The TMEM132B-GABAA receptor complex controls alcohol actions in the brain.

Alcohol is the most consumed and abused psychoactive drug globally, but the molecular mechanisms driving alcohol action and its associated behaviors in the brain remain enigmatic. Here, we have discovered a transmembrane protein TMEM132B that is a GABAA receptor (GABAAR) auxiliary subunit. Functionally, TMEM132B promotes GABAAR expression at the cell surface, slows receptor deactivation, and enhances the allosteric effects of alcohol on the receptor. In TMEM132B knockout (KO) mice or TMEM132B I499A knockin (KI) mice in which the TMEM132B-GABAAR interaction is specifically abolished, GABAergic transmission is decreased and alcohol-induced potentiation of GABAAR-mediated currents is diminished in hippocampal neurons. Behaviorally, the anxiolytic and sedative/hypnotic effects of alcohol are markedly reduced, and compulsive, binge-like alcohol consumption is significantly increased. Taken together, these data reveal a GABAAR auxiliary subunit, identify the TMEM132B-GABAAR complex as a major alcohol target in the brain, and provide mechanistic insights into alcohol-related behaviors.

Alcohol Use Disorder Treatment: Problems and Solutions.

Alcohol use disorder (AUD) afflicts over 29 million individuals and causes more than 140,000 deaths annually in the United States. A heuristic framework for AUD includes a three-stage cycle-binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation-that provides a starting point for exploring the heterogeneity of AUD with regard to treatment. Effective behavioral health treatments and US Food and Drug Administration-approved medications are available but greatly underutilized, creating a major treatment gap. This review outlines challenges that face the alcohol field in closing this treatment gap and offers solutions, including broadening end points for the approval of medications for the treatment of AUD; increasing the uptake of screening, brief intervention, and referral to treatment; addressing stigma; implementing a heuristic definition of recovery; engaging early treatment; and educating health-care professionals and the public about challenges that are associated with alcohol misuse. Additionally, this review focuses on broadening potential targets for the development of medications for AUD by utilizing the three-stage heuristic model of addiction that outlines domains of dysfunction in AUD and the mediating neurobiology of AUD.

The role of neurosteroids in posttraumatic stress disorder and alcohol use disorder: A review of 10 years of clinical literature and treatment implications.

Rates of alcohol use disorder (AUD) are increasing in men and women and there are high rates of concurrent posttraumatic stress disorder (PTSD) and AUD. AUD and PTSD synergistically increase symptomatology and negatively affect treatment outcomes; however, there are very limited pharmacological treatments for PTSD/AUD. Neurosteroids have been implicated in the underlying neurobiological mechanisms of both PTSD and AUD and may be a target for treatment development. This review details the past ten years of research on pregnenolone, progesterone, allopregnanolone, pregnanolone, estradiol, testosterone and dehydroepiandrosterone/dehydroepiandrosterone-sulfate (DHEA/DHEA-S) in the context of PTSD and AUD, including examination of trauma/alcohol-related variables, such as stress-reactivity. Emerging evidence that exogenous pregnenolone, progesterone, and allopregnanolone may be promising, novel interventions is also discussed. Specific emphasis is placed on examining the application of sex as a biological variable in this body of literature, given that women are more susceptible to both PTSD diagnoses and stress-related alcohol consumption.

Brain lncRNA-mRNA co-expression regulatory networks and alcohol use disorder.

Prolonged alcohol consumption can disturb the expression of both coding and noncoding genes in the brain. These dysregulated genes may co-express in modules and interact within networks, consequently influencing the susceptibility to developing alcohol use disorder (AUD). In the present study, we performed an RNA-seq analysis of the expression of both long noncoding RNAs (lncRNAs) and messenger RNAs (mRNAs) in 192 postmortem tissue samples collected from eight brain regions (amygdala, caudate nucleus, cerebellum, hippocampus, nucleus accumbens, prefrontal cortex, putamen, and ventral tegmental area) of 12 AUD and 12 control subjects of European ancestry. Applying the limma-voom method, we detected a total of 57 lncRNAs and 51 mRNAs exhibiting significant differential expression (Padj < 0.05 and fold-change ≥2) across at least one of the eight brain regions investigated. Machine learning analysis further confirmed the potential of these top genes in predicting AUD. Through Weighted Gene Co-expression Network Analysis (WGCNA), we identified distinct lncRNA-mRNA co-expression modules associated with AUD in each of the eight brain regions. Additionally, lncRNA-mRNA co-expression networks were constructed for each brain region using Cytoscape to reveal gene regulatory interactions implicated in AUD. Hub genes within these networks were found to be enriched in several key KEGG pathways, including Axon Guidance, MAPK Signaling, p53 Signaling, Adherens Junction, and Neurodegeneration. Our results underscore the significance of networks involving AUD-associated lncRNAs and mRNAs in modulating neuroplasticity in response to alcohol exposure. Further elucidating these molecular mechanisms holds promise for the development of targeted therapeutic interventions for AUD.

Chronic Alcohol Intake Compromises Lung Immunity by Altering Immunometabolism in Humans and Mouse Models.

Chronic alcohol consumption disrupts lung immunity and host defense mechanisms, rendering individuals with alcohol use disorder more susceptible to developing inflammatory lung conditions with poor prognoses. Here, we focused on investigating the molecular and cellular effects of alcohol ingestion on lung immunity in male and female subjects using population-based human lung transcriptomics analysis and an experimental mouse model of chronic alcohol drinking using the National Institute on Alcohol Abuse and Alcoholism alcohol feeding model. Flow cytometry and transcriptomics analyses in lungs revealed a sexually dimorphic effect of chronic alcohol drinking on lung immunity in both human and mouse. Male lungs were more sensitive to chronic alcohol drinking-induced dysregulation of lung immunity compared with female lungs. Furthermore, comparative transcriptomics analysis using lungs and liver samples from matched human and mouse subjects demonstrated that lungs were more sensitive than liver to the effects of alcohol in downregulating immune-related genes and pathways. Furthermore, the transcriptomics analysis provided evidence that immunometabolic change is a central driver in lung alteration by downregulating the immune pathways and upregulating metabolic pathways. Chronic alcohol consumption resulted in reduced mTOR signaling and decreased immune cell populations. The mTOR signaling axis may serve as an upstream regulator of alcohol-induced dysregulation in lung immunity.

Where alcohol use disorder meets interoception: A meta-analytic view on structural and functional neuroimaging data.

Alcohol use disorder (AUD) has been associated with changes in the processing of internal body signals, known as interoception. Changes in brain structure, particularly in the insula, are thought to underlie impaired interoception. As studies specifically investigating this association are largely lacking, this analysis takes an approach that compares meta-analytic results on interoception with recently published meta-analytic results on gray matter reduction in AUD. A systematic literature search identified 25 eligible interoception studies. Activation likelihood estimation (ALE) was used to test for spatial convergence of study results. Overlap between interoception and AUD clusters was tested using conjunction analysis. Meta-analytic connectivity modeling (MACM) and resting-state functional connectivity were used to identify the functional network of interoception and to test where this network overlapped with AUD meta-analytic clusters. The results were characterized using behavioral domain analysis. The interoception ALE identified a cluster in the left middle insula. There was no overlap with clusters of reduced gray matter in AUD. MACM analysis of the interoception cluster revealed a large network located in the insulae, thalami, basal nuclei, cingulate and medial frontal cortices, and pre- and postcentral gyri. Resting state analysis confirmed this result, showing the strongest connections to nodes of the salience- and somatomotor network. Five of the eight clusters that showed a structural reduction in AUD were located within these networks. The behavioral profiles of these clusters were suggestive of higher-level processes such as salience control, somatomotor functions, and skin sensations. The results suggest an altered salience mapping of interoceptive signals in AUD, consistent with current models. Connections to the somatomotor network may be related to action control and integration of skin sensations. Mindfulness-based interventions, pleasurable touch, and (deep) transcranial magnetic stimulation may be targeted interventions that reduce interoceptive deficits in AUD and thus contribute to drug use reduction and relapse prevention.

Withdrawal from chronic alcohol impairs the serotonin-mediated modulation of GABAergic transmission in the infralimbic cortex in male rats.

The infralimbic cortex (IL) is part of the medial prefrontal cortex (mPFC), exerting top-down control over structures that are critically involved in the development of alcohol use disorder (AUD). Activity of the IL is tightly controlled by γ-aminobutyric acid (GABA) transmission, which is susceptible to chronic alcohol exposure and withdrawal. This inhibitory control is regulated by various neuromodulators, including 5-hydroxytryptamine (5-HT; serotonin). We used chronic intermittent ethanol vapor inhalation exposure, a model of AUD, in male Sprague-Dawley rats to induce alcohol dependence (Dep) followed by protracted withdrawal (WD; 2 weeks) and performed ex vivo electrophysiology using whole-cell patch clamp to study GABAergic transmission in layer V of IL pyramidal neurons. We found that WD increased frequencies of spontaneous inhibitory postsynaptic currents (sIPSCs), whereas miniature IPSCs (mIPSCs; recorded in the presence of tetrodotoxin) were unaffected by either Dep or WD. The application of 5-HT (50 µM) increased sIPSC frequencies and amplitudes in naive and Dep rats but reduced sIPSC frequencies in WD rats. Additionally, 5-HT2A receptor antagonist M100907 and 5-HT2C receptor antagonist SB242084 reduced basal GABA release in all groups to a similar extent. The blockage of either 5-HT2A or 5-HT2C receptors in WD rats restored the impaired response to 5-HT, which then resembled responses in naive rats. Our findings expand our understanding of synaptic inhibition in the IL in AUD, indicating that antagonism of 5-HT2A and 5-HT2C receptors may restore GABAergic control over IL pyramidal neurons. SIGNIFICANCE STATEMENT: Impairment in the serotonergic modulation of GABAergic inhibition in the medial prefrontal cortex contributes to alcohol use disorder (AUD). We used a well-established rat model of AUD and ex vivo whole-cell patch-clamp electrophysiology to characterize the serotonin modulation of GABAergic transmission in layer V infralimbic (IL) pyramidal neurons in ethanol-naive, ethanol-dependent (Dep), and ethanol-withdrawn (WD) male rats. We found increased basal inhibition following WD from chronic alcohol and altered serotonin modulation. Exogenous serotonin enhanced GABAergic transmission in naive and Dep rats but reduced it in WD rats. 5-HT2A and 5-HT2C receptor blockage in WD rats restored the typical serotonin-mediated enhancement of GABAergic inhibition. Our findings expand our understanding of synaptic inhibition in the infralimbic neurons in AUD.

The interaction of genetic sex and prenatal alcohol exposure on health across the lifespan.

Prenatal alcohol exposure (PAE) can reprogram the development of cells and tissues, resulting in a spectrum of physical and neurobehavioral teratology. PAE immediately impacts fetal growth, but its effects carry forward post-parturition, into adolescence and adulthood, and can result in a cluster of disabilities, collectively termed Fetal Alcohol Spectrum Disorders. Emerging preclinical and clinical research investigating neurological and behavioral outcomes in exposed offspring point to genetic sex as an important modifier of the effects of PAE. In this review, we discuss the literature on sex differences following PAE, with studies spanning the fetal period through adulthood, and highlight gaps in research where sex differences are likely, but currently under-investigated. Understanding how sex and PAE interact to affect offspring health outcomes across the lifespan is critical for identifying the full complement of PAE-associated secondary conditions, and for refining targeted interventions to improve the quality of life for individuals with PAE.

Association between public health policies on alcohol and worldwide cancer, liver disease and cardiovascular disease outcomes.

BACKGROUND & AIMS: The long-term impact of alcohol-related public health policies (PHPs) on disease burden is unclear. We aimed to assess the association between alcohol-related PHPs and alcohol-related health consequences. METHODS: We conducted an ecological multi-national study including 169 countries. We collected data on alcohol-related PHPs from the WHO Global Information System of Alcohol and Health 2010. Data on alcohol-related health consequences between 2010-2019 were obtained from the Global Burden of Disease database. We classified PHPs into five items, including criteria for low, moderate, and strong PHP establishment. We estimated an alcohol preparedness index (API) using multiple correspondence analysis (0 lowest and 100 highest establishment). We estimated an incidence rate ratio (IRR) for outcomes according to API using adjusted multilevel generalized linear models with a Poisson family distribution. RESULTS: The median API in the 169 countries was 54 [IQR 34.9-76.8]. The API was inversely associated with alcohol use disorder (AUD) prevalence (IRR 0.13; 95% CI 0.03-0.60; p = 0.010), alcohol-associated liver disease (ALD) mortality (IRR 0.14; 95% CI 0.03-0.79; p = 0.025), mortality due to neoplasms (IRR 0.09; 95% CI 0.02-0.40; p = 0.002), alcohol-attributable hepatocellular carcinoma (HCC) (IRR 0.13; 95% CI 0.02-0.65; p = 0.014), and cardiovascular diseases (IRR 0.09; 95% CI 0.02-0.41; p = 0.002). The highest associations were observed in the Americas, Africa, and Europe. These associations became stronger over time, and AUD prevalence was significantly lower after 2 years, while ALD mortality and alcohol-attributable HCC incidence decreased after 4 and 8 years from baseline API assessment, respectively (p <0.05). CONCLUSIONS: The API is a valuable instrument to quantify the robustness of alcohol-related PHP establishment. Lower AUD prevalence and lower mortality related to ALD, neoplasms, alcohol-attributable HCC, and cardiovascular diseases were observed in countries with a higher API. Our results encourage the development and strengthening of alcohol-related policies worldwide. IMPACT AND IMPLICATIONS: We first developed an alcohol preparedness index, an instrument to assess the existence of alcohol-related public policies for each country. We then evaluated the long-term association of the country's alcohol preparedness index in 2010 with the burden of chronic liver disease, hepatocellular carcinoma, other neoplasms, and cardiovascular disease. The strengthening of alcohol-related public health policies could impact long-term mortality rates from cardiovascular disease, neoplasms, and liver disease. These conditions are the main contributors to the global burden of disease related to alcohol use. Over time, this association has not only persisted but also grown stronger. Our results expand the preliminary evidence regarding the importance of public health policies in controlling alcohol-related health consequences.

Early Liver Transplant for Alcohol-associated Liver Disease Has Excellent Survival but Higher Rates of Harmful Alcohol Use.

BACKGROUND & AIMS: Early liver transplantation (LT) for alcohol-associated liver disease (ALD) has increased worldwide. Short-term outcomes have been favorable, but data on longer-term outcomes are lacking. METHODS: Single-center retrospective study of primary LT recipients between 2010 and 2020, with follow-up through July 1, 2022. Survival analysis was performed using log rank, Cox models, and Kaplan-Meier method. Cox models were created to identify variables associated with mortality; logistic regression to identify variables associated with post-LT alcohol use. RESULTS: Of 708 patients who underwent LT, 110 (15.5%) had ALD and abstinence <6 months prior to LT (ELT), 234 (33.1%) had ALD and alcohol abstinence >6 months (SLT), and 364 (51.4%) had non-ALD diagnoses. Median follow-up was 4.6 years (interquartile range, 2.6-7.3 years). ELT recipients were younger (P = .001) with median abstinence pre-LT of 61.5 days. On adjusted Cox model, post-LT survival was similar in ELT and SLT (hazard ratio [HR], 1.31; P = .30) and superior to non-ALD (HR, 1.68; P = .04). Alcohol use (40.9% vs 21.8%; P < .001) and harmful alcohol use (31.2% vs 16.0%; P = .002) were more common in ELT recipients. Harmful alcohol use was associated with post-LT mortality on univariate (HR, 1.69; P = .03), but not multivariable regression (HR, 1.54; P = .10). Recurrence of decompensated ALD trended toward more common in ELT (9.1% vs 4.4%; P = .09). Greater than 6 months pre-LT abstinence was associated with a decreased risk of harmful alcohol use (odds ratio, 0.42; P = .001), but not in a multivariable model (odds ratio, 0.71; P = .33). CONCLUSIONS: Patients who undergo ELT for ALD have similar or better survival than other diagnoses in the first 10 years after LT despite a higher incidence of post-LT alcohol use.

Misclassified Alcohol-related Liver Disease is Common in Presumed Metabolic Dysfunction-associated Steatotic Liver Disease and Highly Increases Risk for Future Cirrhosis.

BACKGROUND & AIMS: Alcohol overconsumption is a risk factor for disease progression in patients with presumed metabolic dysfunction-associated steatotic liver disease (MASLD). How commonly this occurs and how it affects progression to major adverse liver outcomes (MALOs) is not well known. METHODS: We did a register-based cohort study, including all patients with a diagnosis of MASLD in Sweden between 1987 and 2020. Patients were stratified on co-occurrence of diagnoses of alcohol-related liver disease (ALD) or alcohol use disorder (AUD) prior to MASLD diagnosis. Incident MALOs were derived from national registers. Cox regression was used to calculate hazard ratios (HRs) for incident MALO. RESULTS: A total of 15,107 patients with MASLD were identified. The median age was 55 years, and 52% were female. Of the patients, 1843 (12%) had a prior diagnosis of ALD or AUD. During follow-up, a further 787 patients (5.2%) received a diagnosis of ALD or AUD. Patients with previous ALD or AUD diagnoses at or before baseline had considerably higher rates of MALOs compared with patients without (19.5% vs 7.8%; adjusted HR, 3.12; 95% confidence interval, 2.74-3.55). Acquiring an ALD or AUD diagnosis after MASLD diagnosis was associated with higher rates of MALOs (adjusted HR, 5.81; 95% confidence interval, 4.90-6.88). CONCLUSIONS: ALD or AUD is commonly diagnosed prior to or after MASLD diagnosis. Such patients have considerably higher rates of progression to MALOs. Correctly separating between MASLD and ALD is vital to assess prognosis.

Cost-effectiveness of screening and treating alcohol use and depression among people living with HIV in Zimbabwe: a mathematical modeling study.

BACKGROUND: Alcohol use disorder (AUD) and major depressive disorder (MDD) drive HIV transmission in many sub-Saharan African settings. The impact of screening and treating AUD and MDD on HIV outcomes is unknown. We aimed to identify the cost-effectiveness of AUD and MDD interventions in Zimbabwe, and their potential contribution to reaching Zimbabwe's Ending the HIV Epidemic 2030 goal. METHODS: Using a validated HIV compartmental transmission model in Zimbabwe, we compared four policy scenarios: prevention as usual (baseline); implement AUD screening (using AUDIT) and treatment (motivational interviewing and cognitive-behavioral therapy); implement MDD screening (using PHQ-9) and treatment (cognitive-behavioral therapy); and implement screening and treatment for both. Outcomes were HIV incidence projections, infections averted through 2030, quality-adjusted life-years gained, cost per infection averted, and cost per QALY gained. Analyses considered "spillover," when treatment for AUD also results in an improvement in MDD and the converse. Sensitivity analyses identified cost reductions necessary for AUD and MDD interventions to be as cost-effective as other HIV interventions, particularly the scale-up of long-acting PrEP. RESULTS: AUD and MDD combined will be responsible for 21.1% of new HIV infections in Zimbabwe by 2030. Without considering spillover, compared to the baseline, MDD intervention can reduce new infections by 5.4% at $2039/infection averted and $3186/QALY. AUD intervention can reduce new infections by 5.8%, but at $2,968/infection averted and $4753/QALY, compared to baseline. Both MDD and AUD interventions can reduce new infections by 11.1% at $2810/infection averted and $4229/QALY, compared to baseline. Considering spillover, compared to the baseline, MDD intervention can reduce new infections by 6.4% at $1714/infection averted and $2630/QALY. AUD intervention can reduce new infections by 7.4%, but at $2299/infection averted and $3560/QALY compared to baseline. Both MDD and AUD interventions can reduce new infections by 11.9% at $2247/infection averted and $3382/QALY compared to baseline. For MDD intervention to match the cost-effectiveness of scaling long-acting PrEP, the cost of MDD intervention would need to be reduced from $16.64 to $12.88 per person. CONCLUSIONS: Implementing AUD and MDD interventions can play an important role in HIV reduction in Zimbabwe, particularly if intervention cost can be decreased while preserving effectiveness.

Genetic susceptibility to optic neuropathy in patients with alcohol use disorder.

BACKGROUND: The pathophysiology of toxico-nutritional optic neuropathies remains debated, with no clear understanding of the respective roles played by the direct alcohol toxicity, smoking and the often associated vitamin deficiencies, which are risk factors for optic neuropathy. Our aim was to investigate genetic susceptibility in patients with bilateral infraclinical optic neuropathy associated with chronic alcohol use disorder. METHODS: This retrospective cohort study included 102 visually asymptomatic patients with documented alcohol use disorder from a French reference center. Optic neuropathy was identified with optical coherence tomography (OCT), after which genetic susceptibility in the group of affected patients was investigated. Genetic testing was performed using panel sequencing of 87 nuclear genes and complete mitochondrial DNA sequencing. RESULTS: Optic neuropathy was detected in 36% (37/102) of the included patients. Genetic testing of affected patients disclosed two patients (2/30, 6.7%) with optic neuropathy associated with pathogenic variants affecting the SPG7 gene and five patients (5/30, 16.7%) who harbored variants of uncertain significance close to probable pathogenicity in the genes WFS1, LOXL1, MMP19, NR2F1 and PMPCA. No pathogenic mitochondrial DNA variants were found in this group. CONCLUSIONS: OCT can detect presence of asymptomatic optic neuropathy in patients with chronic alcohol use disorder. Furthermore, genetic susceptibility to optic neuropathy in this setting is found in almost a quarter of affected patients. Further studies may clarify the role of preventative measures in patients who might be predisposed to avoidable visual loss and blindness.

Ketone Supplementation Dampens Subjective and Objective Responses to Alcohol: Evidence From a Preclinical Rat Study and a Randomized, Cross-Over Trial in Healthy Volunteers.

BACKGROUND: Previous preclinical and human studies have shown that a high-fat ketogenic diet and ketone supplements (KS) are efficacious in reducing alcohol craving, alcohol consumption, and signs of alcohol withdrawal. However, the effects of KS on alcohol sensitivity are unknown. METHODS: In this single-blind, cross-over study, 10 healthy participants (3 females) were administered a single, oral dose of a KS (25 g of ketones from D-ß-hydroxybutyric acid and R-1,3-butanediol) or placebo 30 minutes before an oral alcohol dose (0.25 g/kg for women; 0.31 g/kg for men). Assessments of breath alcohol concentration and blood alcohol levels (BAL) and responses on the Drug Effect Questionnaire were repeatedly obtained over 180 minutes after alcohol consumption. In a parallel preclinical study, 8 Wistar rats (4 females) received an oral gavage of KS (0.42 g ketones/kg), water, or the sweetener allulose (0.58 g/kg) followed 15 minutes later by an oral alcohol dose (0.8 g/kg). BAL was monitored for 240 minutes after alcohol exposure. RESULTS: In humans, the intake of KS before alcohol significantly blunted breath alcohol concentration and BAL, reduced ratings of alcohol liking and wanting more, and increased disliking for alcohol. In rats, KS reduced BAL more than either allulose or water. CONCLUSION: KS altered physiological and subjective responses to alcohol in both humans and rats, and the effects were likely not mediated by the sweetener allulose present in the KS drink. Therefore, KS could potentially reduce the intoxicating effects of alcohol.

Medications for Alcohol Use Disorder: Rates and Predictors of Prescription Order and Fill in Outpatient Settings.

BACKGROUND: Alcohol use disorders (AUD) are prevalent and responsible for substantial morbidity and mortality; yet efficacious treatments are underused. Previous studies have identified demographic and clinical predictors of medication fills, yet these studies typically do not include patients who were prescribed a medication but did not fill it. OBJECTIVES: To examine rates of and factors associated with prescription order and prescription fill for medications for AUD (MAUD) among individuals diagnosed with AUD in outpatient settings. DESIGN: In a cross-sectional analysis, we used multivariate logistic regression to identify factors associated with prescription order and fill. PATIENTS: We used data from the Optum Labs Data Warehouse that linked 2016-2021 de-identified claims and electronic health record (EHR) data, allowing us to observe prescription orders and whether they were filled. We identified 14,674 patients aged ≥ 18 who had an index outpatient encounter with an AUD diagnosis in the EHR. KEY MEASURES: We computed the proportion for whom a MAUD prescription was ordered within 1 year of index visit, and for whom one was filled within 30 days of the order. KEY RESULTS: 5.8% of the sample had a MAUD prescription order within 1 year of their index visit. Among those with an order, 87% filled their MAUD prescription within 30 days of receipt (i.e., 5.1% of full sample). After multivariable adjustment, receipt of a MAUD prescription order was more likely for patients who were female (adjusted odds ratio (aOR) [95%CI] = 1.44 [1.24-1.67]), or had moderate or severe AUD (1.74 [1.50-2.01]). Patients receiving an order were more likely to fill it if they had a comorbid mental disorder (1.64 [1.09-2.49]). CONCLUSIONS: The low rate of prescription orders was notable. Low use of MAUD appears to result chiefly from prescription order decisions, rather than from prescription fill decisions made by patients.

Risk for psychiatric and substance use disorders as a function of transitions in Sweden's public educational system: a national study.

BACKGROUND: To clarify, in a national sample, associations between risk for seven psychiatric and substance use disorders and five key transitions in Sweden's public educational system. METHODS: Swedish-born individuals (1972-1995, N = 1 997 910) were followed through 12-31-2018, at mean age 34.9. We predicted, from these educational transitions, risk for major depression (MD), obsessive-compulsive disorder (OCD), bipolar disorder (BD), schizophrenia (SZ), anorexia nervosa (AN), alcohol use disorder (AUD), and drug use disorder (DUD), assessed from Swedish national registers, by Cox regression, censoring individuals with onsets ⩽17. We also predicted risk from the deviation of grades from family-genetic expectations (deviation 1) and from changes in grades from ages 16 to 19 (deviation 2). RESULTS: We observed four major risk patterns across transitions in our disorders: (i) MD and BD, (ii) OCD and SZ, (iii) AUD and DUD, and (iv) AN. Failing early educational transitions had the greatest impact on risk for OCD and SZ while for other disorders, not progressing from basic to upper high school had the largest effect. Completing vocational v. college-prep upper high school was strongly associated with risk for AUD and DUD, had little relation with MD, OCD, BD, and SZ risk, and was protective for AN. Deviation 1 predicted risk most strongly for SZ, AN, and MD. Deviation 2 predicted risk most strongly for SZ, AUD, and DUD. CONCLUSIONS: The pattern of educational transitions and within family and within person development deviations are strongly and relatively specifically associated with future risk for seven psychiatric and substance-use disorders.

Cortical paired associative stimulation shows impaired plasticity of inhibition networks as a function of chronic alcohol use.

BACKGROUND: Response inhibition - or the ability to withhold a suboptimal response - relies on the efficacy of fronto-striatal networks, and is impaired in neuropsychiatric disorders including addiction. Cortical paired associative stimulation (cPAS) is a form of transcranial magnetic stimulation (TMS) which can strengthen neuronal connections via spike-timing-dependent plasticity mechanisms. Here, we used cPAS targeting the fronto-striatal inhibitory network to modulate performance on a response inhibition measure in chronic alcohol use. METHODS: Fifty-five participants (20 patients with a formal alcohol use disorder (AUD) diagnosis (26-74 years, 6[30%] females) and 20 matched healthy controls (HCs) (27-73 years, 6[30%] females) within a larger sample of 35 HCs (23-84 years, 11[31.4%] females) underwent two randomized sessions of cPAS 1-week apart: right inferior frontal cortex stimulation preceding right presupplementary motor area stimulation by either 4 ms (excitation condition) or 100 ms (control condition), and were subsequently administered the Stop Signal Task (SST) in both sessions. RESULTS: HCs showed decreased stop signal reaction time in the excitation condition (t(19) = -3.01, p = 0.007, [CIs]:-35.6 to -6.42); this facilitatory effect was not observed for AUD (F(1,31) = 9.57, p = 0.004, CIs: -68.64 to -14.11). Individually, rates of SST improvement were substantially higher for healthy (72%) relative to AUD (13.6%) groups (OR: 2.33, p = 0.006, CIs:-3.34 to -0.55). CONCLUSION: In line with previous findings, cPAS improved response inhibition in healthy adults by strengthening the fronto-striatal network through putative long-term potentiation-like plasticity mechanisms. Furthermore, we identified a possible marker of impaired cortical excitability, and, thus, diminished capacity for cPAS-induced neuroplasticity in AUD with direct implications to a disorder-relevant cognitive process.

Neural activations during cognitive and affective theory of mind processing in healthy adults with a family history of alcohol use disorder.

BACKGROUND: Social cognition impairments are a common feature of alcohol use disorders (AUD). However, it remains unclear whether these impairments are solely the consequence of chronic alcohol consumption or whether they could be a marker of vulnerability. METHODS: The present study implemented a family history approach to address this question for a key process of social cognition: theory of mind (ToM). Thirty healthy adults with a family history of AUD (FH+) and 30 healthy adults with a negative family history of AUD (FH-), matched for age, sex, and education level, underwent an fMRI cartoon-vignette paradigm assessing cognitive and affective ToM. Participants also completed questionnaires evaluating anxiety, depressive symptoms, childhood trauma, and alexithymia. RESULTS: Results indicated that FH+ individuals differed from FH- individuals on affective but not cognitive ToM processing, at both the behavioral and neural levels. At the behavioral level, the FH+ group had lower response accuracy for affective ToM compared with the FH- group. At the neural level, the FH+ group had higher brain activations in the left insula and inferior frontal cortex during affective ToM processing. These activations remained significant when controlling for depressive symptoms, anxiety, and childhood trauma. CONCLUSIONS: These findings highlight difficulties during affective ToM processing among first-degree relatives of AUD patients, supporting the idea that some of the impairments exhibited by these patients may already be present before the onset of AUD and may be considered a marker of vulnerability.

The joint effects of genetic liability and the death of close relatives on risk for major depression and alcohol use disorder in a Swedish national sample.

BACKGROUND: To determine whether genetic risk factors for major depression (MD) and alcohol use disorder (AUD) interact with a potent stressor - death of spouse, parent, and sibling - in predicting episodes of, respectively, MD and AUD. METHODS: MD and AUD registrations were assessed from national Swedish registries. In individuals born in Sweden 1960-1970, we identified 7586, 388 459, and 34 370 with the loss of, respectively, a spouse, parent, and sibling. We started following subjects at age 18 or the year 2002 with end of follow-up in 2018. We examined time to event - a registration for MD within 6 months or AUD within a year - on an additive scale, using the Nelson-Aalen estimator. Genetic risk was assessed by the Family Genetic Risk Score (FGRS). RESULTS: In separate models controlling for the main effects of death of spouse, parent, and sibling, FGRS, and sex, significant interactions were seen in all analyses between genetic risk for MD and death of relative in prediction of subsequent MD registration. A similar pattern of results, albeit with weaker interaction effects, was seen for genetic risk for AUD and risk for AUD registration. Genetic risk for bipolar disorder (BD) and anxiety disorders (AD) also interacted with event exposure in predicting MD. CONCLUSIONS: Genetic risk for both MD and AUD act in part by increasing the sensitivity of individuals to the pathogenic effects of environmental stressors. For prediction of MD, similar effects are also seen for genetic risk for AD and BD.

Alcohol milestones and internalizing, externalizing, and executive function: longitudinal and polygenic score associations.

BACKGROUND: Although the link between alcohol involvement and behavioral phenotypes (e.g. impulsivity, negative affect, executive function [EF]) is well-established, the directionality of these associations, specificity to stages of alcohol involvement, and extent of shared genetic liability remain unclear. We estimate longitudinal associations between transitions among alcohol milestones, behavioral phenotypes, and indices of genetic risk. METHODS: Data came from the Collaborative Study on the Genetics of Alcoholism (n = 3681; ages 11-36). Alcohol transitions (first: drink, intoxication, alcohol use disorder [AUD] symptom, AUD diagnosis), internalizing, and externalizing phenotypes came from the Semi-Structured Assessment for the Genetics of Alcoholism. EF was measured with the Tower of London and Visual Span Tasks. Polygenic scores (PGS) were computed for alcohol-related and behavioral phenotypes. Cox models estimated associations among PGS, behavior, and alcohol milestones. RESULTS: Externalizing phenotypes (e.g. conduct disorder symptoms) were associated with future initiation and drinking problems (hazard ratio (HR)⩾1.16). Internalizing (e.g. social anxiety) was associated with hazards for progression from first drink to severe AUD (HR⩾1.55). Initiation and AUD were associated with increased hazards for later depressive symptoms and suicidal ideation (HR⩾1.38), and initiation was associated with increased hazards for future conduct symptoms (HR = 1.60). EF was not associated with alcohol transitions. Drinks per week PGS was linked with increased hazards for alcohol transitions (HR⩾1.06). Problematic alcohol use PGS increased hazards for suicidal ideation (HR = 1.20). CONCLUSIONS: Behavioral markers of addiction vulnerability precede and follow alcohol transitions, highlighting dynamic, bidirectional relationships between behavior and emerging addiction.