Group based metacognitive therapy for alcohol use disorder: a pilot study.

Introduction: Alcohol use disorder (AUD) is a severe clinical disorder, which has been associated with 5.3% of death worldwide. Although several treatments have been developed to improve AUD symptomatology, treatment effects were moderate, with a certain amount of patients displaying symptom deterioration after treatment termination. Moreover, outpatient treatment placements become increasingly scarce, thus necessitating more efficient treatment options. Therefore, the aim of the present study was to investigate the efficacy, feasibility, and acceptability of a newly invented, short, group based metacognitive therapy (MCT) for patients diagnosed with AUD. Method: Seven patients were treated with eight sessions of group based MCT using a single case series design with an A-B replication across patients. Patients were assessed one month and one week before treatment, as well as one week and three months after treatment termination. Results: Patients improved significantly and with large effect sizes regarding dysfunctional metacognitive beliefs, desire thinking/craving and depressive symptoms up to three months after treatment termination. AUD symptomatology as well as positive and negative metacognitive beliefs improved at post-treatment, but improvements could not be maintained at follow-up. All included patients completed the treatment and were highly satisfied. Conclusion: The presented findings show preliminary evidence for the efficacy, feasibility, and acceptability of the implemented group based MCT treatment. Large scale randomized controlled trials (RCTs) are needed to confirm the effectiveness of the developed program for patients diagnosed with AUD.

Paravertebral Block for Multiple Rib Fractures in an Anticoagulated Trauma Patient.

This case report presents the complex analgesia management of a 52-year-old male with a significant medical history including atrial fibrillation treated with apixaban, essential trigeminal neuralgia, non-ischemic cardiomyopathy, and chronic systolic heart failure. The patient experienced a loss of control while riding a motorized bicycle, resulting in a fall and head injury with no loss of consciousness. Upon admission, he tested positive for ethanol, cannabinoids, and oxycodone. The physical exam was significant for right cephalohematoma and right elbow hematoma. Imaging revealed multiple injuries, including right rib fractures (T3-12) with hemothorax. Right paravertebral catheters were placed in the intensive care unit (ICU).

The Continuing Challenges of Studying Parallel Behaviours in Humans and Animal Models.

The use of animal models continues to be essential for carrying out research into clinical phenomena, including addiction. However, the complexity of the clinical condition inevitably means that even the best animal models are inadequate, and this may go some way to account for the apparent failures of discoveries from animal models, including the identification of potential novel therapies, to translate to the clinic. We argue here that it is overambitious and misguided in the first place to attempt to model complex, multifacetted human disorders such as addiction in animals, and especially in rodents, and that all too frequently "validity" of such models is limited to superficial similarities, referred to as "face validity", that reflect quite different underlying phenomena and biological processes from the clinical situation. Instead, a more profitable approach is to identify (a) well-defined intermediate human behavioural phenotypes that reflect defined, limited aspects of, or contributors to, the human clinical disorder, and (b) to develop animal models that are homologous with those discrete human behavioural phenotypes in terms of psychological processes, and underlying neurobiological mechanisms. Examples of past and continuing weaknesses and suggestions for more limited approaches that may allow better homology between the test animal and human condition are made.

Synaptic Mechanisms of Ethanol Tolerance and Neuroplasticity: Insights from Invertebrate Models.

Alcohol tolerance is a neuroadaptive response that leads to a reduction in the effects of alcohol caused by previous exposure. Tolerance plays a critical role in the development of alcohol use disorder (AUD) because it leads to the escalation of drinking and dependence. Understanding the molecular mechanisms underlying alcohol tolerance is therefore important for the development of effective therapeutics and for understanding addiction in general. This review explores the molecular basis of alcohol tolerance in invertebrate models, Drosophila and C. elegans, focusing on synaptic transmission. Both organisms exhibit biphasic responses to ethanol and develop tolerance similar to that of mammals. Furthermore, the availability of several genetic tools makes them a great candidate to study the molecular basis of ethanol response. Studies in invertebrate models show that tolerance involves conserved changes in the neurotransmitter systems, ion channels, and synaptic proteins. These neuroadaptive changes lead to a change in neuronal excitability, most likely to compensate for the enhanced inhibition by ethanol.

Sex differences in dorsolateral prefrontal cortical and superior colliculus activities support the impact of alcohol use severity and sleep deficiency on two-back memory.

Background: Working memory refers to a process of temporary storage and manipulation of information to support planning, decision-making, and action. Frequently comorbid alcohol misuse and sleep deficiency have both been associated with working memory deficits. However, how alcohol misuse and sleep deficiency interact to impact working memory remains unclear. In this study, we aim to investigate the neural processes inter-relating alcohol misuse, sleep deficiency and working memory. Methods: We curated the Human Connectome Project (HCP) dataset and investigated the neural correlation of working memory in link with alcohol use severity and sleep deficiency in 991 young adults (521 women). The two were indexed by the first principal component (PC1) of principal component analysis of all drinking metrics and Pittsburgh Sleep Quality Index (PSQI) score, respectively. We processed the imaging data with published routines and evaluated the results with a corrected threshold. We used path model to characterize the inter-relationship between the clinical, behavioral, and neural measures, and explored sex differences in the findings. Results: In whole-brain regression, we identified ß estimates of dorsolateral prefrontal cortex response (DLPFC ß) to 2- vs. 0-back in correlation with PC1. The DLPFC showed higher activation in positive correlation with PC1 across men and women (r=0.16, P<0.001). Path analyses showed the model PC1 → DLPFC ß â†’ differences in reaction time (2- minus 0-back; RT2-0) of correct trials → differences in critical success index (2- minus 0-back; CSI2-0) with the best fit. In women alone, in addition to the DLPFC, a cluster in the superior colliculus (SC) showed a significant negative correlation with the PSQI score (r=-0.23, P<0.001), and the path model showed the inter-relationship of PC1, PSQI score, DLPFC and SC ß's, and CSI2-0 in women. Conclusions: Alcohol misuse may involve higher DLPFC activation in functional compensation, whereas, in women only, sleep deficiency affects 2-back memory by depressing SC activity. In women only, path model suggests inter-related impact of drinking severity and sleep deficiency on 2-back memory. These findings suggest potential sex differences in the impact of drinking and sleep problems on working memory that need to be further investigated.

Changes of attentional bias in patients with alcohol use disorder during abstinence: A longitudinal study.

BACKGROUND: Alcohol Use Disorder (AUD) is linked to an attentional bias towards alcohol-related cues (e.g. images, smells), which acquire incentive properties and promote continued consumption. METHOD: We investigated how the general and alcohol attentional bias evolved longitudinally in AUD patients along two periods of abstinence: t = 0 (baseline, 1-3 months of abstinence) and t = 1 (follow-up; 6 months of abstinence), as well as their relationship with alcohol-related variables. General and alcohol-specific attentional bias were evaluated by the Classic and the Alcohol Stroop tests (neutral and alcohol conditions) in abstinent AUD patients and controls. RESULTS: At t = 0, the AUD group exhibited both general and alcohol-specific attentional biases, with greater effect in the general bias. At t = 1, alcohol-specific attentional bias decreased specifically in the AUD group and reached control levels (with interference index levels increasing from 1-3 months to 6 months). However, general attentional bias showed a trend toward improvement but it did not significantly change through abstinence process (linear mixed models, controlling for age, BMI, sex and education). CONCLUSIONS: In AUD patients, general and alcohol attentional biases exhibit different trajectories during abstinence, with the attentional bias toward alcohol improving significantly throughout this process whereas general attentional bias is maintained.

Low-dose ondansetron: A candidate prospective precision medicine to treat alcohol use disorder endophenotypes.

BACKGROUND: Alcohol use disorder (AUD) is among the leading causes of morbidity and mortality worldwide, and over 95 million people live with alcohol dependence globally. The estimated heritability of AUD is 50-60 %, and multiple genes are thought to contribute to various endophenotypes of the disease. Previous clinical trials support a precision medicine approach using ondansetron (AD04, a 5-HT3 antagonist) by segregating AUD populations by the bio-genetic endophenotype of specific serotonergic genotypes and the bio-psychosocial endophenotype of the severity of drinking or both. By targeting the modulation of biogenetic signaling within the biopsychosocial context of AUD, low-dose AD04 holds promise in reducing alcohol consumption among affected individuals while minimizing adverse effects. METHODS: This was a phase III, 6-month, 25-site, randomized, placebo-controlled clinical trial using AD04 to treat DSM-V-categorized AUD individuals who were pre-stratified into the endophenotypes of heavy or very heavy drinking individuals and possessed a pre-defined profile of genetic variants related to the serotonin transporter and serotonin-3AB receptor. Participants (N = 303) presented moderate to severe AUD, >80 % were men, mostly in their fifties, and >95 % were of European descent. Low-dose AD04 (approx. 033 mg twice daily) or a matching placebo was administered twice daily for 6 months. Brief Behavioral Compliance Enhancement Treatment (BBCET [53]) was administered every two weeks to enhance medication compliance and clinic attendance. RESULTS: There was a significant reduction in the monthly percentage of heavy drinking days, PHDD (-46·7 % (2·7 %), 95 %CI: -52·1 % to -41·2 % vs. -38·1 % (2·9 %), 95 %CI: -43·8 % to -32·5 %, respectively; LS mean difference=-8·5 %; p = 0.03) among AD04-treated vs. placebo-receiving heavy drinking individuals at month 6. Heavy drinking individuals were also less likely to be diagnosed with AUD [Month 1: -32·0 % (2·8 %), 95 %CI: -37·5 % to -26·5 % vs. -23·2 % (2·9 %), 95 %CI: -28·9 to -17·5 %; LS mean difference= -8·8 %; p = 0·026)], and improved on the WHO quality of life BREF scale with a significant effect for at least a 1-level downward shift (OR = 3.4; 95 % CI: 1·03-11·45, p = 0·044). Importantly, heavy drinking individuals, as distinct from very heavy drinking individuals, were the bio-psychosocial endophenotype more predictive of therapeutic response to AD04. AD04 had an exceptional safety and tolerability profile, like the placebo's. CONCLUSIONS: In this Phase 3 clinical trial, AD04 was shown to be a promising treatment for currently drinking heavy drinking individuals with AUD who also possess a specific genotypic profile in the serotonin transporter and serotonin-3AB receptor complex. Using AD04 to reduce the harm of AUD in heavy drinking individuals who are currently drinking, without the necessity of abstinence or detoxification from alcohol use, is an important advance in the field of precision medicine. AD04's adverse events profile, which was like placebo, should enhance accessibility and acceptance of modern medical treatment for AUD by lowering the incorrect but commonly perceived stigma of personal failure.

Effect of the glucagon-like peptide-1 (GLP-1) receptor agonist semaglutide on alcohol consumption in alcohol-preferring male vervet monkeys.

RATIONALE: Glucagon-like peptide-1 (GLP-1) receptor agonists reduce alcohol consumption in rodents and non-human primates. Semaglutide is a new long-acting GLP-1 receptor agonist, widely used in the clinic against type 2 diabetes and obesity. It is also reported to reduce alcohol intake in rodents. OBJECTIVES: This study investigates the possible inhibitory effect of semaglutide on alcohol intake in alcohol-preferring African green monkeys. METHODS: We performed a vehicle-controlled study on male monkeys that had demonstrated a preference for alcohol. In the monkeys selected for voluntary alcohol drinking, alcohol consumption was measured for ten days at baseline (Monday to Friday for two weeks). During this period, the monkeys had access to alcohol 4 h per day and free access to water 24 h per day. After two weeks of baseline measurements, the monkeys were randomized to semaglutide or vehicle. Each group consisted of ten monkeys, and the two groups were balanced with respect to baseline alcohol intake. Following the baseline period, the monkeys were treated with escalating doses of semaglutide (up to 0.05 mg/kg) or vehicle subcutaneously twice weekly for two weeks during which period alcohol was not available. After uptitration, the monkeys had access to alcohol 4 h daily for 20 days (Monday to Friday for 4 weeks), and alcohol consumption was measured. During this alcohol exposure period, treatment with semaglutide (0.05 mg/kg twice weekly) or vehicle continued for three weeks followed by a one-week washout period. RESULTS: Compared to the vehicle, semaglutide significantly reduced alcohol intake. There were no signs of emetic events or changes in water intake. CONCLUSIONS: These data demonstrate for the first time the potent effect of semaglutide in reducing voluntary alcohol intake in non-human primates and further substantiate the need for clinical trials investigating the effect of semaglutide in patients with alcohol-use disorder.

Study on the efficiency of virtual reality in the treatment of alcohol use disorder: study protocol for a randomized controlled trial : E-Reva.

CONTEXT: According to the World Health Organization, alcohol is a major global public health problem, leading to a significant increase in illness and death. To treat alcohol use disorders, new therapeutic tools are being promoted, among which virtual reality (VR) shows promise. Previous research has demonstrated the efficacy of VR in reducing alcohol cravings in patients, but there is a lack of data on its effectiveness in maintaining abstinence or reducing consumption in recently abstinent individuals. The E-Reva study aims to compare the efficacy of a treatment strategy combining virtual reality cue exposure therapy (VR-CET) and cognitive behavioral therapy (CBT) with conventional CBT in reducing alcohol consumption and craving in patients with alcohol use disorder (AUD). In addition to this primary objective, the study will compare the effects of VR-CET combined with CBT on anxiety, depression, rumination, and feelings of self-efficacy versus conventional CBT. METHODS: This prospective randomized controlled trial will be conducted over 8 months in four addiction departments in France. It includes two parallel groups: i) the VR-CET + CBT group, and ii) the CBT-only group, which serves as a control group. Participants will be recruited by the investigating doctor in the addiction centers. The sample will consist of 156 patients diagnosed with AUD and abstinent for at least 15 days. Both treatment groups will participate in four group CBT sessions followed by four individual sessions: i) the VR-CET group will be exposed to virtual environments associated with alcohol-related stimuli, ii) the CBT-only group will receive traditional CBT sessions. After completion of the 8 sessions, patients will be followed up for 6 months. The primary outcome is the cumulative number of standard drinks consumed at 8 months, assessed using the TLFB method. DISCUSSION: Despite the promise of VR-CET to reduce the desire to drink, the effect on alcohol consumption remains uncertain in the existing literature. Our protocol aims to address the limitations of previous research by increasing sample size, targeting consumption reduction, and incorporating neutral environments. E-Reva aims to enrich the literature on the use of VR in the treatment of AUD and open new perspectives for future interventions. TRIAL REGISTRATION: ClinicalTrials.gov ID NCT06104176, Registered 2023/11/13 ( https://clinicaltrials.gov/study/NCT06104176?id=NCT06104176&rank=1 ). N° IDRCB: 2022-A02797-36. Protocol version 1.0, 12/05/2023.

Potential Link Between Exercise and N-Methyl-D-Aspartate Glutamate Receptors in Alcohol Use Disorder: Implications for Therapeutic Strategies.

Alcohol use disorder (AUD) is a significant risk factor, accounting for approximately 13% of all deaths in the US. AUD not only destroys families but also causes economic losses due to reduced productivity, absenteeism, and healthcare expenses. Statistics revealing the sustained number of individuals affected by AUD over the years underscore the need for further understanding of the underlying pathophysiology to advance novel therapeutic strategies. Previous research has implicated the limbic brain regions N-methyl-D-aspartate glutamate receptors (NMDAR) in the emotional and behavioral effects of AUD. Given that aerobic exercise can modulate NMDAR activity and sensitivity to alcohol, this review presents a summary of clinical and basic science studies on NMDAR levels induced by alcohol consumption, as well as acute and protracted withdrawal, highlighting the potential role of aerobic exercise as an adjunctive therapy for AUD. Based on our findings, the utility of exercise in the modulation of reward-linked receptors and AUD may be mediated by its effects on NMDA signaling. These data support further consideration of the potential of aerobic exercise as a promising adjunctive therapy for AUD.

Reward, relief, and habit drinking profiles in treatment seeking individuals with an AUD.

AIMS: This study aimed to compare reward, relief, and habit treatment-seeking individuals on recent drinking, alcohol use disorder (AUD) phenomenology, and mood. The second aim of the study was to evaluate the predictive validity of reward, relief, and habit profiles. METHOD: Treatment-seeking individuals with an AUD (n = 169) were recruited to participate in a medication trial for AUD (NCT03594435). Reward, relief, and habit drinking groups were assessed using the UCLA Reward Relief Habit Drinking Scale. Group differences at baseline were evaluated using univariate analyses of variance. A subset of participants were enrolled in a 12-week, double-blind, placebo-controlled medication trial (n = 102), and provided longitudinal drinking and phenomenology data. The predictive validity of group membership was assessed using linear regression analyses. RESULTS: At baseline, individuals who drink primarily for relief had higher craving and negative mood than those who drink for reward and habit. Prospectively, membership in the relief drinking group predicted greater alcohol use, greater heavy drinking, and fewer days abstinent compared to those in the reward drinking group. Membership in the relief drinking group also predicted greater alcohol craving, more alcohol-related consequences, and more anxiety symptoms over 12 weeks compared to those in the reward drinking group. CONCLUSIONS: This study provides support for reward and relief drinking motive profiles in treatment-seeking individuals with an AUD. Membership in the relief drinking motive group was predictive of poorer drinking outcomes and more negative symptomology over 12 weeks, indicating that individuals who drink for relief may be a particularly vulnerable sub-population of individuals with AUD.

Profiles and the impact of affective temperaments on alcohol use disorder: a cross-sectional study.

AIMS: This study aimed to explore the profiles and impact of affective temperaments, together with social and clinical backgrounds, including affective symptoms, in patients with alcohol use disorder (AUD). METHODS: This study included 314 low-risk drinkers and 257 patients with AUD. To assess affective temperament, we used the short version of the temperament evaluation of Memphis, Pisa, Paris, and San Diego. To evaluate depressive and mixed symptoms, the quick inventory of depressive symptomatology self-report Japanese version and 12-item questionnaire for the quantitative assessment of the depressive mixed state were used. We compared the profiles of affective temperaments as well as social and clinical backgrounds, including affective symptoms, between the two groups and further performed logistic regression analyses to explore the factors contributing to AUD. RESULTS: Our analysis showed higher cyclothymic, hyperthymic, and irritable temperament scores and lower depressive temperament scores in patients with AUD than that in nonclinical drinkers. Regarding other social and clinical backgrounds, patients with AUD were less educated and employed and more experienced depressive and mixed symptoms. Logistic regression analysis identified hyperthymic temperament as a positive contributor and depressive temperament as a negative contributor to AUD. CONCLUSIONS: Our findings indicated potential bipolarity in patients with AUD, as manifested by a more hyperthymic temperament in contrast to less depressive temperament. Despite their self-perceived adaptive temperament profiles, patients showed poorer social outcomes and more affective symptoms. This gap may be partly explained by a lack of insight unique to AUD psychology, which potentially disturbs problem recognition.

Correlations of the CNR1 Gene with Personality Traits in Women with Alcohol Use Disorder.

Alcohol use disorder (AUD) is a significant issue affecting women, with severe consequences for society, the economy, and most importantly, health. Both personality and alcohol use disorders are phenotypically very complex, and elucidating their shared heritability is a challenge for medical genetics. Therefore, our study investigated the correlations between the microsatellite polymorphism (AAT)n of the Cannabinoid Receptor 1 (CNR1) gene and personality traits in women with AUD. The study group included 187 female subjects. Of these, 93 were diagnosed with alcohol use disorder, and 94 were controls. Repeat length polymorphism of microsatellite regions (AAT)n in the CNR1 gene was identified with PCR. All participants were assessed with the Mini-International Neuropsychiatric Interview and completed the NEO Five-Factor and State-Trait Anxiety Inventories. In the group of AUD subjects, significantly fewer (AAT)n repeats were present when compared with controls (p = 0.0380). While comparing the alcohol use disorder subjects (AUD) and the controls, we observed significantly higher scores on the STAI trait (p < 0.00001) and state scales (p = 0.0001) and on the NEO Five-Factor Inventory Neuroticism (p < 0.00001) and Openness (p = 0.0237; insignificant after Bonferroni correction) scales. Significantly lower results were obtained on the NEO-FFI Extraversion (p = 0.00003), Agreeability (p < 0.00001) and Conscientiousness (p < 0.00001) scales by the AUD subjects when compared to controls. There was no statistically significant Pearson's linear correlation between the number of (AAT)n repeats in the CNR1 gene and the STAI and NEO Five-Factor Inventory scores in the group of AUD subjects. In contrast, Pearson's linear correlation analysis in controls showed a positive correlation between the number of the (AAT)n repeats and the STAI state scale (r = 0.184; p = 0.011; insignificant after Bonferroni correction) and a negative correlation with the NEO-FFI Openness scale (r = -0.241; p = 0.001). Interestingly, our study provided data on two separate complex issues, i.e., (1) the association of (AAT)n CNR1 repeats with the AUD in females; (2) the correlation of (AAT)n CNR1 repeats with anxiety as a state and Openness in non-alcohol dependent subjects. In conclusion, our study provided a plethora of valuable data for improving our understanding of alcohol use disorder and anxiety.

The association between ketamine and esketamine with alcohol and substance misuse: Reports to the Food and Drug Administration adverse event reporting system (FAERS).

INTRODUCTION: Ketamine and esketamine have been proven to be effective in treating adults with treatment resistant depression (TRD). Preliminary evidence indicates that, when combined with behavioral and psychological interventions, both agents may offer benefits for individuals with substance use disorder (SUD) and alcohol use disorder (AUD). Notwithstanding, concerns have been raised as to whether either or both agents are associated with abuse and/or gateway activity. METHODS: Herein, we evaluate disproportionate reporting expressed as reporting odds ratios (ROR) for esketamine and ketamine. The outcomes of interest include alcohol problem, alcoholism, alcohol abuse, substance dependence, SUD, substance abuse, drug dependence, drug use disorder and drug abuse as codified by the Medical Dictionary for Regulatory Activities (MedDRA) within the FAERS. The IC025 values were significant for ketamine in cases of alcohol abuse (0.28), substance dependence (1.88), substance use disorder (0.996), substance abuse (0.61), drug dependence (0.56), drug use disorder (1.17) and drug abuse (1.22). Additionally, oxycontin showed significant IC025 values for substance dependence (0.067), substance use disorder (0.094), substance abuse (0.035), and drug dependence (0.27). RESULTS: We observed significant increases in the reporting odds ratios (RORs) for ketamine with respect to various outcomes: alcohol abuse (ROR 2.84, 95 % CI 1.53-5.28; p = 0.0010), substance dependence (ROR 18.72, 95 % CI 8.49-41.30; p ≤ 0.0001), SUD (ROR 11.40, 95 % CI 4.24-30.65; p ≤ 0.0001), substance abuse (ROR 2.29, 95 % CI 1.73-3.04; p ≤ 0.0001), drug dependence (ROR 1.99, 95 % CI 1.64-2.42; p ≤ 0.0001), drug use disorder (ROR 4.50, 2.94-6.88; p ≤ 0.0001) and drug abuse (ROR 3.72, 3.36-4.12; p ≤ 0.0001). For esketamine, we observed that the ROR was significantly reduced for substance abuse (ROR 0.37, 95 % CI 0.22-0.63; p = 0.0003), drug dependence (ROR 0.13, 95 % CI 0.076-0.23; p ≤ 0.0001) and drug abuse (ROR 0.048, 95 % CI 0.030-0.078; p ≤ 0.0001). To our knowledge, this is the first report of spontaneous adverse events related to these outcomes of interest in the FAERS. CONCLUSION: Mixed RORs were observed across aspects of SUD and AUD for both ketamine and esketamine. Due to limitations in the FAERS, establishing causal links between new onset alcohol and substance misuse with either agent remains inconclusive. Possible beneficial effects on measures of SUD and AUD were observed. It is currently unclear, but possible, whether both agents have differential ameliorative effects across dimensions of SUD and AUD, which is a focus of ongoing research.

Analysis of antimicrobial drug usage in psychiatric specialized hospitals during the pandemic in China.

BACKGROUND: This study aims to compare antimicrobial drug usage in our hospital to Jiangsu Province and China from 2020 to 2022. RESEARCH DESIGN AND METHODS: A detailed analysis was performed using data from the National Antimicrobial Drug Clinical Application Monitoring Network. Several parameters were studied: the rate of antimicrobial drug use, number and types of drugs used, the rate of combined use, rate of microbiological examinations, drug use intensity, and cumulative Defined Daily Doses (DDDs). RESULTS: From 2020 to 2022, our hospital's antimicrobial drug usage rate was consistently lower than Jiangsu Province and China. The average number of drug types and the combined drug use rate were higher in 2020 but fell below those in Jiangsu Province and China in 2021 and 2022. Our microbiological examination rate consistently surpassed that of Jiangsu Province and China. Furthermore, our Antimicrobial Usage Density and cumulative DDDs were notably lower. While AUD remained stable, DDDs showed a decreasing trend. The most dominant drug in DDDs was cefditoren, a third-generation cephalosporin. CONCLUSIONS: During the pandemic years, our hospital not only met the requirements for antimicrobial drug usage, microbiological examination, AUD, and cumulative DDDs but also demonstrated a consistent year-by-year decrease in drug usage and DDDs.

PCSK9 inhibition attenuates alcohol-associated neuronal oxidative stress and cellular injury.

Alcohol Use Disorder (AUD) is a persistent condition linked to neuroinflammation, neuronal oxidative stress, and neurodegenerative processes. While the inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) has demonstrated effectiveness in reducing liver inflammation associated with alcohol, its impact on the brain remains largely unexplored. This study aimed to assess the effects of alirocumab, a monoclonal antibody targeting PCSK9 to lower systemic low-density lipoprotein cholesterol (LDL-C), on central nervous system (CNS) pathology in a rat model of chronic alcohol exposure. Alirocumab (50 mg/kg) or vehicle was administered weekly for six weeks in 32 male rats subjected to a 35 % ethanol liquid diet or a control liquid diet (n = 8 per group). The study evaluated PCSK9 expression, LDL receptor (LDLR) expression, oxidative stress, and neuroinflammatory markers in brain tissues. Chronic ethanol exposure increased PCSK9 expression in the brain, while alirocumab treatment significantly upregulated neuronal LDLR and reduced oxidative stress in neurons and brain vasculature (3-NT, p22phox). Alirocumab also mitigated ethanol-induced microglia recruitment in the cortex and hippocampus (Iba1). Additionally, alirocumab decreased the expression of pro-inflammatory cytokines and chemokines (TNF, CCL2, CXCL3) in whole brain tissue and attenuated the upregulation of adhesion molecules in brain vasculature (ICAM1, VCAM1, eSelectin). This study presents novel evidence that alirocumab diminishes oxidative stress and modifies neuroimmune interactions in the brain elicited by chronic ethanol exposure. Further investigation is needed to elucidate the mechanisms by which PCSK9 signaling influences the brain in the context of chronic ethanol exposure.

Role of histaminergic regulation of astrocytes in alcohol use disorder.

Alcohol use disorder (AUD) is a severe, yet not fully understood, mental health problem. It is associated with liver, pancreatic, and gastrointestinal diseases, thereby highly increasing the morbidity and mortality of these individuals. Currently, there is no effective and safe pharmacological therapy for AUD. Therefore, there is an urgent need to increase our knowledge about its neurophysiological etiology to develop new treatments specifically targeted at this health condition. Recent findings have shown an upregulation in the histaminergic system both in alcohol dependent individuals and in animals with high alcohol preference. The use of H3 histaminergic receptor antagonists has given promising therapeutic results in animal models of AUD. Interestingly, astrocytes, which are ubiquitously present in the brain, express the three main histamine receptors (H1, H2 and H3), and in the last few years, several studies have shown that astrocytes could play an important role in the development and maintenance of AUD. Accordingly, alterations in the density of astrocytes in brain areas such as the prefrontal cortex, ventral striatum, and hippocampus that are critical for AUD-related characteristics have been observed. These characteristics include addiction, impulsivity, motor function, and aggression. In this work, we review the current state of knowledge on the relationship between the histaminergic system and astrocytes in AUD and propose that histamine could increase alcohol tolerance by protecting astrocytes from ethanol-induced oxidative stress. This increased tolerance could lead to high levels of alcohol intake and therefore could be a key factor in the development of alcohol dependence.

A Randomized Controlled Pilot Trial of Primary Care Treatment Integrating Motivation and Exposure Treatment (PC-TIME) in Veterans With PTSD and Harmful Alcohol Use.

Individuals with posttraumatic stress disorder (PTSD) often engage in harmful alcohol use. These co-occurring conditions are associated with negative health consequences and disability. PTSD and harmful drinking are typically experienced as closely related-thus treatments that target both simultaneously are preferred by patients. Many individuals with PTSD and harmful alcohol use receive primary care services but encounter treatment barriers in engaging in specialty mental health and substance use services. A pilot randomized controlled trial of a brief integrated treatment for PTSD and harmful drinking versus primary care treatment as usual (PC-TAU) took place in three U.S. Department of Veterans Affairs (VA) primary care clinics. The intervention (primary care treatment integrating motivation and exposure [PC-TIME]) combines motivational interviewing to reduce alcohol use and brief prolonged exposure for PTSD delivered over five brief sessions. Participants (N = 63) were veterans with PTSD and harmful drinking. Multilevel growth curve modeling examined changes in drinking (average number of drinks per drinking day and percentage of heavy drinking days) and self-reported PTSD severity at baseline, 8, 14, and 20 weeks. Participants reported high satisfaction with PC-TIME and 70% (n = 23) completed treatment. As hypothesized, a significantly steeper decrease in self-reported PTSD severity and heavy drinking was evident for participants randomized to PC-TIME compared with PC-TAU. Contrary to expectations, no significant posttreatment differences in PTSD diagnoses were observed. PC-TIME participants were less likely to exceed National Institute for Alcoholism and Alcohol Abuse (NIAAA) guidelines for harmful alcohol use posttreatment compared with PC-TAU participants. PC-TIME is a promising brief, primary care-based treatment for individuals with co-occurring PTSD and harmful alcohol use. A full-scale randomized clinical trial is needed to fully test its effectiveness.

Vulnerable at rest? A resting-state EEG study and psychosocial factors of young adult offspring of alcohol-dependent parents.

BACKGROUND: Offspring of parents with alcohol use disorder (AUD) are more susceptible to developing AUD, with an estimated heritability of around 50%. Vulnerability to AUD in first-degree relatives is influenced by biological factors, such as spontaneous brain activity, and high-risk psychosocial characteristics. However, existing resting-state EEG studies in AUD offspring have shown inconsistent findings regarding theta, alpha, and beta band frequencies. Additionally, research consistently demonstrates an increased risk of internalizing and externalizing disorders, self-regulation difficulties, and interpersonal issues among AUD offspring. METHODS: This study aimed to investigate the absolute power of theta, alpha, and beta frequencies in young adult offspring with a family history of AUD compared to individuals without family history. The psychosocial profiles of the offspring were also examined in relation to individuals without a family history of AUD. Furthermore, the study sought to explore the potential association between differences in frequency bands and psychosocial variables. Resting-state EEG recordings were obtained from 31 young adult healthy offspring of alcohol-dependent individuals and 43 participants with no family history of AUD (age range: 16-25 years). Participants also completed self-report questionnaires assessing anxiety and depressive symptoms, impulsivity, emotion regulation, and social involvement. RESULTS: The results revealed no significant differences in spontaneous brain activity between the offspring and participants without a family history of AUD. However, in terms of psychosocial factors, the offspring exhibited significantly lower social involvement than the control group. CONCLUSIONS: This study does not provide evidence suggesting vulnerability in offspring based on differences in spontaneous brain activity. Moreover, this investigation highlights the importance of interventions aimed at enhancing social connections in offspring. Such interventions can not only reduce the risk of developing AUD, given its strong association with increased feelings of loneliness but also improve the overall well-being of the offspring.