Sexual cues alter working memory performance and brain processing in men with compulsive sexual behavior.

Pornography has been repeatedly at the centre of public attention and has been controversially discussed for a long time. However, little is known about the connection between pornographic stimuli and individual (neuronal) processing of attention and memory. Here, the impact and neural underpinnings of pornographic pictures on working memory processes in a sample of subjects with compulsive sexual behaviour was investigated. Therefore, whilst using functional magnetic resonance imaging (fMRI), a letter n-back task with neutral or pornographic pictures in the background was employed in 38 patients and 31 healthy controls. On the behavioural level, patients were slowed down by pornographic material depending on their pornography consumption in the last week, which was reflected by a higher activation in the lingual gyrus. In addition, the lingual gyrus showed a higher functional connectivity to the insula during processing of pornographic stimuli in the patient group. In contrast, healthy subjects showed faster responses when confronted with pornographic pictures only with high cognitive load. Also, patients showed a better memory for pornographic pictures in a surprise recognition task compared to controls, speaking for a higher relevance of pornographic material in the patient group. These findings are in line with the incentive salience theory of addiction, especially the higher functional connectivity to the salience network with the insula as a key hub and the higher lingual activity during processing of pornographic pictures depending on recent pornography consumption.

Pharmacotherapeutic management of acute alcohol withdrawal syndrome in critically Ill patients.

INTRODUCTION: Alcohol withdrawal syndrome is a common and life-threatening condition in patients suffering from alcohol use disorder. Treatment of this syndrome is challenging, especially in patients that are critically ill, either because of withdrawal symptoms or underlying conditions. For the treatment, several pharmacological agents exist, such as benzodiazepines, barbiturates, or dexmedetomidine. Nonetheless, as alcohol withdrawal syndromes can occur in every clinical setting, it is necessary to provide a guideline for clinicians confronted with this syndrome in varying clinical contexts. AREAS COVERED: The authors provide a systematic review of the literature found in PubMed and Embase following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. EXPERT OPINION: For the treatment of alcohol withdrawal syndrome, medications targeting the GABA system are preferred. Benzodiazepines are regarded as the gold standard. However, as many adjunct therapeutic options exist, it is essential to find symptom-triggered approaches and treatment protocols for the variety of clinical contexts. Apart from that, it is necessary to compare protocols toward clinical variables rather than investigating medications that are in use for the treatment of alcohol withdrawal syndrome.

Leptin Expression and Gene Methylation Patterns in Alcohol-Dependent Patients with Ethyltoxic Cirrhosis-Normalization After Liver Transplantation and Implications for Future Research.

AIMS: Liver transplantation is the only curative treatment available for patients with end-stage alcoholic liver disease. As different studies showed a significant association between leptin plasma levels, gene methylation patterns and the extent of craving in alcohol-dependent patients, we investigated the effect of liver transplantation on leptin expression and promoter methylation. SHORT SUMMARY: The present study shows that in alcohol-dependent patients with liver cirrhosis leptin is significantly higher before liver transplantation and decreases significantly after transplantation. Alcohol-dependent patients on the waiting list had significantly higher leptin promoter methylation values than patients who underwent liver transplantation for other reasons than alcoholic liver disease. METHODS: Only plasma of 118 and peripheral blood mononuclear cells of 121 patients were used: healthy controls (C, n = 24/22), alcohol-dependent patients without ethyltoxic liver cirrhosis (AD, n = 24/22), patients after liver transplantation for other reasons than ethyltoxic liver cirrhosis (C-Tx, n = 18/21), alcohol-dependent patients suffering from ethyltoxic liver cirrhosis on the transplantation waiting list (Pre-Tx, n = 30/28) and patients with prior ethyltoxic liver cirrhosis after liver transplantation (Post-Tx, n = 22/28). RESULTS: Leptin protein was significantly elevated in the pre-transplantation cohort when compared to post-transplantation and alcohol-dependent cohorts. Furthermore, leptin promoter methylation was higher in ethyltoxic patients before transplantation compared to non-ethyltoxic patients after transplantation, but not when compared to ethyltoxic patients after transplantation. C-Tx had lower methylation values than all other groups except for Post-Tx. CONCLUSIONS: Our study outlines the role of leptin protein levels as a marker for AD-related liver damage, contrasting it from AD without severe liver damage. With regard to the results of the methylation analysis, inflammation of the liver appears to cause mechanisms of leptin regulation to deviate from transcriptional regulation. Our data also suggest that leptin regulation is altered in ethyltoxic liver disease when compared to liver cirrhosis caused by other pathologies.

The epigenetic code in depression: implications for treatment.

Major depressive disorder (MDD) is a common and disabling disorder that carries both a substantial personal burden as well as a social one. A better understanding of the epigenetic mechanisms in depression might provide a new framework for individually tailored pharmacologic treatment options. In this review we highlight current knowledge about the role of epigenetic mechanisms in the pathogenesis of depression and treatment implications.

[Binge drinking in adolescents and young adults]. / Rauschtrinken bei Jugendlichen und jungen Erwachsenen.

Various studies in industrialised European and non-European countries have expressed concern about the link between alcoholic drinks (e. g. alcoholic sodas, so called "alcopops") and binge drinking in adolescents and young adults. Binge drinking has been shown to be associated with considerable social harm and disease burden. Adolescent alcohol abuse including binge drinking is common, but the extent of the problem and the specific risk factors leading to binge drinking behaviour remains unclear. Although the long-term health of adolescent binge drinking has not been studied in detail, first studies report an elevated risk for physical injury, aggression, violent or driving offences while intoxicated and high-risk sexual behaviour. To date, a variety of socio-demographical characteristics associated with binge drinking have been studied. However, knowledge in this area is limited, as most research has been conducted among specific groups (i. e. North American college students, adolescents in Australia etc.). More and intensive research in Germany and other European countries is urgently needed, as results from other cultural backgrounds are not necessarily transferable.

The modulating effect of the androgen receptor on craving in alcohol withdrawal of men is partially mediated by leptin.

We reported recently that a functional relevant CAG trinucleotide repeat of the androgen receptor influences craving of men in alcohol withdrawal. It is known to modulate serum concentrations of leptin, which affects hypothalamic appetite regulation. Its plasma levels are elevated during chronic alcohol consumption, normalize within periods of abstinence and are associated with craving. The aim of this study was to further elucidate the role of leptin in mediating the effects of the mentioned polymorphism on craving in men undergoing alcohol withdrawal. We included 110 male in-patients who were admitted for detoxification treatment. Each one had an established diagnosis of alcohol dependence according to the DSM-IV. Our results show on the one hand negative associations between the number of CAG repeats and (i) leptin serum levels (P<0.01) and (ii) craving (P<0.05), and on the other hand, a positive association between leptin and craving of man in alcohol withdrawal (P<0.001). The path analysis revealed direct and mediated effects of the number of CAG repeats on alcohol craving, direct effects (r=-0.144) accounting for 60% and indirect, leptin-mediated effects (r=-0.096) accounting for 40% of the total effect. Dysregulation of sexual hormones influences human metabolism and seems to affect leptin homeostasis. This report suggests that the investigated polymorphism mediates its effect on craving of men in alcohol withdrawal mostly through the regulation of leptin. Nevertheless future studies are needed to further explore the functionality of the androgen receptor gene in terms of craving.

Homocysteine, alcoholism and its molecular networks.

The emerging research on biomarkers in alcohol dependence has lead to a deeper understanding of the neurobiological mechanisms in alcoholism. The molecular networks and the pathophysiological circuits are complex and not completely unrevealed up to now. One of the most interesting biomarkers described to play an important role in alcohol dependence is the amino-acid homocysteine, which has particularly been linked with brain atrophy and withdrawal seizures. However, the molecular networks of homocysteine are complex and include an important impact on epigenetic regulation via homocysteine's action as a methyl-group donator in human metabolism. So, alterations in human homocysteine levels can influence DNA-methylation of specific gene areas which may change expression and synthesis of proteins possibly important for the genesis and maintenance of alcohol dependence.

Herp mRNA expression in patients classified according to Lesch's typology.

Chronic alcoholism is associated with hyperhomocysteinemia. Herp (homocysteine-induced endoplasmic reticulum [ER] protein) levels are elevated as a response to ER stress prior to mitochondrial dysfunction and cell death. The Lesch classification system has been applied in many studies and has been found useful. This study was undertaken to assess Herp mRNA expression in actively drinking patients with alcoholism who were classified according to Lesch's typology. Herp mRNA expression levels were measured by quantitative PCR in the blood of 76 male alcoholic patients. Patients were classified according to Lesch's typology (type I-IV). With respect to Lesch's typology, a significant difference in Herp mRNA expression regarding the four subtypes could be shown (F[3,72]=2.83, P=.044). In a logistic regression model (dependent variable Herp dichotomized by a median-split; adjusted for age and homocysteine levels) the subtype II differed statistically significant from the others (odds ratio, 5.75; 95% confidence interval, 2.07-15.98; P=.001). Type II alcoholic patients had a statistically significant higher expression of Herp mRNA due to upregulation of the expression of this neuroprotective cell non-chaperone by toxic effects of ethanol. These findings might explain why type II patients do not express severe withdrawal symptomatology (i.e., withdrawal seizures). These findings may be useful in the understanding and treatment considerations of different subtypes of alcohol dependence.

[Benzodiazepine dependence: causalities and treatment options]. / Benzodiazepin-Abhängigkeit: Ursachen und Behandlungsmöglichkeiten.

Benzodiazepines are very often prescribed because of their anxiolytic, sedative and hypnotic properties. However, long term treatment is associated with development of benzodiazepine dependence. Besides development of physical dependence, which is linked to a typical benzodiazepine withdrawal syndrome when drug intake is discontinued, also behavioural addiction to benzodiazepines has been described. Benzodiazepines are known to enhance GABAergic neurotransmission. Counter regulation of enhanced GABAergic neurotransmission by enhancement of glutamatergic neurotransmission is thought to be one reason underlying the typical symptoms of benzodiazepine withdrawal. Also alterations in the expression of neuropeptides like Corticotropin Releasing Hormone and Neuropeptide Y are thought to be involved in the development of benzodiazepine dependence. However, until today the knowledge of neural mechanisms underlying the development of benzodiazepine dependence remains incomplete. Because even long term treatment with small doses of benzodiazepines is associated with adverse reactions like cognitive dysfunctions withdrawal from benzodiazepines should be aimed. Anticonvulsants and antidepressants seem to reduce the intensity of benzodiazepine withdrawal and to enhance long term prognosis of dependence.

Treatment with clomethiazole is associated with lower rates of premature discharge during alcohol withdrawal.

INTRODUCTION: Numerous investigations have shown that premature discharge against medical advice from alcohol detoxification treatment is associated with poor outcome. The aim of the present study was to assess the risk of different possible influencing factors. PATIENTS AND METHOD: 168 in-patients admitted for detoxification treatment were included in the study. All patients were detoxified using clome-thiazole and/or carbamazepine in individual, symptom-triggered dosages. Possible influencing factors were recorded using a standardised interview. RESULTS: Cox regression revealed a lower risk of premature discharge being significantly asso-ciated with few preceding withdrawals, intoxication at admission and treatment with clomethiazole. Kaplan-Meier survival statistics showed a significantly lower risk only for being treated with clomethiazole (premature discharge until day 7: chi2=25.07; p<0.001; premature discharge until day 14: chi2=5.19; p=0.023). Other included demographic factors like daily intake of ethanol before admission, duration of alcohol dependence, age or smoking status were not associated with the risk of premature discharge. DISCUSSION: The present findings show that pharmacotherapy with clomethiazole may positively influence the risk of premature discharge. This might be a consequence of the psychoactive properties of the drug which leads to positive reinforcement.

[Pharmacological treatment options for prevention of alcohol relapse]. / Pharmakologische Therapieoptionen zur Prävention des Alkoholrückfalls.

Many studies address the neurobiological mechanisms of alcohol craving. The study results obtained so far show that there may be at least three subtypes of craving, which may be linked to changes in different neurotransmitter systems. Actually in Germany acamprosate and disulfiram are approved for clinical use for the prevention of alcohol relapse. Also off-label therapy with naltrexone is possible. However studies show that these substances are not effective in all patients. In the light of hypothetical changes in different neurotransmitter systems, subtype specific therapy may be necessary for successful prevention of alcohol relapse. Therefore new therapy options are needed in order to treat alcohol dependent persons. Substances that seem to have efficacy in preclinical or preliminary clinical studies are baclofen, topiramate, odansetron, rimonabant and memantine.

Apolipoprotein E polymorphism, homocysteine serum levels and hippocampal volume in patients with alcoholism: an investigation of a gene-environment interaction.

There is growing evidence that disadvantageous influences of the apolipoprotein E4 allele in the central nervous system are modified by environmental and dietary conditions. The present study investigated the gene-environment interaction of apolipoprotein E4 with homocysteine serum levels in patients with alcohol dependence with regard to alcohol-related hippocampal volume loss using volumetric high-resolution magnetic resonance imaging. We included 52 patients with alcohol-dependence. ApoE genotypes, homocysteine serum levels and hippocampal volumes were determined. We found a significant impact of homocysteine (F=13.2; df=1; P<0.001; 1-beta=0.95), not for ApoE4 genotype (F=0.482; df=1; P=0.49; 1-beta=0.05) on hippocampal volume. There was a significant interaction between both factors (ApoE4 x Hcy; F=8.8; df=1; P=0.005; 1-beta=0.80). The ApoE4 allele constitutes a risk factor for hippocampal volume loss in patients with alcohol dependence under the conditions of hyperhomocysteinemia. We suggest that the disadvantageous effects of apolipoprotein E4 on alcohol-related brain volume loss are based on certain gene-environment interactions.

[New options in the treatment of depression]. / Neue Wege in der Depressionsbehandlung.

Despite the advances in the psychopharmacology, the treatment of depressive disorder is still not satisfactory. All current pharmacological substances are affecting the monoamines in the central nervous system. The present review discusses advances in the field of monoaminergic antidepressants as well as new treatment alternatives. The new monoaminergic substances include metabolites of known antidepressants, direct serotonin-agonists, and triple-reuptake inhibitors, blocking the transport of serotonin, norepinephrine, and dopamine. Non-monoaminergic strategies include substances affecting melatonin or neuropeptides. Glutamate modulating agents such as ketamine or riluzole are another promising approach in the treatment of depression. Some advances have also been achieved in the field of HPA-axis modulation.