Emerging drugs in phase II and III clinical development for the treatment of alcohol use disorder.

INTRODUCTION: Alcohol Use Disorder (AUD) poses an ongoing significant global health burden. AUD is highly prevalent and affects not only the individuals with AUD, but also their communities and society at large. Even though pharmacotherapy is an integral part of AUD treatment, the few available substances show limited efficacy and limited clinical impact. Thus, there is a need for new innovative pharmacotherapeutic approaches. AREAS COVERED: This paper provides a comprehensive review of drugs approved for the treatment of AUD as well as those currently in phase II and III development. Data from recent clinical trials has been reviewed and supplemented by additional literature based on a systematic search of the PubMed database and clinical trials registries. Compounds discussed include disulfiram, naltrexone, nalmefene, acamprosat, baclofen, sodium oxybate, doxazosin, varenicline, zonisamide, gabapentin, apremilast, ibudilast, ivermectin, tolcapone, mifepristone, suvorexant, ketamine, psilocybin, semaglutide, oxytocin and cannabidiol. EXPERT OPINION: Even though the majority of the discussed compounds lack sufficient evidence to support their efficacy, multiple promising new treatment options are currently under investigation. Future research has to consider specific phenotypes and subgroups of AUD as well as a possible enhancement of the effects of psychotherapy through combination with pharmacotherapy. Practitioners should be encouraged to use available compounds to support existing therapeutic regimens.

Suicide risk after discharge from in-patient psychiatric care: A 15-year retrospective cohort study of individual patient data.

BACKGROUND: Suicide rates are known to be increased in patients after discharge from in-patient psychiatric treatment. However, evidence on risk factors for suicide within this patient group are contradictory. Thus, this study aims to investigate suicide after discharge from a sizeable psychiatric care facility to determine associated risk factors. METHODS: Data on individual patient level from a 15-year single-centre cohort were linked to data from the national death registry and cumulative incidence rates were calculated applying competing risk models. Independent variables included the patients' sex, age at admission, diagnosis, and length of admission. For each of these factors, subdistribution hazards ratios were calculated using a Fine-Gray model. RESULTS: In our sample of 18,425 discharges, when using patients with the diagnosis of substance-use-disorders as a comparator, a significant increase in hazard of post-discharge suicide for male sex (SHR = 1.67;p = 0.037) as well as the discharge diagnoses of affective disorders (SHR = 3.56;p = 0.017) and neurotic stress and somatoform disorders (SHR = 3.73;p = 0.024) were found. Interestingly, the hazard of suicide significantly decreased in more recent discharges (SHR = 0.93;p = 0.006). No statistically significant association of the length of admission with the suicide risk was found (SHR = 0.98;p = 0.834). LIMITATIONS: Suicides may have been mis-identified as natural death in the national death register. CONCLUSION: Male sex and distinct diagnoses were associated with an increased risk for suicide after discharge from a psychiatric care institution. The markedly increased suicide risk within this patient collective highlights the need for the development of tools to assess suicidal behaviour in this group of patients reliably.

Drug safety in older patients with alcohol use disorder: a retrospective cohort study.

Background: Older patients with alcohol use disorder are at particular risk of developing adverse drug reactions due to multimorbidity, polypharmacy, and altered organ function. Objectives: In this study, we investigated the frequency and characteristics of potentially serious alcohol-medication interactions, potentially inappropriate medications (PIMs) for older adults, and potential drug-drug interactions (pDDIs) in a population of older patients with alcohol use disorder over a 10-year period. Design: Retrospective monocentric cohort study. Methods: Prescribed medications were screened for potentially serious alcohol-medication interactions, PIMs, and pDDIs using the POSAMINO (POtentially Serious Alcohol-Medication INteractions in Older adults) criteria, the PRISCUS 2.0 list, the FORTA (Fit fOR The Aged) classification, and the drug interaction program AiDKlinik®. Results: We enrolled 114 patients aged ⩾65 years with alcohol use disorder, who were treated in an addiction unit of a university hospital in Germany. About 80.7% of the study population had at least one potentially serious alcohol-medication interaction. Potentially serious alcohol-medication interactions most commonly affected the cardiovascular (57.7%) and the central nervous system (32.3%). A total of 71.1% of the study population received at least one prescription of a FORTA C or D drug, compared with 42.1% who received at least one PIM prescription according to the PRISCUS 2.0 list. A total of 113 moderate and 72 severe pDDIs were identified in the study population. Conclusion: Older patients with alcohol use disorders are frequently exposed to potentially serious alcohol-medication interactions, PIMs, and pDDIs. Improvements in the quality of prescribing should primarily target the use of cardiovascular and psychotropic drugs.

Methylation of the Oxytocin, Oxytocin Receptor, and Vasopressin Gene Promoters in Tobacco Use Disorder during Cessation.

INTRODUCTION: Vasopressin (AVP) and oxytocin (OT) exert sex-specific effects on social pair bonding and stress reactions while also influencing craving in substance use disorders. In this regard, intranasal oxytocin (OT) and AVP antagonists present potential treatments for tobacco use disorder (TUD). Since transcription of both hormones is also regulated by gene methylation, we hypothesized sex-specific changes in methylation levels of the AVP, OT, and OT receptor (OXTR) gene during nicotine withdrawal. METHODS: The study population consisted of 49 smokers (29 males, 20 females) and 51 healthy non-smokers (25 males, 26 females). Blood was drawn at day 1, day 7, and day 14 of smoking cessation. Craving was assessed with the questionnaire on smoking urges (QSU). RESULTS: Throughout cessation, mean methylation of the OT promoter gene increased in males and decreased in females. OXTR receptor methylation decreased in females, while in males it was significantly lower at day 7. Regarding the AVP promoter, mean methylation increased in males while there were no changes in females. Using mixed linear modeling, CpG position, time point, sex, and the interaction of time point and sex as well as time point, sex, and QSU had a significant fixed effect on OT and AVP gene methylation. The interaction effect suggests that sex, time point, and QSU are interrelated, meaning that, depending on the sex, methylation could be different at different time points and vice versa. There was no significant effect of QSU on mean OXTR methylation. DISCUSSION: We identified differences at specific CpGs between controls and smokers in OT and AVP and in overall methylation of the AVP gene. Furthermore, we found sex-specific changes in mean methylation levels of the mentioned genes throughout smoking cessation, underlining the relevance of sex in the OT and vasopressin system. This is the first study on epigenetic regulation of the OT promoter in TUD. Our results have implications for research on the utility of the AVP and OT system for treating substance craving. Future studies on both targets need to analyze their effect in the context of sex, social factors, and gene regulation.

Cytosine methylation in GABA B1 receptor identifies alcohol-related changes for men in blood and brain tissues.

AIMS: Alcohol use alters the reward signaling processes contributing to the development of addiction. We studied the effects of alcohol use disorder (AUD) on brain regions and blood of deceased women and men to examine sex-dependent differences in epigenetic changes associated with AUD. We investigated the effects of alcohol use on the gene promoter methylation of GABBR1 coding for GABAB receptor subunit 1 in blood and brain. METHODS: We chose six brain regions associated with addiction and the reward pathway (nucleus arcuatus, nucleus accumbens, the mamillary bodies, amygdala, hippocampus and anterior temporal cortex) and performed epigenetic profiling of the proximal promoter of the GABBR1 gene of post-mortem brain and blood samples of 17 individuals with AUD pathology (4 female, 13 male) and 31 healthy controls (10 female, 21 male). RESULTS: Our results show sex-specific effects of AUD on GABBR1 promoter methylation. Especially, CpG -4 showed significant tissue-independent changes and significantly decreased methylation levels for the AUD group in the amygdala and the mammillary bodies of men. We saw prominent and consistent change in CpG-4 across all investigated tissues. For women, no significant loci were observed. CONCLUSION: We found sex-dependent differences in GABBR1 promoter methylation in relation to AUD. CpG-4 hypomethylation in male individuals with AUD is consistent for most brain regions. Blood shows similar results without reaching significance, potentially serving as a peripheral marker for addiction-associated neuronal adaptations. Further research is needed to discover more contributing factors in the pathological alterations of alcohol addiction to offer sex-specific biomarkers and treatment.

Comparing DRD2 Promoter Methylation Between Blood and Brain in Alcohol Dependence.

AIMS: The dopamine receptor D2 (DRD2) is substantially involved in several forms of addiction. In addition to genetic polymorphisms, epigenetic mechanisms have emerged as an important means of regulation. Previously, DRD2 hypo- and hyper-methylation have been observed in alcohol use disorder (AUD). Blood samples are commonly used as a surrogate marker of epigenetic alterations in epigenetic research, but few specific comparisons between blood and brain tissue samples in AUD exist. METHODS: We used post-mortem brain tissue samples of 17 deceased patients with AUD and 31 deceased controls to investigate the relationship between blood and brain methylation of the DRD2 promoter. RESULTS: When investigating individual cytosine methylation sites (CpG), several significant differences were found in the nucleus accumbens and hippocampus in the study population. Investigating binding sites with significant differences in methylation levels revealed hypomethylated CpGs targeting mainly activating transcription factors. CONCLUSION: These findings support an altered transcription of the DRD2 gene in AUD specimens with a consecutively changed reward response in the brain. While methylation between specific brain regions and blood is comparable, our study further suggests that blood methylation cannot provide meaningful perspectives on DRD2 promoter methylation in the brain.

Cognitive decline and alcohol consumption in the aging population-A longitudinal analysis of the Survey of Health, Ageing and Retirement in Europe.

BACKGROUND: Prevalence of cognitive decline and dementia is rising globally, with more than 10 million new cases every year. These conditions cause a significant burden for individuals, their caregivers, and health care systems. As no causal treatment for dementia exists, prevention of cognitive decline is of utmost importance. Notably, alcohol is among the most significant modifiable risk factors for cognitive decline. METHODS: Longitudinal data across 15 years on 6,967 individuals of the Survey of Health, Ageing and Retirement in Europe were used to analyze the effect of alcohol consumption and further modifiable (i.e., smoking, depression, and educational obtainment) and non-modifiable risk factors (sex and age) on cognitive functioning (i.e., memory and verbal fluency). For this, a generalized estimating equation linear model was estimated for every cognitive test domain assessed. RESULTS: Consistent results were revealed in all three regression models: A nonlinear association between alcohol consumption and cognitive decline was found-moderate alcohol intake was associated with overall better global cognitive function than low or elevated alcohol consumption or complete abstinence. Furthermore, female sex and higher educational obtainment were associated with better cognitive function, whereas higher age and depression were associated with a decline in cognitive functioning. No significant association was found for smoking. CONCLUSION: Our data indicate that alcohol use is a relevant risk factor for cognitive decline in older adults. Furthermore, evidence-based therapeutic concepts to reduce alcohol consumption exist and should be of primary interest in prevention measures considering the aging European population.

Dysregulated Methylation Patterns in Exon IV of the Brain-Derived Neurotrophic Factor (BDNF) Gene in Nicotine Dependence and Changes in BDNF Plasma Levels During Smoking Cessation.

Introduction: Several studies reported dysregulated protein levels of brain-derived neurotrophic factor (BDNF) in smokers and during cessation. However, the epigenetic regulation of the BDNF gene has not yet been investigated. We measured the plasma levels of BDNF and the epigenetic regulation of exon IV of the BDNF gene in smokers compared to healthy controls over a cessation period of 14 days. Method: We measured BDNF plasma levels and BDNF promoter methylation in 49 smokers and 51 non-smokers at baseline, day 7, and day 14 of smoking cessation. Mean methylation levels of 11 Cytosine Guanosine dinucleotides of exon IV of the BDNF gene were determined via bisulfite sequencing. Results: BDNF plasma and methylation levels were significantly lower in healthy controls when compared with smokers across all time points. BDNF levels for smokers decreased significantly during the cessation period. Comparing the sexes, female smokers showed significantly lower plasma BDNF levels than healthy controls at baseline and over 14 days of cessation. Male and female smokers showed significantly higher mean methylation rates than non-smokers at baseline. In male smokers, mean methylation levels decreased significantly during the cessation period. Conclusion: Our findings replicate the findings of previous studies that BDNF plasma levels are altered in smokers. Furthermore, BDNF expression and gene methylation are altered during the first 14 days of cessation. Our novel findings of dysregulated methylation patterns in exon IV of the BDNF gene further support the thesis that BDNF plays a role in nicotine dependence.

Distinct promoter regions of the oxytocin receptor gene are hypomethylated in Prader-Willi syndrome and in Prader-Willi syndrome associated psychosis.

Prader-Willi syndrome (PWS) is a rare neurodevelopmental disorder caused by a loss of usually paternally expressed, maternally imprinted genes located on chromosome 15q11-q13. Individuals with PWS display a specific behavioral phenotype and have a higher susceptibility than the general population for certain psychiatric conditions, especially psychosis. An impairment of the oxytocin system has been described in Prader-Willi syndrome, but has not yet been investigated in detail on the epigenetic level. Recent studies have pointed out altered methylation patterns of the oxytocin receptor gene (OXTR) in various psychiatric disorders, including psychosis. In this study, we investigated methylation rates of CpG dinucleotides in the promoter region of the oxytocin receptor gene via bisulfite-sequencing using DNA extracted from peripheral blood samples of 31 individuals with PWS and 14 controls matched for age, sex, and BMI. Individuals with PWS show significantly lower methylation in the intron 1 region of the OXTR than neurotypical controls (p = 0.012). Furthermore, male PWS subjects with psychosis show significantly lower methylation of the OXTR exon 1 region than those without psychosis (p = 0.002). Transcription factor binding site analysis revealed E2F1 as a transcription factor potentially binding to the exon 1 region. E2F1 is physiologically regulated by Necdin, an anti-apoptotic protein whose corresponding gene is located within the PWS locus. This study provides evidence of a disruption of the Oxytocin system on an epigenetic level in PWS in general and in individuals with PWS and psychosis.

Neurohumoral Profiles and Childhood Adversity of Patients with Multisomatoform Disorder and Pain as the Leading Bodily Symptom.

OBJECTIVE: Patients suffering from chronic pain often present with multifactorial underlying conditions, sometimes without concrete pathological physical findings. Functional somatic syndromes (FSS) and somatoform disorders show a high prevalence of 8-20% and are often associated with adverse childhood experiences (ACE) and chronic stress. As many different FSS have overlapping symptoms, the concept of multisomatoform disorder (MSD) has been introduced as an encompassing concept. We hypothesize that a common neurohumoral profile is present in patients with MSD that is distinct from gender- and age-matched controls and thus provides insight into possible common underlying mechanisms. DESIGN: In 151 patients with MSD (138 females) and 149 matched controls (131 females), we determined ACE by the Childhood Trauma Questionnaire (CTQ) and chronic stress by the Trier Inventory for Chronic Stress (TICS). Furthermore, the serum levels of leptin, FSH, LH, cortisol, DHEA-S, and IGF-1 have been assessed. RESULTS: There were significant differences in the levels of leptin, FSH, IGF-1, and cortisol between patients and controls, mainly driven by female participants. Levels of leptin were significantly correlated with BMI in patients, in controls, and in the female subgroup. This correlation was exaggerated in female patients when compared to female controls. Both CTQ and TICS predicted MSD directly and indirectly through the levels of leptin. CONCLUSION: There is evidence of a distinct neurohumoral profile in female patients with MSD when compared to matched healthy controls, similar to what has been demonstrated in other chronic pain states. The observed profile can be taken as possible evidence for a dysregulated response to chronic stress and metabolic balance as well as a state of hypocortisolism and HPA-axis dysfunction. ACE and chronic stress play a major role in the development of MSD and altered neurohumoral profile.

Leptin promoter methylation in female patients with painful multisomatoform disorder and chronic widespread pain.

BACKGROUND: Different functional somatic syndromes (FSS), fibromyalgia (FMS) and other unexplained painful conditions share many common clinical traits and are characterized by troubling and functionally disabling somatic symptoms. Chronic pain is most frequently reported and at the center of patients' level of disease burden. The construct of multisomatoform disorder (MSD) allows to subsume severely impaired patients suffering from FSS, FMS and other unexplained painful conditions to be examined for common underlying processes. Altered leptin levels and a pathological response of the HPA-axis as a result of chronic stress and childhood trauma have been suggested as one of the driving factors of disease development and severity. Previous studies have demonstrated that methylation of the leptin promoter can play a regulatory role in addiction. In this study, we hypothesized that methylation of the leptin promoter is influenced by the degree of childhood traumatization and differs between patients with MSD and controls. A cohort of 151 patients with MSD and 149 matched healthy volunteers were evaluated using clinical and psychometric assessment while methylation level analysis of the leptin promoter was performed using DNA isolated from whole blood. RESULTS: In female controls, we found CpG C-167 to be negatively correlated with leptin levels, whereas in female patients CpG C-289, C-255, C-193, C-167 and methylation cluster (C-291 to C-167) at putative bindings sites for transcription factors Sp1 and c/EBPalpha were negatively correlated with leptin levels. Methylation levels were significantly lower in female patients CpG C-289 compared with controls. When looking at female patients with chronic widespread pain methylation levels were significantly lower at CpG C-289, C-255 and methylation cluster (C-291 to C-167). CONCLUSION: Our findings support the hypothesis that epigenetic regulation of leptin plays a role in the regulation of leptin levels in patients with MSD. This effect is more pronounced in patients with chronic widespread pain.

Differences in the promoter methylation of atrial natriuretic peptide and vasopressin in alcohol use disorder. A longitudinal case-control-study during withdrawal therapy.

BACKGROUND: Both atrial natriuretic peptide (ANP) and vasopressin (VP) influence alcohol intake and withdrawal as well as craving and are also regulated by epigenetic factors. Disturbances in expression and promoter methylation status have been described in patients suffering from alcohol use disorder and alcohol withdrawal therapy. OBJECTIVES: In this study, we wanted to map the progression of cytosine-phosphatidyl-guanine (CpG) methylation of the respective gene promoter of ANP and VP immediately after starting alcohol withdrawal therapy when compared with healthy controls METHODS: We recruited 34 males suffering from alcohol addiction or harmful use alongside 43 healthy male controls. Blood samples for methylation analyses were drawn on days 1, 2, 3, 4, and 7-10. RESULTS: There was no difference in mean methylation for both VP and ANP during withdrawal. There was no difference at the ANP CpG-sites after correction for multiple testing. Regarding VP, methylation was significantly higher at CpG 033, CpG 064, CpG 103, CpG 118, and CpG 194 and significantly lower at CpG 053, CpG 060, and CpG 214 when compared to healthy controls. Via in silico analysis, we identified transcription factor binding sites that could potentially influence methylation-dependent gene transcription. CONCLUSIONS: While there was no change in methylation status during withdrawal, significant differences in average methylation of specific CpG sites were observed for VP. We also identified the role of transcription factors in the context of promoter methylation as one potential mechanism that could explain the differences in VP levels between alcohol-dependent patients and healthy controls.

Prevalence of Child Maltreatment in Adults With Congenital Heart Disease and Its Relationship With Psychological Well-Being, Health Behavior, and Current Cardiac Function.

Background: The prevalence of child maltreatment in adults with congenital heart disease (ACHD) has not been assessed so far. Child maltreatment is a major risk factor for unfavorable behavioral, mental, and physical health outcomes and has been associated with decreased quality of life. Given the increased survival time of ACHD, it is essential to assess factors that may worsen the quality of life and interact with classical cardiovascular risk factors and mental well-being. Methods: In a cross-sectional study, 196 ACHD (mean age 35.21 ± 11.24 y, 44,4% female, 55.6% male) completed a thorough psychiatric and cardiac evaluation. Child maltreatment was assessed using the Childhood Trauma Questionnaire (CTQ) and rates were compared to already existing data from the German general population. Further psychological measurements included the WHO Quality of Life Questionnaire, Hospital Anxiety and Depression Scale (HADS) and assessment of lifestyle factors (exercise, smoking, alcohol consumption, body mass index). To identify a relationship between current cardiac function and child maltreatment, we used logistic regression. Results: ACHD reported significantly higher rates of emotional neglect and emotional abuse and sexual abuse and lower rates of physical neglect when compared to the general German population. In addition, total CTQ-scores, emotional abuse, emotional neglect, physical abuse, and sexual abuse correlated with symptoms of depression, anxiety, and negatively correlated with QoL. Furthermore, CTQ scores contributed significantly in predicting higher New York Heart Association (NYHA) scores (p = 0.009). Conclusion: Child maltreatment is more common in ACHD and associated with decreased quality of life and depression and anxiety. Furthermore, we found evidence that self-reported child maltreatment is associated with decreased cardiac function. Given the longer survival time of patients with ACHD, identifying factors that may negatively influence the disease course is essential. The negative consequences of child maltreatment may be the subject of psychosocial interventions that have demonstrated efficacy in treating posttraumatic stress disorders.

Epigenetic Regulation of Neural Transmission after Cerebellar Fastigial Nucleus Lesions in Juvenile Rats.

Structural and functional abnormalities in the cerebellar midline region, including the fastigial nucleus, have been reported in neuropsychiatric disorders, also comprising the cerebellar cognitive affecting syndrome. In rats, early fastigial lesions reduce social interaction during development and lead to cognitive and emotional deficits in adults, accompanied by compromised neuronal network activity. Since epigenetic mechanisms are implicated in the etiology of neuropsychiatric disorders, we investigated whether fastigial nucleus lesions in juvenile rats would impact epigenetic regulation of neural transmission. The fastigial nucleus was lesioned bilaterally in 23-day-old male rats. Sham-lesion and naïve rats served as controls. DNA methylation was investigated for target genes of the GABAergic, dopaminergic, glutamatergic and oxytocinergic systems in brain regions with anatomic connections to the fastigial nucleus, i.e., medial prefrontal cortex, nucleus accumbens, striatum, thalamus, and sensorimotor cortex. Protein expression was examined for the respective target genes in case of altered DNA methylation between lesion and control groups. Lesioning of the fastigial nucleus led to significant differences in the epigenetic regulation of glutamate decarboxylase 1 and the oxytocin receptor in the nucleus accumbens and the prefrontal cortex. No differences were found for the other target genes and brain regions. Our findings indicate that epigenetic dysregulation after lesioning of the fastigial nucleus may influence long-term recovery and the emergence of behavioral changes. Together with previous behavioral and electrophysiological investigations of this rat model, these observations can play a role in the cerebellar cognitive affective syndrome and other neuropsychiatric disorders.

[Central pontine myelinolysis during qualified alcohol withdrawal therapy. A case report]. / Das Auftreten der zentralen pontinen Myelinolyse während des qualifizierten Entzugs von Alkohol. Ein Fallbericht.

Central pontine myelinolysis is a rare but severe disease that often occurs in alcohol-dependent and malnourished patients. One pathological mechanism is the rapid correction of chronic hyponatremia, even though the disease can occur independently of decreased serum sodium levels. Here, we present a patient suffering from malnutrition, alcohol dependency, and a severe depressive disorder, who presented himself to our clinic wishing for qualified withdrawal treatment. Because the patient reported significant weight loss and nocturnal sweating without fever, we performed different diagnostic investigations and examinations. Cranial MRI revealed the presence of a central pontine myelinolysis. In the clinical neurological examination, the patient only showed slight gait ataxia. The depressive symptoms had improved while the patient now showed problems in his short-term memory. At presentation, only slight hyponatremia was present, while no rapid correction occurred throughout treatment. The presented case reveals the importance of considering osmotic demyelination disorders as a differential diagnosis in patients suffering from neurological symptoms during alcohol withdrawal therapy. This is important independently of hyponatremia.

The effect of sex on suicide risk during and after psychiatric inpatient care in 12 countries-An ecological study.

BACKGROUND: Suicide risk in patients is markedly elevated during psychiatric inpatient care, as well as after discharge. However, it is unclear whether, and to what extent, this increased suicide risk varies between sex. Thus, the aim of this study was to analyze sex differences for suicides during and after psychiatric hospitalization in various countries. METHODS: National suicide mortality rates and inpatient-related suicide rates (three intervals: during psychiatric inpatient treatment, 1 month, and 1 year after discharge) from 12 countries for 2000-2016 were analyzed, and a logistic model was used to quantify the effect of sex. RESULTS: Persons admitted to or discharged from psychiatric inpatient care exhibited significantly increased rates of suicide compared to those in the general population. Furthermore, increase of suicide risk was significantly higher for females than for males for all investigated time intervals (inpatient suicide odds ratio [OR] 1.85; suicide within 1 month after discharge-OR 1.94; suicide within 1 year after discharge-OR 2.04). CONCLUSION: Analysis confirmed the time during and after psychiatric inpatient care to be significantly associated with an elevated risk for suicide. Further, a significant sex effect was observed, with females in this population being at a proportionally higher risk for suicide during psychiatric inpatient treatment as well as the year following discharge. Our study implicates that more effective suicide preventive measures during inpatient stay, focusing on female patients, are needed.

[Addictive disorders in physicians]. / Abhängigkeitserkrankungen bei Ärzten.

Despite their knowledge about the risks and treatment options for substance abuse disorders, physicians are not immune to them. Meanwhile, a number of studies have shown that physicians have an increased risk of depression, addictive diseases and burnout due to the occupation-linked mental and physical burden and in particular an increased prevalence of substance-related disorders, especially alcohol abuse or dependence and drug abuse. Drug dependence among physicians seems to be even higher than in the general population due to the relatively easy access to psychoactive medications, in particular hypnotic drugs, benzodiazepines, ketamine and opioids; however, the prognosis is good. According to data from the medical associations, three quarters of those affected for the first time and every sixth relapsed physician can be helped with preservation of the license and working as physicians.

DNA-methylation of the dopamin receptor 2 gene is altered during alcohol withdrawal.

The dopaminergic neurotransmission is known to be of crucial importance in addictive behavior. Epigenetic regulation like methylation of DNA influences the function of dopaminergic transmission. The present study investigated alterations of DNA methylation in the dopamine D2 receptor (DRD2)-gene in patients suffering from alcohol dependence. The study sample consists of 99 alcohol dependent males admitted for alcohol withdrawal treatment and a control group of 33 healthy participants. Blood samples underwent bisulfite sequencing to determine levels of DNA-methylation of the promoter region of the DRD2 gene. Mixed linear modeling was used to test differences between patients and controls, course of methylation during detoxification. While DRD2-gene methylation did not differ significantly between patients and controls, we found a significant increase of DRD2-gene methylation during alcohol withdrawal/early abstinence. Craving, measured with the Obsessive Compulsive Drinking Scale (OCDS), was significantly associated with DRD2-gene methylation. Furthermore, smoking significantly influenced DRD2-gene methylation in both, patients and controls. As in other types of addictive disorders, DRD2-gene methylation is altered during alcohol withdrawal/early abstinence. The findings regarding an association with alcohol craving and tobacco consumption point towards a crucial role of DRD2-gene methylation in the neurobiology of addictive behavior.

Thiamine Substitution in Alcohol Use Disorder: A Narrative Review of Medical Guidelines.

AIMS: Patients with alcohol use disorder (AUD) frequently suffer from cognitive deficits ranging from mild symptoms to most severe forms. Wernicke encephalopathy (WE), caused by thiamine deficiency, is a potentially fatal syndrome characterized by the clinical triad of ophthalmoplegia, ataxia, and confusion. WE frequently presents in patients with AUD and, if left untreated, can progress to Wernicke-Korsakoff syndrome, which constitutes severe anterograde amnesia, confabulation, and behavioral abnormalities. Due to oftentimes indistinct clinical presentation, WE remains undiagnosed in up to 80% of cases. We conducted a review of current treatment guidelines for AUD in order to identify recommendations for the use of thiamine. METHODS: Three different keyword combinations ("alcohol treatment guideline," "alcohol withdrawal guideline," and "alcohol treatment recommendation") were entered in PubMed and Scopus, additional guidelines were searched screening the online sites of the respective agencies or societies. In total, 14 guidelines were included. RESULTS: Thiamine was mentioned in all but one of the reviewed publications. Specifications on application modalities and indications varied considerably. While the majority of reviewed guidelines recommended parenteral thiamine only for patients at high risk for WE, some gave no information regarding the application form or dosage. CONCLUSION: Substitution of parenteral thiamine in individuals with suspected WE is a well-established treatment regimen. However, suggestions according to guidelines vary widely. Furthermore, hardly any evidence-based recommendations exist on a more general use of thiamine as a preventative intervention in individuals with AUD. Further research is of utmost importance to raise awareness for this potentially undervalued problem.

DNA Methylation of the Leptin Gene Promoter is Altered by Chronic Alcohol Exposure in an Animal Model for Alcohol Dependence.

Appetite-regulating peptides, such as leptin, are linked to craving and have been in the focus of alcohol dependence research for years. The objective of our study was to investigate the dynamics of leptin gene promoter methylation during alcohol withdrawal and specific treatment in a rodent (rat) model for alcohol dependence. DNA methylation was measured using direct bisulfite sequencing at 0 h, 24 h, and 6 days of alcohol withdrawal as well as after treatment with alpha-melanocyte-stimulating hormone (alpha-MSH), Beta-Endorphin, or saline. We found significantly lower methylation levels in alcohol-consuming animals compared to alcohol-naïve animals. During 6 days of alcohol deprivation, this difference in methylation vanished. Leptin methylation of the alpha-MSH-treated group and 6 days alcohol-deprived animals was significantly higher than that in saline-treated animals, possibly indicating compensatory effects of the treatment. Our results further expand on previous findings from human studies that explain leptin's role in bridging the gap between alcohol consumption and appetite regulation.