previous high-performance liquid chromatography (HPLC) methods with evaporative light scattering detection (ELSD), the LC-MS/MS-method is more sensitive--with a limit of detection below 20 ng/ml--and more selective for single PEth homologues, while ELSD has been used for detection of the sum of PEth homologues with approximately 10 times less sensitivity. LC-MS/MS enables monitoring of PEth homologues as biomarkers for harmful and prolonged alcohol consumption as with HPLC/ELSD earlier, where PEth is measurable in blood only after more than 50 g ethanol daily intake for more than 2 weeks. Because of its higher sensitivity, there is a potential to detect single heavy drinking by LC-MS/MS, when PEth is formed in very low concentrations. This opens a new field of application of PEth to uncover single or multiple heavy drinking at a lower frequency and with a larger window of detection in blood than before by HPLC/ELSD or by use of other direct markers, e.g. ethyl glucuronide or ethyl sulfate.

Tobacco smoking and depression--results from the WHO/ISBRA study.

AIMS: To elucidate the relationship between tobacco smoking and depression, and to estimate the impact of other substance dependencies. DESIGN: Cross-sectional. PARTICIPANTS: A total of 1,849 men and women were interviewed face-to-face using a validated structured questionnaire. According to their tobacco smoking behavior, participants were grouped into never smokers, ex-smokers and current smokers. MEASUREMENTS: Data were generated through the WHO/ISBRA study, an international multicenter study with a cross-sectional design. A standardized questionnaire was administered face-to-face by trained interviewers. Logistic regression analysis was used to predict depression. RESULTS: There was a significant difference across the 3 smoking groups in the number of subjects who had major depression (DSM-IV) during their lifetime. The highest rate of depressives was found in current smokers (23.7%), the lowest rate in never smokers (6.2%), while the rate of those who had quit smoking (14.6%) was between both. In a logistic regression analysis, alcohol dependence (both current and during lifetime) as well as cocaine dependence were significant predictors of depression. However, the association between smoking and depression still remained statistically significant. CONCLUSIONS: This study adds support to the evidence that smoking is linked to depression. It also elucidates the importance of taking into account alcohol and cocaine dependence since they have a significant impact on the relationship between smoking and depression.

Detection of recent ethanol intake with new markers: comparison of fatty acid ethyl esters in serum and of ethyl glucuronide and the ratio of 5-hydroxytryptophol to 5-hydroxyindole acetic acid in urine.

BACKGROUND: At present, recent ethanol consumption can be routinely detected with certainty only by direct measurement of ethanol concentration in blood or urine. Because ethanol is rapidly eliminated from the circulation, however, the time span for this detection is in the range of hours. Several new markers have been proposed to extend the detection interval, but their characteristics have not yet justified their use in routine clinical practice. We therefore investigated three new markers and compared their kinetics and sensitivities: (1) fatty acid ethyl esters (FAEEs) in serum, (2) ethyl glucuronide (EtG) in urine, and (3) the ratio of 5-hydroxytryptophol to 5-hydroxyindole acetic acid (5-HTOL/5-HIAA) in urine. METHODS: Seventeen healthy men participated in a drinking experiment. Blood and urine samples were collected twice daily on three consecutive days and once daily on days 4 and 5. Ethanol concentration was determined by gas chromatography, FAEE levels, by gas chromatography with mass spectrometry, EtG concentration, by liquid chromatography-tandem mass spectrometry, and 5-HTOL/5-HIAA ratio, by high-performance liquid chromatography. RESULTS: The peak serum ethanol concentrations of the subjects ranged from 5.4 to 44.7 mmol/liter (mean +/- SD, 30.1 +/- 9.1 mmol/liter). In the case of the serum ethanol determination, 100% sensitivity was reached only immediately after the end of the drinking experiment, and in the case of FAEE levels and 5-HTOL/5-HIAA ratio, it tested for 6.7 hr after the end of the ethanol intake. Thereafter, these latter parameters declined until 15.3 hr (FAEEs) and 29.4 hr (5-HTOL/5-HIAA), subsequently remaining in a stable range until 78.5 hr without further decrease. In contrast, EtG concentration showed 100% sensitivity until 39.3 hr and thereafter decreased, falling to below the limit of quantification of 0.1 mg/liter at 102.5 hr. CONCLUSION: After moderate drinking, EtG in the urine proved to be a superior marker of recent ethanol consumption in healthy subjects. This is because EtG is a direct ethanol metabolite, it occurs in the urine only when ethanol has been consumed, and its sensitivity remains at the level of 100% for 39.3 hr.

[How and to what extent is suicide postvention part of the routine of health care professionals in psychiatric hospitals after inpatient suicide?]. / Umgang mit dem Patientensuizid in therapeutischen Teams psychiatrischer Kliniken - Ergebnisse einer Umfrage -

OBJECTIVE: To elucidate how and to what extent suicide postvention is part of the routine of health care professionals in psychiatric hospitals after inpatient suicide was aim of the study. METHODS: In 11 South German psychiatric hospitals the head of the nursing team of the ward, the therapist and the medical assistant director were asked how suicide postvention after the last suicide was handled. RESULTS: Suicide postvention is part of the routine in these hospitals and discussion on the issue is rather open. The members of the team confronted with suicide feel mostly sufficiently supported. (2/3) of both therapists and heads of nursing teams considered the procedere to be adequate. CONCLUSION: Mainly for the nursing team there seems to be a need to further improve procedures for suicide postvention to gain more team satisfaction with regard to how the situation is managed.

[The aftermath of suicide of a psychiatric inpatient - experiences in psychiatric hospitals with relatives as suicide survivors]. / Nach dem Suizid eines Patienten - Erfahrungen mit Angehörigen von Suizidenten in der psychiatrischen Klinik.

OBJECTIVE: In a first part we describe the situation of suicide survivors after the suicide of a family member in USA and Germany by reviewing the literature. In a second part we try to elucidate typical patterns of reactions and coping of relatives. METHODS: On the basis of either own experience or from supervision cases, we try to elaborate reaction types of relatives of inpatients who committed suicide. RESULTS: Relatives as suicide survivors show reactions from shock, disbelief, grief, guilt, self-doubt, anger and relief to accusation and threat of lawsuit toward therapists. An attempt is made to subsummarize these reactions in three preliminary categories. CONCLUSIONS: Generally, relatives should be offered the opportunity of more than one common talk with the health care professionals. Postvention is preventive work, that aims at avoiding that the suicide survivors becomes a patient himself.

[Substance dependence and suicide in hospitalized patients. A description]. / Substanzabhängigkeit und Suizid im stationären Rahmen. Eine Deskription.

OBJECTIVE: The research group "Suicide and Psychiatric Hospital" has studied inpatient suicides in psychiatric hospitals in Baden-Württemberg and Bavaria (Germany) from 1970-1996. Whereas suicides in depression and schizophrenia are described very well, a description of addicted inpatients who committed suicide is still missing. PATIENTS AND METHODS: We studied the data of substance dependent patients of the collective of 726 inpatient suicides. RESULTS AND CONCLUSIONS: Among the generally rare suicides of addicted inpatiens--33 of 726--about 81% were alcohol dependent. The frequency of suicide in this group of patients decreased from 6.7% in the years 1970-1984 to 1.4% between 1990 and 1996. Whereas the age remained more or less stable in the middle of the fifth decade, the time from hospitalisation until suicide shortened from 192 days (mean) to 52 days. Suicide of alcohol dependent and poly-drug-abusing patients today almost exclusively takes place during treatment on an open station and among patients being in treatment on a voluntary basis. Suicide attempts in the anamnesis are extraordinarily rare in alcohol dependent suiciders.

Ethyl glucuronide: a marker of recent alcohol consumption with clinical and forensic implications.

A marker with a specific time spectrum of detection and both high sensitivity and specificity is required to diminish the clinically as well as forensically important gap on the time axis between short- and long-term markers of alcohol consumption like ethanol and CDT, GGT or MCV, respectively. Ethyl glucuronide (EtG) is a non-volatile, water-soluble, stable upon storage, direct metabolite of ethanol with a molecular weight of 222 g/mol that can be detected in body fluids for an extended time period after the complete elimination of alcohol from the body. We investigated 107 urine and 78 serum samples of a total of 107 inpatients in 4 groups: (1) 33 inpatients in acute alcohol withdrawal and long term treatment; (2/3) 29 and 15 addicted forensic psychiatric inpatients (#64 StGB, penal code); (4) 30 recently detoxified inpatients of a station for long term treatment by LC/MS-MS with the internal standard d5-EtG and additionally in the fourth group of patients also by gas chromatography/mass spectrometry (GC/MS). In 2 out of 33 inpatients of the first group, EtG could be determined 3 days after hospitalization; in an other subject, a relapse could be detected. In 2 out of 29 and in 1 out of 15 forensic inpatients of group 2 and 3, respectively--where neither clinical impression nor routine laboratory findings gave an indication for relapse--concentrations of EtG ranged between 0.1 and 18 mg/l in urine. For the serum samples of the 30 inpatients of group 4, we could demonstrate a total agreement for the results of the GC/MS and the LC/MS-MS method as to whether a sample was found to be positive or negative for EtG. We suggest that these results strengthen our earlier findings that ethyl glucuronide is a marker of alcohol consumption in general that can be detected for an extended time period after the complete elimination of alcohol from the body and a marker for relapse control with a specific time frame of detection intermediate between short- and long-term markers.

[Direct ethanol metabolite ethyl glucuronide. Its value as alcohol intake and recurrence marker, methods of detection and prospects]. / Der direkte Ethanolmetabolit Ethylglucuronid. Seine Bedeutung als Alkoholkonsum- und Rückfallmarker, Nachweismethoden und Perspektiven.

In clinical as well as in forensic practice biological state markers of high sensitivity and specificity capable of monitoring alcohol consumption of those in treatment for alcohol dependence or poly-drug abusers are required. The known markers cannot be considered satisfactory in respect of these parameters. Furthermore, they do not cover the entire time axis for alcohol consumption. These traditional markers are often influenced besides by alcohol, by age, gender and various of substances and non-alcohol-associated diseases. Ethyl glucuronide (EtG) is a non volatile, water soluble, stable upon storage, direct metabolite of ethanol with a molecular weight of 222 g/mol that was determined by our group in more than 1200 samples of body fluids, tissues and hair from over 200 patients, almost 200 drivers and postmortem with different GC/MS and ESI-LC/MS-MS methods using deuterium-labelled EtG as internal standard. With its specific time frame of detection intermediate between short-term and long-term markers and a particularly high sensitivity and specificity, ethyl glucuronide is a promising marker of alcohol consumption in general that can be detected for an extended time period after the complete elimination of alcohol from the body (up tp 80 h) and a marker for relapse control enabling the therapist to intervene at an early stage of relapsing behaviour. The complementary use of EtG together with other upcoming markers of alcohol consumption like phosphatidyl ethanol should lead to an improvement in treatment outcome, quality of life and cost reduction.

Ethyl glucuronide--a marker of alcohol consumption and a relapse marker with clinical and forensic implications.

Ethyl glucuronide (EtG) is a non-volatile, water-soluble, direct metabolite of ethanol that can be detected in body fluids and hair. We investigated urine and serum samples from three patient groups: (1) 33 in-patients in acute alcohol withdrawal; (2) 30 detoxified in-patients (treated for at least 4 weeks) from a 'motivation station'; and (3) 43 neuro-rehabilitation patients (non-alcoholics; most of them suffering from stroke, traumatic brain injury, Parkinson's disease etc.) using gas chromatography/mass spectrometry (GC/MS) with deuterium-labelled EtG as the internal standard and additionally in the second group of patients using liquid chromatography (LC/MS-MS). We found no correlation between the concentration of EtG in urine at hospitalization and the blood-ethanol concentration (r = 0.17), the time frame of detection (r = 0.5) or the total amount of clomethiazole required for the treatment of withdrawal symptoms (r = 0.28). In four out of 30 in-patients from the 'motivation station'--where neither clinical impression nor routine laboratory findings gave indications of relapse--concentrations of EtG in urine ranged between 4.2 and 196.6 mg/l. EtG concentrations in urine of between 2.89 and 23.49 mg/l were found in seven out of 43 neuro-rehabilitation patients using GC/MS. The GC/MS and the LC/MS-MS results showed a correlation of 0.98 with Pearson's correlation test and 1.0 with Spearman's correlation test. We suggest that EtG is a marker of alcohol consumption that can be detected for an extended time period after the complete elimination of alcohol from the body. When used as a relapse marker with a specific time frame of detection intermediate between short- and long-term markers, EtG fills a clinically as well as forensically important gap. Its specificity and sensitivity exceed those of all other known ethanol markers.