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Alcohol use disorder (AUD) is a severe illness, for which we lack sufficient mechanistic understanding. Preliminary evidence associates AUD with the oxytocin (OXT) system. Here we investigated alterations in endogenous OXT blood concentrations in patients with AUD and their association with alcohol drinking and prospective course. In sex-separated analyses, OXT serum concentrations of 200 in-patients with AUD (56.5% male; baseline, 24-72 h of abstinence) were compared with those of 240 age-matched healthy controls (55.4% male), investigated longitudinally (follow-up, 5 days later), and tested for associations with alcohol drinking behavior and prospective 24-month alcohol-related hospital readmissions. At baseline, the patients showed increased OXT concentrations relative to controls (men, 156%, P0.001; women, 124%, P = 0.002). The elevations normalized at follow-up. In male patients, baseline OXT concentrations correlated positively with alcohol concentration at admission, the amount of alcohol consumption per drinking year, and the number of previous withdrawal treatments (Rho0.195, P0.044). In beverage type-specific analysis, baseline OXT concentrations correlated with liquor consumption positively in male and negatively in female patients (|Rho|0.277, P0.017). Higher baseline OXT concentrations predicted more readmissions and fewer days to the first readmission (|Rho|0.185, P0.050) in male patients. This study provides novel and sex-separated insights into the role of the OXT system in AUD. We identified a mechanism that might underlie the sex-separated choice of beverage type and established that increased OXT concentrations during early abstinence predict a worse outcome in male patients with AUD.

Background/Aims: Opioid dependence is a severe disease which is associated with a high risk of relapse, even in cases of successful withdrawal therapy. Studies have shown alterations of the hypothalamic-pituitary-gonadal axis in opioid-dependent patients, such as decreased testosterone serum levels in affected males. Sex hormones and the steroid 5-alpha-reductase 2 (SRD5A2) V89L polymorphism are associated with craving during alcohol withdrawal, but little is known about their impact on symptomatology of opioid dependence. Methods: In this study, we analyzed 2 independent male cohorts of opioid-dependent patients for possible alterations in testosterone serum levels compared to non-opioid-dependent controls. In one of the cohorts, we additionally investigated associations of testosterone serum levels and 3 SRD5A2 polymorphisms with symptoms of opioid dependence, measured by the Heroin Craving Questionnaire (HCQ). Results: In the patient groups, we found significantly decreased testosterone serum levels compared to the control groups. Furthermore, we found significant associations of both the testosterone serum levels and the SRD5A2 V89L polymorphism with opioid craving assessed by the HCQ. Conclusion: Our data show a possible role of testosterone metabolism in opioid dependence, which may be relevant for the establishment of future treatment strategies.

Mental disorders are highly comorbid and occur together with physical diseases, which are often considered to arise from separate pathogenic pathways. We observed in alcohol-dependent patients increased serum activity of neutral sphingomyelinase. A genetic association analysis in 456,693 volunteers found associations of haplotypes of SMPD3 coding for NSM-2 (NSM) with alcohol consumption, but also with affective state, and bone mineralisation. Functional analysis in mice showed that NSM controls alcohol consumption, affective behaviour, and their interaction by regulating hippocampal volume, cortical connectivity, and monoaminergic responses. Furthermore, NSM controlled bone–brain communication by enhancing osteocalcin signalling, which can independently supress alcohol consumption and reduce depressive behaviour. Altogether, we identified a single gene source for multiple pathways originating in the brain and bone, which interlink disorders of a mental–physical co-morbidity trias of alcohol abuse—depression/anxiety—bone disorder. Targeting NSM and osteocalcin signalling may, thus, provide a new systems approach in the treatment of a mental–physical co-morbidity trias. Deutsche Forschungsgemeinschaft (German Research Foundation) https://doi.org/10.13039/501100001659

OBJECTIVE Alcohol use disorders inflict a great individual and societal burden. Although sex hormone effects have been implicated in alcohol dependence, research has mostly neglected estrogen activities and female alcohol-dependent patients. Here, we investigated associations of estrogen receptor 1 (ESR1) genetics and serum estradiol activities with aspects of alcohol dependence. METHOD Serum estradiol activities of early-abstinent alcohol-dependent in-patients (n[♂] = 113, n[♀] = 87) were followed for at median 5 days and compared with healthy controls (n[♂] = 133, n[♀] = 107). All participants were genotyped for five ESR1 single nucleotide polymorphisms (rs6902771, rs11155819, rs6557171, rs2982683, rs2982712). RESULTS Bioavailable estradiol levels decreased during withdrawal treatment (P[♂]

Human studies have reported inconsistent associations between the length ratio of the second finger to the fourth finger (2D:4D), which is a proxy for prenatal androgen load, and substance or computer use in adolescents and adults. This meta-analysis quantifies the magnitude of this relationship and investigates the roles of sex, definition of caseness, different forms of addiction, the hand measured (right hand versus left hand), and other cohort characteristics. Univariate random-effects meta-analyses were performed, and moderators were tested with Bonferroni-corrected meta-regression analyses. The study included 18 independent samples with a total of 175,955 participants (96,316 males and 79,639 females). There was a significant difference in 2D:4D between the substance and computer-using subjects and the controls for the combined sample (Hedge’s g = − 0.178 [− 0.291; − 0.064]) and for males (Hedge’s g = − 0.260 [− 0.399; − 0.122]), but not for females. These effects were amplified when only analyzing studies that compared dependent versus non-dependent subjects (combined sample: g = − 0.325 [− 0.492; − 0.157]; males: g = − 0.427 [− 0.564; − 0.291]), but did not reach significance in the subgroup of studies examining other parameters of substance and computer use. When analyzing different forms of substance and computer use separately, alcohol intake and computer use revealed a significant difference in the standardized mean. Again, the effects were amplified when analyzing the subgroup of males and the subgroup of studies comparing dependent versus non-dependent subjects, with effect sizes showing Hedge’s g values as many as − 0.552 [− 0.785; − 0.319] (alcohol-dependent males). Thus, this meta-analysis confirms that lower 2D:4D is associated with substance and computer dependency. Further studies are encouraged to explore the link between intrauterine hormone environment and addiction risk. Electronic supplementary material The online version of this article (10.1007/s00702-019-02002-2) contains supplementary material, which is available to authorized users.

Objective Addictive alcohol drinking, craving, and overeating share common etiopathological mechanisms. We investigated whether body mass index (BMI) and craving predict outcome of alcohol-dependent in-patients. Method The prospective study included 101 male and 72 female early-abstinent alcohol-dependent in-patients. Craving was quantified by Obsessive-Compulsive Drinking Scale (OCDS) scores. We documented alcohol-related readmissions over 24 months. Results In males, a higher BMI was associated with alcohol-related hospital readmission (median 26.1 vs. 23.1 kg/m2, P = .007) and correlated with more (ρ = 0.286, P = .004) and earlier readmissions (ρ = −0.256, P = .010). These associations were stronger in the subgroup of active smokers (n = 79; median 25.9 vs. 22.3 kg/m2, P = .005; ρ = 0.350, P = .002; ρ = −0.340, P = .002). BMI did not significantly predict outcome in females. Males with at least one readmission reported higher OCDS scores than those without (OCDS-total, OCDS-obsessive, OCDS-compulsive, P 0.244, P Conclusion BMI and craving are easily accessible outcome predictors of alcohol-related readmission following in-patient withdrawal treatment. They might be used to individualize relapse prevention in the future.

Suicide is a devastating public health issue that imposes severe psychological, social, and economic burdens not only for the individuals but also for their relatives, friends, clinicians, and the general public. Among the different suicidal behaviors, suicide completion is the worst and the most relevant outcome. The knowledge of biological etiopathological mechanisms involved in suicide completion is limited. Hitherto, no objective markers, either alone or in combination, can reliably predict who will complete a suicide. However, such parameters are strongly needed to establish and optimize prediction and prevention. We introduce here a novel ideation-to-completion framework in suicide research and discuss the problems of studies aiming at identifying and validating clinically useful markers. The male gender is a specific risk factor for suicide, which suggests that androgen effects are implicated in the transition from suicidal ideation to suicide completion. We present multiple lines of direct and indirect evidence showing that both an increased prenatal androgen load (with subsequent permanent neuroadaptations) and increased adult androgen activity are involved in suicide completion. We also review data arguing that modifiable maternal behavioral traits during pregnancy contribute to the offspring's prenatal androgen load and increase the risk for suicide completion later in life. We conclude that in utero androgen exposure and adult androgen levels facilitate suicide completion in an synergistic manner. The androgen model of suicide completion provides the basis for the development of novel predictive and preventive strategies in the future.

Activation of mesolimbic mu-opioid receptor by its endogenous ligand, β-endorphin, mediates part of the rewarding effects of alcohol, yet there is controversial evidence surrounding the relationship between the functional mu-opioid receptor gene (OPRM1) A118G single nucleotide polymorphism and alcohol dependence risk. Some preclinical evidence suggests that sex and sex hormone-dependent prenatal brain organization may interact with the opioid system to influence alcohol drinking behavior. We genotyped 200 alcohol-dependent patients and 240 healthy individuals for the A118G variant and measured serum β-endorphin level at recruitment and during acute withdrawal. We then evaluated the association between these factors and alcohol dependence risk and outcome in the context of both sex and second-to-fourth digit length ratio (2D:4D) – a biomarker of prenatal sex hormone load. For the first time, the AA genotype was found to be associated with elevated alcohol-related hospital readmission risk, more readmissions, and fewer days until first readmission in male but not female patients. Upon accounting for 2D:4D, the G-allele predicted alcohol dependence and more readmissions (1 vs ≥2) in males, suggesting prenatal sex hormones interact with OPRM1 to influence addiction pathology. Withdrawal β-endorphin level also correlated negatively with withdrawal severity in females but not in males, indicating β-endorphin might protect against withdrawal-induced stress in a sex-specific manner. Organizational effects of sex hormones may prime individuals for alcohol dependence by inducing permanent changes to the endogenous opioid system.

Unfavourable intrauterine environmental factors increase the risk of delivery complications as well as postpartum developmental and behavioural problems in children and adolescents with ongoing effects into older age. Biomarker studies show that maternal stress and the use of alcohol and tobacco during pregnancy are associated with a higher intrauterine testosterone exposure of the child. The antenatal testosterone load, in turn, is a risk factor for lasting adverse health effects which extend into adulthood. A 15-week, mindfulness-oriented, app-based programme for the reduction of stress as well as for the reduction of alcohol and tobacco use in pregnant women is established. In the monocentre, prospective, controlled, and investigator-blinded MINDFUL/PMI (Maternal Health and Infant Development in the Follow-up after Pregnancy and a Mindfulness Intervention) study, pregnant women carry out the programme. Its effect on antenatal testosterone exposure of the child is examined by assessing the index/ring finger length ratio and other biomarkers in the 1-year-old children. In addition, the programme's effects on self-regulation, the developmental status and the mental health of the children at the age of one year will be investigated. Additional aspects of the course of the pregnancy and delivery represent exploratory study objectives. This longitudinal study project is intended to improve the understanding of the impact of intrauterine environmental factors on early childhood development and health. Maternal stress as well as alcohol and tobacco use during pregnancy are modifiable factors and represent potential preventive targets.Ungünstige intrauterine Umweltfaktoren erhöhen das Risiko für Geburtskomplikationen sowie postpartale Entwicklungs- und Verhaltensauffälligkeiten bei den Kindern und Jugendlichen mit permanenten Auswirkungen bis ins höhere Alter. Biomarkerstudien zeigen, dass mütterlicher Stress und Konsum von Alkohol und Tabak während der Schwangerschaft mit höherer intrauteriner Testosteronexposition des Kindes assoziiert sind. Die pränatale Testosteronlast ist wiederum ein Risikofaktor für anhaltende und bis ins Erwachsenenalter reichende Gesundheitsbeeinträchtigungen. Es wird ein 15-wöchiges, achtsamkeitsorientiertes, App-basiertes Programm zur Reduktion von Stress sowie zur Verminderung von Alkohol- und Tabakkonsum bei schwangeren Frauen etabliert. In der monozentrischen, prospektiven, kontrollierten und untersucherverblindeten MINDFUL/PMI (Maternal Health and Infant Development in the Follow-up after Pregnancy and a Mindfulness Intervention)-Studie führen schwangere Frauen das Programm durch. Dabei wird der Effekt auf die pränatale Testosteronexposition des Kindes untersucht, die mit dem Zeige-/Ringfingerlängenverhältnis und weiteren Biomarkern bei den 1-jährigen Kindern erhoben wird. Außerdem soll beforscht werden, wie sich das Programm auf die Selbstregulation, den Entwicklungstand und die psychische Gesundheit der Kinder im Alter von einem Jahr auswirkt. Weitere Aspekte des Schwangerschafts- und Geburtsverlaufs stellen explorative Studienziele dar. Dieses longitudinale Studienprojekt soll das Verständnis der Bedeutung intrauteriner Umweltfaktoren für die frühe kindliche Entwicklung und Gesundheit verbessern. Mütterlicher Stress sowie Alkohol- und Tabakkonsum während der Schwangerschaft sind modifizierbare Faktoren und stellen potenzielle präventive Ansatzpunkte dar.

Background Male depression syndrome (Male-DS) refers to alternative depression symptoms related to the male sex, such as externalizing behaviors, emotional suppression, substance misuse, and risk-seeking. Although these symptoms contribute to gender bias in the diagnosis of depression, Male-DS can be found in both sexes. In this cross-sectional study, we analyzed associations between Male-DS and clinical personality accentuations. Methods We compared clinical personality accentuations between 78 depressed patients with high Male-DS scores (46% women; mean age ± standard error of the mean: 36.5 ± 1.6 years) and 76 depressed patients with low Male-DS scores (43% women; age 44.8 ± 1.7 years). We also explored differences between the two patient groups and 176 healthy controls (51% women; age 37.2 ± 1.0 years). Results Depressed patients with high Male-DS scores showed stronger borderline (partial η2 0.121), impulsive (0.112), and antisocial (0.078) personality accentuations than those with low Male-DS scores after Bonferroni adjustment and controlling for sex, depression severity, and age. Relative to healthy controls, patients with high Male-DS values scored higher in all personality dimensions except for the narcissistic dimension. Patients with low Male-DS values scored higher in all Cluster A and C dimensions and the impulsive and borderline dimensions, but their scores were lower in the narcissistic dimension. Limitations Cross-sectional design and focus on in-patients. Conclusions We found pronounced Cluster B personality in patients with high Male-DS scores versus patients with low scores. Further prospective research is needed to verify that Cluster B personality traits represent a pre-morbid risk factor for Male-DS.

Objective Binge drinking is a highly prevalent behavior in adolescents and young adults and a risk factor to develop alcohol use disorder. Body mass index (BMI) and blood levels of leptin peptide and its soluble receptor have been implicated in alcohol use disorder; however, their role in binge drinking remains to be investigated. Method We studied associations of BMI, serum levels of soluble leptin receptor (ObRe) and leptin as well as the free leptin index with binge drinking in 93 male and 99 female young adults. Results In men, binge drinkers showed significantly higher BMI (kg/m2) than non-binge drinkers (23.67 vs. 22.08) and higher BMI correlated significantly with more severe binge drinking episodes (ρ = 0.251). In women, we found significantly higher ObRe (ng/ml) / BMI (kg/m2) values in binge drinkers than in non-binge drinkers (0.52 vs. 0.44) and ObRe/BMI values correlated significantly with more severe binge drinking episodes (ρ = 0.210). Conclusion This study confirms that higher BMI associates with binge drinking in men and shows for the first time a role of ObRe/BMI in binge drinking in women. Our data emphasize the importance of further research in the field of metabolic markers and implications in neurobiological processes of binge drinking.

Directly measuring hypothalamic pituitary adrenal (HPA) axis function, an important player in affective disorders, is intensive and invasive. A crucial component of this system, the activity of the glucocorticoid receptor (GR), can be assessed ex vivo instead. Here, we investigated GR sensitivity in patients with major depressive disorder (MDD) to determine its predictive potential. Psychometric data and blood samples were collected from patients experiencing a major depressive episode (MDE, n = 87), healthy control subjects (n = 49), and patients with remitted MDD (n = 31) at baseline and (for patients) after median 20 days of follow-up after treatment as usual. Blood cells were stimulated ex vivo with lipopolysaccharide and the effect was suppressed by increasing dexamethasone (DEX) concentrations. The resultant cytokine secretion profile (for IL-6, IL-10, and TNF-α) was considered indicative of GR activity. Higher baseline scores of the Montgomery–Åsberg Depression Rating Scale (MADRS) were associated with a stronger decrease of logIC IL-6 (indicating an increase of GR sensitivity). Higher baseline logEC IL-10 (indicating a lower GR sensitivity) and a stronger reduction of logEC IL-10 (indicating a stronger increase in GR sensitivity) were associated with a stronger decrease in the MADRS score. Patients with remitted MDD showed higher logIC TNF-α values (indicating lower GR sensitivity) in comparison to patients with a current MDD at baseline and follow-up. Initially low GR sensitivity measured ex vivo in peripheral blood cells that increases over the course of treatment could serve as a predictive marker for stronger improvement in depression severity.

Moderately sized, case-control studies have related alcohol dependence in middle-aged in-patients to lower second-to-fourth finger length ratio (2D:4D), a proxy for prenatal hyperandrogenization. As primary aim, we here intended to confirm that lower 2D:4D is also associated with Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV/-5 alcohol dependence and alcohol use disorder in a large population-based cohort of young males. Exploratory aims included underlying mechanisms. We analyzed self-reported data on 2D:4D, DSM-IV/-5 criteria, anticipated subjective responses to alcohol, and willingness to purchase alcoholic drinks from 4989 Swiss men of the Cohort Study on Substance Use Risk Factors (C-SURF). The mean of right-hand 2D:4D and left-hand 2D:4D was lower in men with DSM-IV alcohol dependence than in those without (0.975 vs 0.981, P = .035) and lower in men with moderate to severe (0.974) than in those with mild (0.982, P = .001) or no (0.981, P = .003) DSM-5 alcohol use disorder. Moreover, mean 2D:4D was lower in those reporting recent use of health services due to substance use problems (0.968 vs 0.981, P = .046). Lower mean 2D:4D correlated with a stronger anticipation to feel high following alcohol consumption (total cohort: ρ = -0.033, P = .026) and with a willingness to purchase more higher-priced alcoholic drinks (DSM-IV alcohol dependence subgroup: ρmin = -0.162, P = .002). This is the first population-based study on young males to demonstrate lower 2D:4D in DSM-IV alcohol dependence, DSM-5 alcohol use disorder, and the related use of health care services. We also provide novel insight into cognitive-behavioral mechanisms. These results should help to establish more effective preventive and therapeutic strategies targeting 2D:4D and prenatal androgen exposure.

The second-to-forth digit length ratio (2D:4D) is considered to be a biomarker for intrauterine androgen levels. It is associated with adult and child mental health problems, primarily with behavioral symptoms and predominantly in males. Using a cross-sectional design, we examined whether 2D:4D was associated with conduct disorder (CD) symptoms in 138 primary-school aged children (54% boys, Mage = 7.70 years) and considered child sex as a moderating factor. Children's digit lengths were measured from hand scans and mothers rated the behavioral/emotional symptoms of their child. The regression analyses revealed that 2D:4D ratios were associated with behavioral symptoms in boys (β = −0.260, p = 0.026), but not in girls (β = −0.040, p = 0.762). Child emotional symptoms, analyzed as a control, were not significantly correlated with 2D:4D. In conclusion, prenatal brain hyperandrogenization - operationalized by the 2D:4D biomarker - could result in behavioral symptoms in boys at early school age, reflecting one predictor for early onset CD. Our data support the use of 2D:4D as a marker of prenatal androgen exposure.

Objective Alcohol use disorder (AUD) shows a high prevalence and often takes a severe and chronic course. However, the underlying mechanisms still need to be better understood. There is increasing evidence for a role of sex hormones in AUD and for the importance of sex-separated concepts in addiction research. Nevertheless, only few data give insight into how progesterone is involved in AUD. Method Serum progesterone levels were measured at baseline (during early abstinence) in 186 in-patients with AUD (19% premenopausal females, 20% postmenopausal females, 61% males) and at median 5 days later. They were compared with those of 233 healthy control subjects (24% premenopausal females, 19% postmenopausal females, 57% males). We quantified craving with the Obsessive Compulsive Drinking Scale (OCDS) and visual analogue scales (VAS). Alcohol-related hospital readmissions within a 24-month period following initial in-patient treatment were recorded. We conducted analyses separately for sex and for menopausal status in female participants. Results Postmenopausal females with AUD reported higher craving than premenopausal females. In postmenopausal females, higher baseline progesterone levels correlated with lower OCDS total craving and VAS craving, i.e., lower state craving and lower average, maximum, and less frequent craving during withdrawal. In males with AUD, progesterone levels at baseline tended to be higher than in controls and declined to follow-up. Alcohol-related readmissions were not significantly associated with serum progesterone levels. Conclusion We provide first evidence that progesterone levels correlate with craving in females with AUD.

(1) This longitudinal study aimed to investigate the link between prenatal alcohol exposure and prenatal maternal depression with the offspring’s low-grade inflammatory status. (2) Prenatal alcohol exposure was determined via maternal self-report during the 3rd trimester of pregnancy (self-report+: n = 29) and the meconium alcohol metabolite Ethyl Glucuronide (EtG), collected at birth (≥30 ng/g: n = 23). The Edinburgh Postnatal Depression Scale (EPDS) was used to screen for prenatal maternal depressive symptoms during the 3rd trimester (≥10: n = 35). Fifteen years later, 122 adolescents (M = 13.32 years, 48.4% female) provided blood samples for the analysis of high sensitivity C-reactive protein (hsCRP, M = 0.91, SD = 1.28). (3) Higher hsCRP levels were found in EtG positive adolescents (p = 0.036, ηp2 = 0.04) and an inverse non-significant dose–response relation with hsCRP (r = −0.35, p = 0.113). For maternal self-reported prenatal alcohol consumption (p = 0.780, ηp2 = 0.00) and prenatal depressive symptoms (p = 0.360, ηp2 = 0.01) no differences for hsCRP levels between the affected and unaffected groups were found. (4) Adolescents with prenatal alcohol exposure are at risk for low-grade systemic inflammation. The EtG biomarker may be more accurate compared to self-reports. The findings suggest that prenatal maternal depression does not evoke low-grade systemic inflammation.

Objective Alcohol dependence is more prevalent in men than in women. The evidence for how prenatal and adult androgens influence alcohol dependence is limited. We investigated the effects of prenatal and adult androgen activity on alcohol dependence. Moreover, we studied how the behaviours of pregnant women affect their children's prenatal androgen load. Method We quantified prenatal androgen markers (e.g., second-to-fourth finger length ratio [2D : 4D]) and blood androgens in 200 early-abstinent alcohol-dependent in-patients and 240 controls (2013–2015, including a 12-month follow-up). We also surveyed 134 women during pregnancy (2005–2007) and measured the 2D : 4D of their children (2013–2016). Results The prenatal androgen loads were higher in the male alcohol-dependent patients compared to the controls (lower 2D : 4D, P = 0.004) and correlated positively with the patients’ liver transaminase activities (P

Objective Alcohol dependence affects metabolic processes. Further research is needed to apply this knowledge clinically. In this study, possible differences in serum lipids and/or leptin activities between alcohol-dependent in-patients and healthy controls and possible associations with alcohol-related blood parameters and with prospective outcomes in alcohol dependence were assessed sex-specifically. Method We measured and compared (median) serum lipids (triglycerides and total, HDL, and LDL cholesterol) and leptin activities (leptin, soluble leptin receptor [ObRe], and free leptin index) in 200 (males 56.5 %) early-abstinent alcohol-dependent in-patients and 240 (males 55.4 %) healthy controls and assessed alcohol-related readmissions during a 24 -month post-inclusion period. Results Male patients showed higher HDL cholesterol (61 versus 48 mg/dl), lower LDL/HDL ratios (2.06 versus 3.04), and lower free leptin index (0.30 versus 0.59) at study inclusion compared to healthy controls. In patients, ObRe levels were higher than in controls and decreased from inclusion to the second study-visit (at median 5 days later; males: 16.7–13.8 versus 11.0 ng/ml; females: 17.0–13.4 versus 12.1 ng/ml). The free leptin index increased between the two time points in females (0.80 versus 1.20). Lipids and leptin activities correlated with carbohydrate-deficient transferrin levels and liver enzyme activities. None of the serum parameters were significantly associated with alcohol-related readmissions. Conclusion Our data support that serum lipid levels and leptin activities are involved in alcohol dependence. The parameters appear as possible indirect biomarkers for alcohol dependence.

BACKGROUND Available predictors of hospital readmission following withdrawal in alcohol-dependent patients are limited. However, such parameters are needed to optimize individualized treatment strategies. This study investigated whether crossed eye/hand laterality, eyedness, and handedness may predict outcomes in alcohol dependence. METHODS The prospective study included 200 early-abstinent alcohol-dependent inpatients (n[males] = 113, n[females] = 87) and 240 control subjects (n[males] = 133, n[females] = 107). We assessed eyedness and handedness using the hole-in-the-card and Shimizu tests and documented alcohol-related readmissions over 12 and 24 months. RESULTS Crossed eye/hand laterality and left-eyedness were associated with a reduced risk for alcohol-related readmission (12-month: odds ratios [OR] = 0.41, p = 0.008, OR = 0.42, p = 0.004; 24-month: OR = 0.57, p = 0.097, OR = 0.47, p = 0.016), fewer median readmissions (12-month: 0 vs. 1, p = 0.005, 0 vs. 1, p = 0.005; 24-month: 1 vs. 2, p = 0.014, 1 vs. 2, p = 0.006), and more mean days to the first readmission (12-month: 270 vs. 209, p = 0.007, 269 vs. 207, p = 0.003; 24-month: 462 vs. 335, p = 0.039, 461 vs. 323, p = 0.005). They also interacted with treatment and alcohol drinking history to predict the outcome. In sex-specific analyses, most of these effects remained significant in males but not in females. Handedness alone did not significantly predict outcome. Moreover, the laterality markers did not significantly differ between alcohol-dependent patients and control subjects. CONCLUSIONS Determining crossed eye/hand laterality and eyedness may help to individualize relapse prevention in the future. Both are easily accessible predictors of alcohol-related readmission following inpatient withdrawal treatment.

By catalyzing the hydrolysis of sphingomyelin into ceramide, acid sphingomyelinase (ASM) changes the local composition of the plasma membrane with effects on receptor-mediated signaling. Altered enzyme activities have been noted in common human diseases, including alcohol dependence. However, the underlying mechanisms remain largely unresolved. Blood samples were collected from early-abstinent alcohol-dependent in-patients (n[♂] = 113, n[♀] = 87) and matched healthy controls (n[♂] = 133, n[♀] = 107), and analyzed for routine blood parameters and serum ASM activity. We confirmed increased secretory ASM activities in alcohol-dependent patients compared to healthy control subjects, which decreased slightly during detoxification. ASM activity correlated positively with blood alcohol concentration, withdrawal severity, biomarkers of alcohol dependence (liver enzyme activities of gamma-glutamyl transferase, alanine aminotransferase, aspartate aminotransferase, homocysteine, carbohydrate-deficient transferrin, mean corpuscular volume, and creatine kinase). ASM activity correlated negatively with leukocyte and thrombocyte counts. ASM and gamma-glutamyl transferase were also associated in healthy subjects. Most effects were similar for males and females with different strengths. We describe previously unreported associations between ASM activity and markers of liver damage and myelosuppression. Further research should investigate whether this relationship is causal, or whether these parameters are part of a common pathway in order to gain insights into underlying mechanisms and develop clinical applications.

Although women attempt suicides equally or more often than men do, men are more likely to die of suicide than women (sex paradox of suicidal behavior). Furthermore, the male traits of aggression and impulsivity predict suicide completion. Here, we studied the second-to-fourth-finger length ratio (2D:4D), a proxy for prenatal androgen exposure, in 46 suicide corpses and 25 non-suicide corpses. We report significantly lower 2D:4D in male suicide corpses than non-suicide corpses (p = .030, partial η 2 = .147). There was no significant association between 2D:4D and the suicide method. Our findings indicate increased risk of suicide following higher prenatal androgen exposure in males. The results may improve future efforts to predict and prevent suicides.

Background Major depressive disorder (MDD) is a highly prevalent and burdening mental illness. Approximately 30% of the major depressive episodes (MDE) are classified as therapy-refractory. Further knowledge of the pathophysiological mechanisms underlying MDD and predictive biomarkers are needed to improve treatment options. Methods Serum lipid levels were compared between patients with a current MDE (n = 130) or remitted MDD (n = 39) and healthy control subjects (n = 61) and associated with the severity (17-item Hamilton Depression Rating Scale [HAMD] scores) and the prospective course of depression (direct follow-up of at median 20 days post-inclusion). Results We found higher levels of LDL cholesterol (152.5 vs. 134.0 mg/dl, U = 3021, P = 0.008) and LDL/HDL ratio (2.82 vs. 2.21, U = 2912, P = 0.003) in patients with a current MDE than in healthy control subjects. In patients with a current MDE, higher HAMD scores correlated also with higher values of triglycerides (ρ = 0.213, P = 0.015), total cholesterol (ρ = 0.199, P = 0.023), LDL cholesterol (ρ = 0.224, P = 0.010), and LDL/HDL ratio (ρ = 0.196, P = 0.026). Moreover, higher total cholesterol (ρ = −0.233, P = 0.010), LDL cholesterol (ρ = −0.235, P = 0.010), and LDL/HDL ratio (ρ = −0.199, P = 0.029) were associated with a stronger decline in HAMD score between study inclusion and direct follow-up. Limitations We employed an associational study design, performed only a short-term follow-up, and excluded suicidal study subjects. Conclusions Serum lipid levels are associated with depression per se, the depression severity, and the prospective 3-week course. These observations build the basis for future investigations on individualized lipid metabolism-related treatment strategies in depressed patients.

Alcohol binge drinking behavior is an important public health issue. Causal rodent and human associational studies show that reinforcement of prenatal androgen signaling increases alcohol consumption in adulthood. However, the effects of prenatal androgen exposure on adult binge drinking patterns have not been investigated yet.We analyzed data from 2225 participants of an online survey (conducted 06-07/2016) to evaluate biomarkers for prenatal androgen exposure (second-to-fourth finger length ratio [2D:4D], age at spermarche or menarche as hallmark for pubertal onset) in binge drinking (≥1 episode of 15+, 10+, and/or 5+ standard drinks of ~13 g of alcohol within 2 h during the 24 month- and 2 week-recall periods).Men reported binge drinking more often than women (ORs 1.4, P .001). For the 24 month-recall period, binge drinkers showed lower 2D:4D (P = .006) and reported later pubertal onset (P = .022) than non-binge drinkers. These findings consistently suggest excess prenatal androgen exposure in adult binge drinkers. Moreover, 2D:4D was negatively associated with severity (15+/10+/5+/non-binge drinking, P = .005) and frequency of binge drinking episodes (P = .044). All of these effects were stronger in men than in women. For the 2 week-recall period, the biomarkers were not significantly related to binge drinking behavior.Our results indicate that increased prenatal androgen exposure is involved in the development of alcohol binge drinking behavior in adults.

Males with a female co-twin are more likely to become alcohol-dependent than males with a male co-twin. According to the twin testosterone transfer model, this finding can be interpreted as indirect evidence for a role of prenatal testosterone in alcohol dependence.

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 (P0.01) and (ii) craving (P0.05), and on the other hand, a positive association between leptin and craving of man in alcohol withdrawal (P0.001). 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.

Frontotemporal dementia is more frequently diagnosed because of revised diagnostic procedures. Due to the lack of pharmacological trials it is a disease that is difficult to manage in the way of evidence based medicine. Deficits in serotonergic and dopaminergic signal-transmission are well known. The cholinergic system does not seem to be affected. Case reports and clinical trials show a benefit by using antidepressants, neuroleptics and mood stabilizers. Nevertheless only paroxetine, trazodone and rivastigmine are tested by double-blind, placebo-controlled studies. While paroxetine shows inconsistent data, trazodone improves behavioural symptoms. Patients report a treatment-emergent adverse effect including fatigue, dizziness and hypotension. Rivastigmine leads to a significant decrease in the Neuropsychiatric Inventory Score. Finally, we present a two-cases-report that shows improve of disease symptoms under treatment with repetitive transcranial magnet stimulation.

The internet age bears new challenges that include health risks. It is agreed that excessive internet use may reach pathological levels. However, the concept of internet addiction lacks specificity and, therefore, warrants studies on its diagnostic and etiologic classification. This study was conducted to characterize the novel DSM-5 criteria for internet gaming disorder and the adapted criteria for the “social network disorder”. Based on the established association of handedness and substance use disorders, we also explored whether internet use related to laterality. For this study, 3,287 volunteers participated in the online survey and gave particulars concerning their internet use in general, internet gaming and use of social networks, laterality markers (hand, foot, eye, ear, rotational preference in gymnastics, and head turning asymmetry) and health status. Of the participants, 1.1 % fulfilled the criteria for internet gaming disorder, and 1.8 % fulfilled the criteria for social network disorder. The applied criteria were highly correlated with the time spent on the respective internet activities (p −56). The analyses of comorbidity and working hours support the thresholds of 5/9 criteria and ≥30 h/week spent on the internet for the classification as pathological (p −2). Moreover, we found that left-handedness related to more affirmed criteria and longer times spent on social networks (p ≤ 4 × 10−2). The provided criteria proved to be user-friendly, comprehensible and well accepted. The results contribute to a better understanding of pathological internet gaming and social network use and provide evidence that biological markers of substance use disorders are involved in internet addiction.

Vascular endothelial growth factor A (VEGF-A) is a key regulator of angiogenesis. This study investigated VEGF-A serum levels during alcohol withdrawal (days 1, 7 and 14, 76 male patients, 38 healthy controls). Patients showed significantly higher VEGF-A serum levels (t = 2.620, P = 0.010), which increased significantly during withdrawal (F = 4.484, P = 0.014, mean difference = -36.835, P = 0.037). The increase of VEGF-A serum levels was significantly associated with initial breath alcohol concentration and the sumscore of the severity scale of alcohol dependence (SESA questionnaire, F = 5.252, P = 0.008). Increase of VEGF-A serum levels is closely associated to alcohol intoxication and severity of alcohol dependence.

Preclinical study results suggest that neurotrophic peptides like nerve growth factor (NGF) and vascular endothelial growth factor A (VEGF-A) may be associated with symptoms of addictive behavior like withdrawal symptoms and rewarding effects. We investigated alterations in NGF and VEGF-A serum levels in opiate-dependent patients (25 male patients), who received diamorphine (DAM, heroin) treatment within a structured opiate maintenance program, and compared the results with the NGF and VEGF-A serum levels of healthy controls (23 male controls). NGF and VEGF-A serum levels were assessed before and after DAM administration twice a day (in the morning (16 h after last application – t1) and in the afternoon (7 h after last application – t3)) in order to detect a possible immediate or summative (in the afternoon) heroin effect on these two neuropeptides. Moreover, we investigated possible associations between the serum levels of these neurotrophic growth factors and psychometric dimensions of addictive behavior, e.g. craving, withdrawal, depression. Whereas there was no direct effect of DAM application on the serum levels of both neurotrophic growth factors neither in the morning nor in the afternoon, the NGF serum levels of the patient group were found to be significantly increased at all four time points of investigation compared with the healthy controls. In contrast, VEGF-A serum levels did not differ significantly in the patient and control groups. We found a significant positive association between the NGF serum levels and several items of the short opiate withdrawal scale as well as a negative association between self-reported mood (measured by visual analogue scale) and mood before heroin application (in the morning as in the afternoon). Moreover, we found a significant positive association between the NGF serum levels (t1 and t3) and the self-reported craving for methadone. In contrast, we found a negative association between the VEGF-A serum levels and avoidance, anxiety, suicide intentions of the SCL-90 as well as a positive association between the VEGF-A serum levels and the subscales of the heroin craving questionnaire measuring the rewarding effects of heroin. In conclusion, the results of this pilot study show that there might be an association between symptoms of opiate dependence and withdrawal and serum levels of VEGF-A and NGF.

Im randomisiert kontrollierten Vergleich reduziert eine internetbasierte Intervention die Anzahl von konsumierten Standardgetranken/Woche und den AUDIT-Score bei jungen Mannern mit ungesundem Alkoholkonsumverhalten.

Preclinical studies suggest that chronic drug abuse profoundly alters stress-responsive systems. The best studied of the stress-responsive systems in humans is the hypothalamic-pituitary-adrenal (HPA) axis. Apart from cortisol, arginine vasopressin peptide (AVP), and atrial natriuretic peptide (ANP) are known to directly impact upon the HPA axis in addictive behavior. We investigated alterations in ANP, AVP and cortisol serum levels in opiate-dependent patients who received diacetylmorphine treatment within a structured opiate maintenance program. ANP serum levels were significantly increased in opiate-dependent patients as compared to healthy controls, whereas AVP and cortisol serum levels were reduced. The ANP, AVP and cortisol serum levels were not significantly associated with the psychometric dimensions of heroin craving. In conclusion, chronic drug abuse profoundly alters stress-responsive systems like the HPA axis. Alterations of AVP, ANP and cortisol appear to constitute an important component in the neurobiology of opiate-dependent patients.

A causal role of sex hormones in the onset and course of alcohol dependence is well established. We recently demonstrated that the genetics of the androgen receptor and aromatase relate to craving in alcohol addicts during withdrawal. This relationship involves the modulation of leptin, which affects the mesolimbic dopamine reward circuit. The steroid 5-α reductase 2 (SRD5A2) converts testosterone to dihydrotestosterone and thereby causes increased androgenic potency.In this study, we explored whether functionally relevant genetic polymorphisms in SRD5A2 (V89L, A49T, [TA](n)) are linked to alcohol addiction and craving.We investigated 118 male alcohol-addicted inpatients admitted for withdrawal treatment and compared them to 50 healthy age- and body mass index-matched controls. The two groups did not differ in their allelic distributions. Subsequent analyses revealed an association between the V89L genotype and alcohol craving within the patient group (p0.05). Leptin accounted for 55 % of this relationship. Compared to VL and VV carriers, LL carriers had reduced serum leptin levels (p0.05) and lower levels of craving (p0.01). Furthermore, we observed an interaction between the V89L and the TTTAn aromatase polymorphisms (p0.05). No effects were found for A49T or (TA)(n).These findings further support a crucial role of sex hormone biosynthetic genes and signaling in alcohol withdrawal. Craving is an accepted risk factor for alcohol relapse. Hence, these results might be helpful in predicting the outcomes of alcohol addicts after detoxification. With SRD5A2 inhibitors already in clinical use worldwide, this study may also guide future preventive and therapeutic strategies.

Aims: In recent years, various studies were able to show a link between serum levels of appetite-regulating peptides and alcoholism. The adipocytokines, adiponectin and resistin seem to be altered during withdrawal. We recently showed that a trinucleotide polymorphism within the coding region of the androgen receptor (AR) is linked to craving in alcohol withdrawal, an effect that was mostly mediated by leptin. The aim of the present preliminary retrospective study was to further elucidate whether adiponectin and resistin serum levels are regulated by this AR polymorphism as well. Methods: We included 50 male in-patients who were admitted for detoxification treatment. Each had a diagnosis of alcohol dependence (DSM-IV). Results: Our analyses revealed that adiponectin serum levels significantly decreased, whereas resistin levels slightly increased between the day of admission and Day 7. Beyond that, we were not able to demonstrate significant associations between the investigated CAG polymorphism of the AR and adiponectin, resistin or leptin-corrected adipocytokines, either on the day of admission or on Day 7. Moreover, the polymorphism did not influence the time response of adiponectin and resistin during withdrawal. Conclusions: Genetic determinants of the AR influence alcohol withdrawal. Anyway, this preliminary retrospective analysis does not support the hypothesis that the investigated AR polymorphism has a major modifying effect on adiponectin or resistin serum levels in patients with alcoholism.

Nicotine induces various acute and chronic pharmacological effects which can be long lasting and might lead to nicotine dependence. Nicotinic acetylcholine receptors (nAChRs) are involved in nicotine-induced phosphorylation of CREB (cyclic AMP response element-binding protein) in PC12h cells. Several studies, mainly done in animal models, report that CREB plays a role in anxiety, memory and substance abuse as well as in affective disorders. Information regarding nicotine effects on gene expression in humans in vivo is rare. The aim of our study was to determine whether or not there are differences between smokers and non-smoking controls in terms of CREB expression and phosphorylation in human buffy coat. Comparing 32 smokers with 76 non-smoking controls we found significantly elevated relative (p=0.043) and absolute (p=0.040) CREB phosphorylation in the blood of smokers who had smoked two cigarettes in the past 6 h. In contrast, the score of the State and Trait Anxiety Inventory, total-CREB and mRNA-CREB were not significantly different. Multiple regression analysis revealed a significant relation between the number of cigarettes smoked daily (R²=0.143, p=0.023), the Fagerstrm Test for Nicotine Dependence score (R²=0.145, p=0.022) and the expression of CREB. Moreover, in accord with previously published data our analysis suggests gender and age as factors that significantly influence expression and phosphorylation of CREB. It appears that human buffy coat is suitable for studying pharmacological effects of substances such as nicotine on selected signal transduction pathways in humans in vivo. This kind of study may be helpful for translating findings from animal models and cell cultures. Copyright © CINP 2010.

Epigenetic mechanisms like DNA methylation are known to influence gene expression and to contribute to the pathophysiology of different psychiatric disorders including alcohol dependence. This also applies for the function of endocrine pathways in addictive behavior. Results show that the …

Eine positive Familienanamnese und der Asp-Tragerstatus der Asn40Asp-Variante des μ-Opioidrezeptors konnen ein Ansprechen auf Naltrexon vorhersagen.

1. Tabula Gratulatoria 2. preface (by Lehmann, Elmar) 3. Chaucer's Slow-motion Camera - and What it Does to the Fabliau (by Diller, Hans-Jurgen) 4. "Man's Distinctive Mark": Paradoxical Distinctions Between Man and His Bestial Other in Early Modern Texts (by Pfister, Manfred) 5. Authority and Representation in the Pre-Shakespearean Prologue (by Weimann, Robert) 6. The Rise of a New Literary Genre: Thomas Deloney's Bourgeois Novel Jack of Newbury (by Stemmler, Theo) 7. Love Stories. Antony and Cleopatra Plays of the 16th and 17th Centuries (by Lehmann, Elmar) 8. "I Repeat and Repeat." Repetition as Structure in Defoe's Robinson Crusoe (by Suerbaum, Ulrich) 9. Undermining Public Opinion. The Function of Narrative in Fielding's Tom Jones (by Stratmann, Gerd) 10. Falling and the Fall in Sterne's Tristram Shandy (by Wolff, Erwin) 11. Preachers and Preaching. Emotionalism in Eighteenth-Century Homiletics and Homilies (by Lenz, Bernd) 12. Philosophers as Story-Tellers. Difficulties of the Enlightenment With Morality (by Warning, Rainer) 13. Of Ants And Alien: Wells's The War of the Worlds as Menippean Satire (by Koppenfels, Werner von) 14. History as Romance, Tragedy and Farce. Narrative Versions of the Anglo-boer War (by Reckwitz, Erhard) 15. Common Traits of Chaucer's and Joyce's Narrative Art (by Erzgraber, Willi) 16. Can Stories be Read as Music? Possibilities and Limitations of Applying Musical Metaphors to Fiction (by Wolf, Werner) 17. How Boris Pil'niak Came to Know "The Way" - Japanese -"Stories are Created"* (by Maurer, Karl) 18. Austrian Auden (by Firchow, Peter) 19. Totalitarianism: A New Story? An Old Story? (by Lerner, Laurence) 20. A Further Case of the 'Detective Novel Unbound'. Thornton Wilder's the Eighth Day and the Mystery Novel (by Borgmeier, Raimund) 21. The Authorial Mind and The Question of Gender (by Schabert, Ina) 22. Ulrich Broich - List of Publications