[Guideline-oriented treatment of alcohol-related disorders]. / Leitlinienorientierte Behandlung alkoholbezogener Störungen.

Alcohol use disorders (e.g. abuse and dependence) account for a plethora of consequences for affected individuals and for a substantial proportion of the overall burden of disease for the community. To date, existing treatment options are either poorly known by doctors or they are not fully applied and only approximately 15% of potential patients are treated with a mean latent period of 10 years between early symptoms and the first intervention. So-called S3 treatment guidelines were recently developed to close this gap. Representatives of more than 50 learned societies, families and patients were involved. A systematic literature search from 2005 to 2012 was performed and more than 120 recommendations were made. Financing came exclusively from those societies and the academic and treatment institutes involved.This article summarizes the recommendations pertinent for psychiatrists and include early detection and intervention, acute withdrawal and long-term psychotherapy and pharmacotherapy. Classical and new treatment goals are discussed. If the new guidelines were properly applied an increase in patients receiving treatment to 30-40% could be expected, which would improve the quality of lives of affected persons and their families and in Germany would save several thousand lives per year.

Genome-wide association study of alcohol dependence:significant findings in African- and European-Americans including novel risk loci.

We report a GWAS of alcohol dependence (AD) in European-American (EA) and African-American (AA) populations, with replication in independent samples of EAs, AAs and Germans. Our sample for discovery and replication was 16 087 subjects, the largest sample for AD GWAS to date. Numerous genome-wide significant (GWS) associations were identified, many novel. Most associations were population specific, but in several cases were GWS in EAs and AAs for different SNPs at the same locus,showing biological convergence across populations. We confirmed well-known risk loci mapped to alcohol-metabolizing enzyme genes, notably ADH1B (EAs: Arg48His, P=1.17 × 10(-31); AAs: Arg369Cys, P=6.33 × 10(-17)) and ADH1C in AAs (Thr151Thr, P=4.94 × 10(-10)), and identified novel risk loci mapping to the ADH gene cluster on chromosome 4 and extending centromerically beyond it to include GWS associations at LOC100507053 in AAs (P=2.63 × 10(-11)), PDLIM5 in EAs (P=2.01 × 10(-8)), and METAP in AAs (P=3.35 × 10(-8)). We also identified a novel GWS association (1.17 × 10(-10)) mapped to chromosome 2 at rs1437396, between MTIF2 and CCDC88A, across all of the EA and AA cohorts, with supportive gene expression evidence, and population-specific GWS for markers on chromosomes 5, 9 and 19. Several of the novel associations implicate direct involvement of, or interaction with, genes previously identified as schizophrenia risk loci. Confirmation of known AD risk loci supports the overall validity of the study; the novel loci are worthy of genetic and biological follow-up. The findings support a convergence of risk genes (but not necessarily risk alleles) between populations, and, to a lesser extent, between psychiatric traits.

Involvement of the atrial natriuretic peptide transcription factor GATA4 in alcohol dependence, relapse risk and treatment response to acamprosate.

In alcoholism, both relapse to alcohol drinking and treatment response are suggested to be genetically modulated. This study set out to determine whether the top 15 single nucleotide polymorphisms (SNPs) of a recent genome-wide association (GWA) and follow-up study of alcohol dependence are associated with relapse behavior and pharmacological treatment response in 374 alcohol-dependent subjects who underwent a randomized, double-blind, placebo-controlled trial with acamprosate, naltrexone or placebo. The single nucleotide polymorphism, rs13273672, an intronic SNP in the gene for GATA-binding protein 4 (GATA4), was associated with relapse within the 90-day medical treatment period (P<0.01). Subsequent pharmacogenetic analyses showed that this association was mainly based on patients treated with acamprosate (P<0.01). In line with the observation that natriuretic peptide promoters are modulated by GATA4, a significant gene dose effect on the variance of atrial natriuretic peptide (ANP) plasma concentration in the different GATA4 genotypes (P<0.01) was found. Hence, genetic variations in GATA4 might influence relapse and treatment response to acamprosate in alcohol-dependent patients via modulation of ANP plasma levels. These results could help to identify those alcohol-dependent patients who may be at an increased risk of relapse and who may better respond to treatment with acamprosate.

No association of alcohol dependence with HOMER 1 and 2 genetic variants.

Several lines of evidence indicate that alterations of the central cortico-accumbens glutamate pathway are involved in the development and maintenance of alcohol- and substance-use disorders. The HOMER protein family is encoded by 3 genes HOMER (1-3) which are components of the excitatory postsynaptic density complex and function to modulate synaptic activity by the regulation of glutamate signaling. HOMER 1 and 2 have been reported to contribute to chronic alcohol-induced long-term neurochemical changes in the endogenous reward system. Data from animal models suggest a potential role of the Homer protein family in the development of alcohol and substance use. The aim of this study is to assess potential associations between HOMER 1 and 2 genetic variants in a larger sample of alcohol-dependent individuals and unrelated controls. Five genetic variants of HOMER 1 and 3 of HOMER 2 were genotyped in a multi-site sample of 1,923 German healthy controls and 2,039 alcohol-dependent subjects. Neither single SNP nor haplotype analysis could detect significant associations with alcohol dependence (AD) and related phenotypes. While most of the HOMER 1 and 2 SNPs are in low-to-moderate linkage disequilibrium, three major haplotypes of HOMER 1 and 4 haplotypes of HOMER 2 are present in the majority of alcohol-dependent and control subjects. In conclusion, our results suggest that single SNPs, respectively, haplotypes of the HOMER 1 and 2 genes are unlikely to play a major role in the pathophysiology of AD.

Personality disorders in alcohol-dependent individuals: relationship with alcohol dependence severity.

The rate of axis II disorders in alcohol-dependent individuals is suggested to be high. The aim of this investigation is to assess the rate of DSM-IV axis II diagnoses in alcohol-dependent inpatients and their correlation with clinical characteristics of alcohol dependence (AD). 1,079 inpatients with DSM-IV AD from three inpatient addiction treatment centers ('qualified detoxification', open psychiatric university hospital wards) were included. Characteristics of AD were obtained using standardized structured interviews. Diagnoses of DSM-IV personality disorders (PDs) were generated with SCID-II-PQ and SCID-II interviews. Alcoholism severity was measured using the number of DSM-IV criteria endorsed and age at first drinking. Approximately 60% of the sample had at least one PD. However, rates of Axis II disorders differed significantly across centers. The most frequent PDs were obsessive-compulsive, borderline, narcissistic and paranoid PD. Diagnosis of any PD was related to a more severe clinical profile of AD. Regression analyses revealed that obsessive-compulsive PD was related to the number of DSM-IV criteria endorsed while antisocial PD was related to early age at first drinking. The majority of alcohol-dependent individuals had one or more comorbid axis II disorders. Univariate and multivariate analyses indicate that different PDs are related to age at first dinking and alcoholism severity.

[The impact of attachment styles and ADHD on alcohol dependence]. / Einfluss unsicherer Bindungsstile und ADHS auf Alkoholabhängigkeit.

BACKGROUND: Insecure attachment (IA) and attention-deficit/hyperactivity disorder (ADHD) are discussed as risk factors for increased alcohol intake and the development of alcoholism. METHODS: Among a sample of 517 consecutively admitted German inpatients with alcohol dependence we investigated the contribution of IA to alcoholism phenotypes, taking into consideration comorbid ADHD. RESULTS: IA was significantly associated with increased alcohol consumption, increased frequency of withdrawal symptoms, increased frequency of physical or psychological problems that are likely to have been worsened by alcohol, and reduced social activities because of alcohol use. ADHD has no significant effect on these parameters. CONCLUSIONS: IA developed as a result of social interactions during childhood long before alcohol dependence. The results point to an important effect of IA on the severity and acceleration of alcohol dependence. Therefore, it might be helpful to improve efforts in primary prevention and psychotherapy of alcohol dependence by considering the specific needs of subjects with an IA.

Different effects of a CD14 gene polymorphism on disease outcome in patients with alcoholic liver disease and chronic hepatitis C infection.

AIM: Clinical and experimental data suggest that gut-derived endotoxins are an important pathogenic factors for progression of chronic liver disease. Recently, a C-T (-159) polymorphism in the promoter region of the CD14 gene was detected and found to confer increased CD14 expression and to be associated with advanced alcoholic liver damage. Here, we investigated this polymorphism in patients with less advanced alcoholic liver disease (ALD) and chronic hepatitis C virus (HCV) infection. METHODS: CD14 genotyping was performed by PCR-RFLP analysis in (a) 121 HCV patients, (b) 62 patients with alcohol-associated cirrhosis (Alc-Ci), (c) 118 individuals with heavy alcohol abuse without evidence of advanced liver damage (Alc-w/o Ci), and (d) 247 healthy controls. Furthermore, serum levels of soluble CD14 (sCD14) and transaminases were determined. RESULTS: The TT genotype was significantly more frequent in Alc-Ci compared to Alc-w/o Ci or controls (40.3% vs 23.7% or 24.0%, respectively). In Alc-w/o Ci, serum levels of transaminases did not differ significantly between patients with different CD14 genotypes. In HCV patients, TT-homozygotes had significantly higher sCD14 levels and sCD14 serum levels were significantly higher in patients with advanced fibrosis or cirrhosis. However, no association was found between CD14 genotypes and histological staging or grading. CONCLUSION: Considering serum transaminases as surrogate markers for alcoholic liver damage, the CD14 polymorphism seems to exhibit different effects during the course of ALD. Differences in genotype distribution between cirrhotic HCV patients and alcoholics and the known functional impact of this polymorphism on CD14 expression levels further indicate differences in the pathophysiological role of CD14 and CD14-mediated lipopolysaccharides signal transduction with regard to the stage as well as the type of the underlying liver disease.

3H-spiroperidol binding to peripheral mononuclear cells in schizophrenic and healthy subjects.

3H-spiroperidol binding to peripheral blood mononuclear cells was measured in 28 patients, who fulfilled DSM-III-R-criteria for schizophrenia and 17 healthy subjects. There were no significant differences in characteristic binding parameters (Kd, Bmax) between schizophrenic and healthy subjects. Moreover, there was no relation of binding parameters to any of the subtypes of schizophrenia or to the course of illness according to DSM-III-R-criteria. However, some patients exhibited higher Bmax values without having a unique clinical symptomatology according to known diagnostic criteria. Neuroleptic treatment had no consistent effect on binding parameters intraindividually. Kd and Bmax values were not related to age or gender. In conclusion, despite our previously reported improved methodology, we were not able to corroborate the clinical importance of this "peripheral marker" as a tool for diagnosing schizophrenia or for predicting the response to neuroleptic treatment in our sample of schizophrenic patients.

3H-spiroperidol binding to human peripheral mononuclear cells: methodological aspects.

3H-spiroperidol binding to lymphocytes has been proposed as a vulnerability marker for schizophrenia. However, the biological significance and even existence of this "binding site" are still in controversy. Therefore, the present study reevaluated methodological details using a filtration binding assay. The results indicated that some well-known, but obviously uncontrolled pitfalls might contribute to this controversy [e.g., unspecific filter binding, which increased in the presence of (+)-butaclamol, or a variable amount of contaminating granulocytes). Moreover, due to an atypically shaped saturation curve, different mathematical methods to analyze the data were used and compared. The present data should help us to understand the biological relevance of this marker, as viewed in different laboratories.

Disturbed glucocorticoid receptor autoregulation and corticotropin response to dexamethasone in depressives pretreated with metyrapone.

We studied glucocorticoid receptor autoregulation and corticotropin response to dexamethasone in depressed patients and controls, attempting to control for the confounding effect of endogenous glucocorticoids. After depletion of endogenous cortisol, depressed patients showed an attenuated suppressibility of corticotropin by dexamethasone in the face of unchanged dexamethasone plasma levels. Beta-endorphin levels were strongly correlated with adrenocorticotropic hormone (ACTH) concentrations. Although metyrapone administration resulted in a marked rise of glucocorticoid receptor sites per cell in controls, this effect was not present in depressives. These data support the hypothesis of a decreased glucocorticoid receptor plasticity and a partial steroid resistance in depression.

Characterization of Glucocorticoid Binding Capacity in Human Mononuclear Lymphocytes: Increase by Metyrapone is Prevented by Dexamethasone Pretreatment.

Abstract Autoregulation of receptor systems by their own ligands is a well established biological phenomenon. While down-regulation of the glucocorticoid binding capacity by glucocorticoids has been shown in animals and humans, data on up-regulation processes in humans are lacking. To further explore glucocorticoid receptor plasticity in relation to endogenous ligands, glucocorticoid binding parameters were assessed in 15 healthy controls before and after oral administration of 1.5 g metyrapone with and without dexamethasone pretreatment. Administration of metyrapone resulted in blockade of the feedback of the hypothalamic-pituitary-adrenal system as shown by the rise in adrenocorticotropin levels, while pretreatment with 1 mg dexamethasone completely suppressed adrenocorticotropin concentrations. Glucocorticoid binding sites per lymphocyte exhibited an increase of 63% following metyrapone administration, which was prevented by dexamethasone pretreatment. Comparison of morning and afternoon glucocorticoid binding sites per cell in 11 healthy volunteers further revealed a diurnal rhythm of glucocorticoid receptor sites. These data suggest that human lymphocyte glucocorticoid receptors are under autoregulatory control.

3H-spiperone binding to peripheral mononuclear cells in psychiatric in-patients.

1. There is an ongoing controversy, if increased binding of 3H-spiperone to lymphocytes might discriminate between schizophrenia and other psychiatric diseases or even be a genetic vulnerability marker for schizophrenia, or predict the response to neuroleptic treatment. 2. Some critical methodological details which might contribute to this controversy are described. 3. 3H-spiperone binding was evaluated in 31 patients with schizophrenia, 7 patients with schizoaffective disorder, bipolar type, 6 patients with a manic episode and 6 patients with a depressive episode of bipolar major affective disorder (DSM-III-R criteria), and in 19 healthy subjects. 4. There were no significant differences in characteristic binding parameters (KD, Bmax) between all groups of psychiatric in-patients and in comparison to healthy subjects. Moreover, there was no relation of binding parameters to any of the subtypes of schizopherenia or to the course of illness according to DSM-III-R-criteria. 5. Neuroleptic treatment or clinical response to treatment had no consistent effect on binding parameters intra-individually. 6. In summary, 3H-spiperone binding to lymphocytes failed to differentiate between the diagnostic subgroups (DSM-III-R) and between treatment responders and non-responders in our sample of patients.

Alcohol withdrawal and dopamine receptor sensitivity after prolonged abstinence.

1. Forty-four male inpatients suffering from moderate to severe alcohol dependence (DSM-III-R and ICD-10) as well as 14 healthy controls entered this study. Individuals were classified according to the severity of their withdrawal symptoms during detoxification i.e. group 1) no withdrawal, group 2) autonomic hyperactivity, group 3) withdrawal delirium and group 4) controls. 2. During the 6th week of treatment, that is, when all patients were recovered, controlled abstinent, and several weeks away from the end of their withdrawal syndrome, dopamine receptor sensitivity was neuroendocrinologically assessed by stimulating human growth hormone (HGH) with apomorphine (APO). 3. In a repeated measures model ANOVA, the four groups differed significantly in their HGH release. However, when excluding the controls from the analysis and focusing on alcoholics only (group 1 - 3), the significant difference disappeared. Covariates such as age, weight, quantity of drinking and duration of dependence were not related to the dependent variable. 4. In conclusion, the first significant result (with controls) reflects a blunted HGH response in alcoholics. It confirms earlier reports. The second, non significant result with the alcohol dependents only, suggests that the severity of withdrawal is not reflected by the amount of HGH released. Therefore, in alcoholics, a reduced dopamine receptor function after six weeks of abstinence, as neuro-endocrinologically assessed with apomorphine, seems to be related to alcohol dependence rather than to the severity of alcohol withdrawal.

Growth hormone response to placebo, apomorphine and growth hormone releasing hormone in abstinent alcoholics and control subjects.

Abstinent alcoholics and control subjects were challenged with placebo (saline), growth hormone releasing hormone (GHRH) and apomorphine (APO). While both groups did not differ in their growth hormone response (HGH) to placebo and GHRH, the alcoholics revealed a significant lower HGH response to dopamine receptor stimulation with APO. These findings provide no evidence that in abstinent alcoholics HGH blunting after dopamine receptor stimulation could be related to an alteration at the pituitary level but they give neuroendocrinological support to the hypothesis of a lower dopamine receptor sensitivity in abstinent alcoholics.

Normal lymphocyte responsiveness to lectins but impaired sensitivity to in vitro glucocorticoids in major depression.

The mitogen-induced lymphocyte proliferative response and its sensitivity to in vitro (10(-10)-10(-6) M) dexamethasone (DEX) administration were investigated in 12 severely depressed patients and 13 healthy controls. Patients with major depressive disorder exhibited no impairment of lectin-induced blastogenesis, but a significantly weaker suppressive effect of in vitro DEX on 1.0 microgram/ml phytohemagglutinin A-induced proliferation. The inhibitory potency of in vitro DEX was inversely correlated with in vivo adrenal cortical hormone levels at 4.00 p.m. These effects were not observed with pokeweed mitogen- and concanavalin A-stimulated cells. There were no correlations with age, weight, sex or severity of depression. These results do not support the hypothesis of a primarily impaired cell-mediated immunity, but might be indicative of reduced glucocorticoid receptor sensitivity in major depressive disorder.

Lymphocyte glucocorticoid receptor binding during depression and after clinical recovery.

Lymphocyte glucocorticoid receptor binding parameters were studied in 15 severely depressed patients during depression and after clinical recovery, and in 15 healthy controls. There was no difference in glucocorticoid receptor number or affinity between depressed patients and recovered or control subjects. Afternoon ACTH and cortisol concentrations did not differ significantly between the three groups. No relationship could be established between glucocorticoid receptor binding and antidepressant medication. These data support the view of an impaired ligand-induced plasticity of glucocorticoid receptor regulation rather than the hypothesis of decreased glucocorticoid receptor numbers during depression.

Cell-mediated immunity and its glucocorticoid-sensitivity after clinical recovery from severe major depressive disorder.

This follow-up study investigated lymphocyte blastogenesis induced by concanavalin A, phytohemagglutinin A, and pokeweed mitogen and their sensitivity to in vitro dexamethasone administration in 12 patients clinically recovered from severe major depression. Although cortisol-levels at 4.00 p.m. decreased significantly after clinical remission, mitogen-driven lymphocyte proliferative responses were unchanged when assessed intra-individually. No impairment of in vitro glucocorticoid-sensitivity of lectin-induced lymphocyte blastogenesis could be observed in clinically recovered patients. The inhibitory potency of in vitro dexamethasone was found to be inversely correlated with in vivo adrenal cortical hormone levels. There were no correlations with age, weight, sex, antidepressant medication, severity or duration of depression. No differences from age- and sex-matched healthy individuals were found. These results indicate that reduced glucocorticoid receptor sensitivity occurs only during the acute depressive illness.

In vivo and in vitro effects of glucocorticoids on lectin-induced blastogenesis in atopic dermatitis.

The effects of glucocorticoids administered in vivo and in vitro on lectin-induced proliferation of lymphocytes sampled from venous blood were investigated in patients with atopic dermatitis (AD) and in normal controls. Stimulation by concanavalin A (Con A), phytohaemagglutinin A (PHA) and pokeweed mitogen (PWM) in patients and controls did not differ significantly under baseline conditions. After in vivo administration of methylprednisolone the decline of Con A-induced blastogenesis of leucocytes was similar in both groups, whereas PHA stimulation caused a significant reduction in the controls only. In vitro addition of different dexamethasone concentrations had a pronounced suppressive effect on Con A- and PHA-induced blastogenesis in both groups, whereas PWM stimulation was unaffected. Pretreatment in vivo with methylprednisolone further decreased the suppression of the Con A and PHA lymphocyte proliferation rate by dexamethasone added in vitro in controls but not in patients. With regard to B-cell proliferation generated by PWM, no consistent glucocorticoid effect could be observed. The impaired effect on lymphocyte blastogenesis of glucocorticoids administered in vivo, in contrast to a normal in vitro reaction to dexamethasone, together with recent findings of an altered glucocorticoid receptor pharmacology in AD, points to a decreased biological in vivo efficiency of methylprednisolone in atopic dermatitis.

Glucocorticoid receptors on mononuclear leukocytes in Alzheimer's disease.

Several lines of evidence suggest disturbances of the hypothalamic-pituitary-adrenal (HPA) system in Alzheimer's disease (AD). In an exploration of the potential role of the glucocorticoid receptor (GR) in AD, GR density and affinity were assessed on mononuclear leukocytes of 12 AD patients and 12 healthy controls. GR binding characteristics did not differ between patients and controls or between patients subdivided according to diagnosis or associated clinical features. These data suggest that the abnormalities of the HPA system in AD are not related to a GR deficiency.

Peripheral-type benzodiazepine receptors in diagnostic subtypes of schizophrenic patients.

The peripheral-type benzodiazepine receptor (pBZD-R; also called the omega-3 receptor or the mitochondrial benzodiazepine receptor) seems to play a critical role in the production of neurosteroids, which are able to alter the electrical properties of neuronal membranes and thus the firing patterns of neurons. Putative endogenous ligands are the diazepam-binding inhibitor and its processing products, as well as porphyrins, some of them, in the case of porphyria, are well known to give rise to certain aspects of neuropsychiatric disorders, such as schizophrenic-like symptoms. Previous findings of altered benzodiazepine binding sites in post-mortem brain samples and platelets from small samples of schizophrenic patients have been inconclusive. Therefore we investigated characteristic binding parameters (Bmax, Kd) of the granulocytic pBZD-R by using the selective ligand PK11.195 in 53 subjects, fulfilling ICD-10 and DSM-IV criteria of schizophrenia. The binding parameters in our total group of 53 schizophrenic patients did not differ from those in healthy subjects. However, Bmax values were significantly reduced in schizophrenic patients with predominantly negative symptoms (residual type) compared to schizophrenic patients with predominantly positive symptoms, i.e. paranoid (-50%) and catatonic subtype (-38%). Moreover, only residual type schizophrenics exhibited a significantly reduced binding capacity compared to healthy subjects (-38%). More studies are warranted to clarify the functional significance of this binding site in the pathogenesis of negative symptoms.