Comorbid Alcohol Use Disorder Research Articles

Emotion differentiation among individuals in a randomized clinical trial for alcohol use disorder: Within- and between-person associations with affect, craving, and alcohol use in daily life

Emotion differentiation refers to cognitively distinguishing among discrete, same-valenced emotions. Negative emotion differentiation (NED) is a transdiagnostic indicator of emotional functioning. The role of positive emotion differentiation (PED) in clinical disorders, including alcohol use disorder (AUD), is less understood. Further, despite consensus that emotions are highly variable, little is known about within-person fluctuations in NED/PED. The current study leveraged 84 consecutive daily smartphone surveys from participants (N = 181) in a clinical trial of cognitive behavioral therapy for AUD to investigate whether between-person differences in overall NED/PED, or within-person variability in daily NED/PED, were associated with affect intensity, craving, drinking, and heavy drinking in daily life. Subsequent analyses explored whether associations were moderated by baseline alexithymia. At the between-persons level, greater average PED, but not NED, was associated with lower heavy drinking odds. At the within-persons level, higher-than-usual PED was associated with lower negative affect and odds of any drinking. Individuals with baseline alexithymia had stronger negative within-person associations between daily NED and both any and heavy drinking. PED is a skill linked to less alcohol use between- and within-persons irrespective of baseline alexithymia, whereas greater daily NED appears especially important for reduced alcohol use among individuals with co-morbid AUD and alexithymia.

Current treatments of alcohol use disorder.

Emerging treatments for alcohol dependence reveal an intricate interplay of neurobiological, psychological, and circumstantial factors that contribute to Alcohol Use Disorder (AUD). The approved strategies balancing these factors involve extensive manipulations of neurotransmitter systems such as GABA, Glutamate, Dopamine, Serotonin, and Acetylcholine. Innovative developments are engaging mechanisms such as GABA reuptake inhibition and allosteric modulation. Closer scrutiny is placed on the role of Glutamate in chronic alcohol consumption, with treatments like NMDA receptor antagonists and antiglutamatergic medications showing significant promise. Complementing these neurobiological approaches is the progressive shift towards Personalized Medicine. This strategy emphasizes unique genetic, epigenetic and physiological factors, employing pharmacogenomic principles to optimize treatment response. Concurrently, psychological therapies have become an integral part of the treatment landscape, tackling the cognitive-behavioral dimension of addiction. In instances of AUD comorbidity with other psychiatric disorders, Personalized Medicine becomes pivotal, ensuring treatment and prognosis are closely defined by individual characteristics, as exemplified by Lesch Typology models. Given the high global prevalence and wide distribution of AUD, a persistent necessity exists for development and improvement of treatments. Current research efforts are steadily paving paths towards more sophisticated, effective typology-based treatments: a testament to the recognized imperative for enhanced treatment strategies. The potential encapsulated within the ongoing research suggests a promising future where the clinical relevance of current strategies is not just maintained but significantly improved to effectively counter alcohol dependence.

Progesterone Attenuates the Stress Response in Individuals with Alcohol Dependence and Post-Traumatic Stress Disorder – A Pilot Study

Objective: Evidence from laboratory studies suggests that progesterone may be effective in reducing stress and craving, and may improve cognitive performance in smokers and individuals with cocaine dependence. The objective of this study was to examine if progesterone would attenuate stress-induced craving, anxiety, affect and physiological measures, as well as improve stress-induced cognitive performance (processing speed and selective attention) in individuals diagnosed with alcohol use disorder (AUD) and post traumatic stress disorder (PTSD). Methods: This laboratory study included (n = 13) participants who were diagnosed with current AUD and PTSD who were randomly assigned to recive either progesterone (200mg bid) or placebo in identical looking capsules for 3 days. On the fourth day they completed a laboratory session. In the morning of the test session, they received the last dose of medication and completed the rest of the laboratory procedures. The procedures included presentation in random order of personalized trauma and neutral scripts with relaxation in between. Main outcomes included measure of craving, anxiety, affect and cognitive performance. Results: Consistent with other research, trauma scripts produced significantly greater increases in craving, anxiety and negative affect when compared with neutral scripts. Progesterone significantly reduced stress-induced symptoms of craving, anxiety, fear, anger and sadness but had no effect on positive emotions (joy, relaxation). Progesterone was effective in ameliorating stress-induced decreases in cognitive performance. Conclusions: The findings from this study demonstrate that progesterone can be effective in reducing stress-induced craving, anxiety and negative affect in a laboratory setting in individuals with comorbid AUD and PTSD. Interestingly, progesterone also improved cognitive performance. These findings require replication in a larger clinical trial and may have implications for treatment among individuals with AUD and PTSD. This study was registered as NCT02187224, at www.clinicaltrials.gov

Vicarious defeat stress induces increased alcohol consumption in female mice: Role of neurokinin-1 receptor and interleukin-6.

There is a high frequency of comorbidity of alcohol use disorder (AUD) and depression in human populations. We have studied this relationship in our lab using the social defeat stress (SDS) model, which results in both depression-like behaviours and increased alcohol consumption in male mice. However, standard SDS procedures are difficult to use in female mice due to a lack of territorial aggression. In the experiments presented here, we used vicarious defeat stress (VDS) to assess social withdrawal and alcohol consumption in female C57BL6/J mice. We also assessed the expression of interleukin-6 (IL6), which is a proinflammatory cytokine that is associated with depression in humans and sensitivity to SDS in mice. In these experiments, C57BL/6 female mice underwent 10 days of VDS where they witnessed the physical defeat of a male conspecific by an aggressive CD1 mouse. After the end of VDS, mice were either given access to alcohol or sacrificed for the measurement of IL6 expression. We found that VDS increased alcohol consumption and IL6 expression in the frontal cortex and hippocampus. Given that the neurokinin-1 receptor (NK1R) can mediate both stress-induced alcohol consumption and IL6 expression, we tested the ability of NK1R antagonism to reduce VDS-induced alcohol consumption and found that this treatment reduced alcohol intake in both VDS-exposed mice and in unstressed controls. The observed increase in alcohol consumption suggests that VDS is a model that can be utilized to study stress-induced alcohol consumption in female mice, and that this is sensitive to NK1R antagonism.

Co‐occurring BD and AUD associated with increased craving

Researchers studied reward circuitry dysfunction, which may be a mechanism of co‐occurring bipolar disorder (BD) and alcohol use disorder (AUD), using functional magnetic resonance imaging (fMRI). The objective was to find out how alcohol cue processing differs in people with co‐occurring BD and AUD compared with people who have either one of the disorders. They used a visual alcohol cue reactivity paradigm following one week or more of abstinence from alcohol and other drugs. They rated past‐week mood symptoms for depression and mania, as well as obsessive‐compulsive drinking and impulsiveness. Function MRI was analyzed focusing on the ventral striatum, dorsal striatum, and ventromedial prefrontal cortex. The researchers analyzed associations between cue reactivity and select behavioral correlates, namely, alcohol craving, impulsivity, maximum number of alcohol drinks on a single occasion and days since last alcohol drink). Of the 112 participants, 28 (25.0%) had BD and AUD, 26 (23.2%) had AUD alone, 31 (27.7%) had BD alone, and 27 (24.1%) were healthy controls. The mean age was 38.7 years, 50 (45.5%) were female, 33 (30%) were smokers, and 37 (34.9%) reported recent alcohol consumption. Individuals with BD and AUD exhibited reduced activation compared with all other groups. Other groups did not significantly differ from one another. The hypo‐activations were associated with increased impulsivity and obsessive‐compulsive alcohol craving exclusively among individuals with BD and AUD. The researchers concluded that the potential interaction between BD and AUD blunted the response to rewards and decreased inhibitory control. They added that reduced right inferior frontal gyrus and insula alcohol cue reactivity is a novel biomarker of comorbid BD and AUD that may respond to pharmacological interventions targeting impulsivity‐related neural mechanisms for improved executive control. The study, “Alcohol Cue Processing in Co‐Occurring Bipolar Disorder and Alcohol Use Disorder, is by William H. Mellick, Ph.D., and colleagues, and was conducted at the Medical University of South Carolina, Addiction Sciences Division and published Nov. 1 in JAMA Psychiatry.

Abstract 14287: Real-World Healthcare Resource Utilization Among Patients With Hypertension or Congestive Heart Failure and Comorbid Alcohol Use Disorder

Introduction: Excessive alcohol consumption has been associated with increased risk of cardiovascular (CV) disease. Hypertension (HTN) is a known risk factor for CV disease, in general, including congestive heart failure (CHF). Healthcare resource utilization (HRU) and costs associated with comorbid alcohol use disorder (AUD) among patients with HTN or CHF were evaluated. Methods: This retrospective cohort study identified adults with moderate-to-severe AUD from patients with ≥1 inpatient, or ≥2 outpatient claims on separate days, for HTN or CHF (MarketScan® and Medicare [1/1/2016-12/31/2020], Medicaid [1/1/2016-12/31/2019] databases), and ≥1 year of continuous healthcare enrollment prior to diagnosis (baseline) and 3 months after. Monthly HRU and costs were compared between propensity-score matched patients based on AUD presence using rate ratios in generalized linear models. Results: Of 4,015,785 patients with HTN, 1% were diagnosed with AUD. Use of HTN pharmacotherapy was similar for all patients, except for less frequent use of angiotensin receptor blockers (ARBs) in those with AUD. HTN patients with comorbid AUD had a higher risk of inpatient visits (89%), ED visits (39%), longer inpatient stays (98%), and outpatient visits (9%) relative to non-AUD patients. Of 294,892 patients with CHF, 2% had comorbid AUD. CHF pharmacotherapy use was similar for all patients, except for less frequent ARB use in those with AUD. CHF with comorbid AUD had a higher risk of inpatient visits (31%), ED visits (25%), and longer inpatient stays (34%) relative to non-AUD patients. Outpatient visits were 5% lower in CHF patients with AUD. AUD was associated with higher acute care costs, fewer pharmacy claims, and lower pharmacy costs in both HTN and CHF cohorts. Patients with AUD in both cohorts were more likely to be younger, male, enrolled in Medicaid, with a higher comorbidity burden. Conclusion: In this real-world study, the presence of AUD in patients with either HTN or CHF was associated with greater comorbidity burden, higher acute care utilization and costs, and lower outpatient pharmacy utilization relative to patients without AUD. These findings suggest that AUD impacts care for both HTN and CHF, which could be an opportunity for improved screening and treatment.

Comorbid alcohol use disorder and posttraumatic stress disorder: A proof-of-concept randomized placebo-controlled trial of buprenorphine and naltrexone combination treatment.

Effective pharmacologic treatments for comorbid alcohol use disorder (AUD) and posttraumatic stress disorder (PTSD) are lacking. Kappa (κ) opioid receptor antagonists may address this unmet need. Buprenorphine is a κ-opioid antagonist and a partial agonist of mu (μ) opioid receptors. Whereas naltrexone blocks all μ-mediated effects combining it with buprenorphine yields a pharmacologic net effect of opioid receptor antagonism. Because no κ-opioid receptor antagonist it available for clinical use, we tested this combination in a proof-of-concept study. Consenting participants were enrolled in a Phase II, multisite, double-blind, randomized, placebo-controlled trial evaluating the effectiveness of sublingual (SL) buprenorphine combined with extended-release (XR) injectable naltrexone for the treatment of comorbid AUD and PTSD. Eligible participants (n = 75) were randomized (1:1:1) to receive either buprenorphine 2 mg/day plus naltrexone-XR (n = 35), buprenorphine 8 mg/day plus naltrexone-XR (n = 6) or SL plus injectable placebo (n = 34) for 12 weeks. The buprenorphine 8 mg/day plus naltrexone-XR arm was dropped early in the trial due to the negative impact of COVID-19 on enrollment. A binary primary outcome of response at week 8 was defined as a decrease from baseline of ≥10 points on the past week Clinician-Administered PTSD Scale (CAPS-5) and a reduction of ≥1 of past month alcohol risk level, as defined by the World Health Organization (WHO) and measured by the Timeline Follow-Back. Based on the results of a futility analysis, enrollment was stopped prior to reaching the initial goal of 90 participants. At the week eight primary timepoint, there were no statistically significant differences between buprenorphine plus naltrexone-XR and placebo group for the primary composite outcome (OR = 0.63; p-value = 0.52), or the subcomponents of the PTSD outcome (OR = 0.76; p-value = 0.69) and AUD outcome (OR = 0.17; p-value = 0.08). The placebo arm had a significantly higher proportion of participants with ≥1 WHO risk level reduction than the buprenorphine plus naltrexone-XR arm (OR = 0.18, p value = 0.02). This is the first study to evaluate the potential of κ-opioid receptor antagonism for the treatment of comorbid AUD and PTSD. The combination of buprenorphine and naltrexone-XR showed no significant improvement over placebo for the composite, PTSD, or alcohol measures.

Age-Accelerated Increase of White Matter Hyperintensity Volumes Is Exacerbated by Heavy Alcohol Use in People Living With HIV

BackgroundAntiretroviral treatment has enabled people living with HIV infection to have a near-normal life span. With longevity comes opportunities for engaging in risky behavior, including initiation of excessive drinking. Given that both HIV infection and alcohol use disorder (AUD) can disrupt brain white matter integrity, we questioned whether HIV infection, even if successfully treated, or AUD alone results in signs of accelerated white matter aging and whether HIV+AUD comorbidity further accelerates brain aging. MethodsLongitudinal magnetic resonance imaging-FLAIR data were acquired over a 15-year period from 179 control individuals, 204 participants with AUD, 70 participants with HIV, and 75 participants with comorbid HIV+AUD. White matter hyperintensity (WMH) volumes were quantified and localized, and their functional relevance was examined with cognitive and motor testing. ResultsThe 3 diagnostic groups each had larger WMH volumes than the control group. Although all 4 groups exhibited accelerating volume increases with aging, only the HIV groups showed faster WMH enlargement than control individuals; the comorbid group showed faster acceleration than the HIV-only group. Sex and HIV infection length, but not viral suppression status, moderated acceleration. Correlations emerged between WMH volumes and attention/working memory and executive function scores of the AUD and HIV groups and between WMH volumes and motor skills in the 3 diagnostic groups. ConclusionsEven treated HIV can show accelerated aging, possibly from treatment sequelae or legacy effects, and notably from AUD comorbidity. WMH volumes may be especially relevant for tracking HIV and AUD brain health because each condition is associated with liability for hypertensive processes, for which WMHs are considered a marker.

Sex differences in the comorbidity of patients seeking a first treatment for Alcohol Use Disorder

Abstract Background The CohRTA multicenter study aims to characterize patients undergoing a first treatment for alcohol use disorder (AUD). The objective is to analyze sex-specific differences in the comorbidity of AUD when starting the first treatment for the disorder. Methods A multicenter study was carried out between 2014 and 2021 in 6 public centers in Spain. Sociodemographic characteristics were collected, variables related to alcohol consumption, medical comorbidity according to Cumulative Illness Rating Scale-Substance Abuse (CIRS-SA), antecedent of psychiatric comorbidity, general blood test and screening for drugs in urine. Logistic regression models were used to establish associations. Results A total of 896 patients (634 M, 262 W) were included. Median age at admission was 48 years [IQR:41–56 years]. Men reported beginning regular alcohol consumption at an earlier age and drank more alcohol. The most frequent medical comorbidities were hepatic, respiratory, vascular and neurological. The median number of affected systems was three, with no differences between men and women. However, depressive disorder was more frequent in women. In the multivariate analysis, women were up to 4 times more likely to have a major depressive disorder, elevated ESR and elevated total cholesterol than men. Men started alcohol consumption earlier, had a higher body mass index (BMI), a higher probability of using cocaine and a higher frequency of GGT and bilirubin alteration than women. Conclusion Differences by sex were found among individuals beginning first treatment for AUD. These differences must be taken into account when designing specific therapeutic strategies for men and women.

Treatment outcomes in major depressive disorder in patients with comorbid alcohol use disorder: A STAR*D analysis

IntroductionGuidance on Major Depressive Disorder (MDD) treatment in those with comorbid Alcohol Use Disorder (AUD) is limited. We performed a secondary analysis on the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, examining the association between comorbid AUD and depression outcomes. MethodsSTAR*D was a real-world effectiveness trial starting with citalopram in level 1. Non-responding participants progressed through 3 other sequential treatment levels with different switch or augmentation options. Antidepressant outcomes were compared between MDD (n = 2826) and comorbid MDD and AUD (n = 864). Logistic regressions were performed to evaluate remission and response predictors in the total STAR*D sample and the AUD-comorbidity interaction. ResultsChi-squared tests showed no significant difference in response or remission rates from depression between groups across treatment levels. Higher Hamilton Rating Scale for Depression (HRSD) score was associated with overall lower odds of remission in treatment level 1 (OR = 0.93, p < 0.001) and 2 (OR = 0.95, p < 0.001), with no significant interaction with comorbid AUD. Higher baseline suicidality had overall lower odds of remission in level 1 (OR = 0.82, p < 0.001) and 2 (OR = 0.1, p < 0.001), but with comorbid AUD compared to no AUD, suicidality increased odds of level 1 remission (OR = 1.30, p = 0.012). In comorbid AUD in level 2, venlafaxine was associated with lower odds of remission (OR = 0.13, p = 0.013) and response (OR = 0.12, p = 0.006); bupropion with lower odds of response (OR = 0.22, p = 0.024). LimitationsOpen label study design and lack of alcohol use data. ConclusionsComorbid AUD may interact with predictors of antidepressant response in MDD and using venlafaxine or bupropion may be less effective. Addressing this comorbidity requires unique assessment and treatment approaches.

Characteristics of amplitude of low-frequency fluctuations in the resting-state functional magnetic resonance imaging of alcohol-dependent patients with depression.

The high comorbidity of alcohol use disorder and depressive disorder is associated with poor patient prognosis. The mechanisms underlying this comorbidity, however, are largely unknown. By applying the amplitude of low-frequency fluctuations parameter in resting-state functional magnetic resonance imaging, this study investigated changes in the brain functioning of alcohol-dependent patients with and without depression. Alcohol-dependent patients (n = 48) and healthy controls (n = 31) were recruited. The alcohol-dependent patients were divided into those with and without depression, according to Patients Health Questionnaire-9 scores. Amplitude of low-frequency fluctuations in resting-state brain images were compared among the alcohol-dependent patients with depression, alcohol-dependent patients without depression, and healthy controls groups. We further examined associations between amplitude of low-frequency fluctuations alterations, alcohol-dependence severity, and depressive levels (assessed with scales). Compared with the healthy controls group, both alcohol groups showed amplitude of low-frequency fluctuations enhancement in the right cerebellum and amplitude of low-frequency fluctuations abatement in the posterior central gyrus. The alcohol-dependent patients with depression group had higher amplitude of low-frequency fluctuations in the right cerebellum than the alcohol-dependent patients without depression group. Additionally, we observed a positive correlation between amplitude of low-frequency fluctuations value and Patients Health Questionnaire-9 score in the right superior temporal gyrus in the alcohol-dependent patients with depression group. Alcohol-dependent subjects showed abnormally increased spontaneous neural activity in the right cerebellum, which was more significant in alcohol-dependent patients with depression. These findings may support a targeted intervention in this brain location for alcohol and depressive disorder comorbidity.

Molecular Toxicology and Pathophysiology of Comorbid Alcohol Use Disorder and Post-Traumatic Stress Disorder Associated with Traumatic Brain Injury.

The increasing comorbidity of alcohol use disorder (AUD) and post-traumatic stress disorder (PTSD) associated with traumatic brain injury (TBI) is a serious medical, economic, and social issue. However, the molecular toxicology and pathophysiological mechanisms of comorbid AUD and PTSD are not well understood and the identification of the comorbidity state markers is significantly challenging. This review summarizes the main characteristics of comorbidity between AUD and PTSD (AUD/PTSD) and highlights the significance of a comprehensive understanding of the molecular toxicology and pathophysiological mechanisms of AUD/PTSD, particularly following TBI, with a focus on the role of metabolomics, inflammation, neuroendocrine, signal transduction pathways, and genetic regulation. Instead of a separate disease state, a comprehensive examination of comorbid AUD and PTSD is emphasized by considering additive and synergistic interactions between the two diseases. Finally, we propose several hypotheses of molecular mechanisms for AUD/PTSD and discuss potential future research directions that may provide new insights and translational application opportunities.

Preliminary evidence that individuals with remitted alcohol use disorder and major depressive disorder exhibit enhanced neural responses to reward: An EEG study

IntroductionDisruptions in neural responses to reward are implicated in risk for Alcohol Use Disorder (AUD) and Major Depressive Disorder (MDD). It is not clear whether these findings extend to those in remission from AUD and MDD, a critical question as studies of remission can (a) rule out effects due to current symptoms, and (b) can reveal potential trait-like differences. MethodsIndividuals with and without remitted AUD (rAUD) and/or rMDD (rMDD) were drawn from a larger study to create four groups: rAUD (n = 54), rMDD (n = 66), rAUD + rMDD (n = 53), and a community control group (CCG; n = 81). Participants completed a validated monetary reward task during electroencephalogram (EEG). Multilevel models examined group differences in event-related potentials and time–frequency indices of reward and loss responsiveness, namely, reward positivity (RewP), feedback negativity (FN), reward-related delta power, and loss-related theta power. ResultsAnalyses revealed that the rAUD + rMDD group had significantly higher reward-related delta activity than the three other groups (p-values < 0.01), which did not differ from each other. Sensitivity analyses revealed this relationship fell just above the threshold set for significance after controlling for residual current MDD and AUD symptoms (p =.05). There were no other group differences or significant interactions (p-values > 0.05). ConclusionsTo our knowledge, this is the first study to show that individuals with remitted AUD and MDD demonstrate increased sensitivity to rewards compared to individuals with remitted AUD alone, MDD alone, and without AUD or MDD. These findings suggest heightened motivational salience to reward might be an important factor in comorbid AUD and MDD.

Comorbidity of Post-Traumatic Stress Disorder and Alcohol Use Disorder: Animal Models and Associated Neurocircuitry

Post-traumatic stress disorder (PTSD) and alcohol use disorder (AUD) are prevalent neuropsychiatric disorders and frequently co-occur concomitantly. Individuals suffering from this dual diagnosis often exhibit increased symptom severity and poorer treatment outcomes than those with only one of these diseases. Lacking standard preclinical models limited the exploration of neurobiological mechanisms underlying PTSD and AUD comorbidity. In this review, we summarize well-accepted preclinical model paradigms and criteria for developing successful models of comorbidity. We also outline how PTSD and AUD affect each other bidirectionally in the nervous nuclei have been heatedly discussed recently. We hope to provide potential recommendations for future research.

Childhood Maltreatment and Use of Aggression among Veterans with Co-occurring PTSD and Alcohol Use Disorder: The Mediating Role of Hostile Cognitions

ABSTRACT History of childhood maltreatment is common among military veterans, particularly those with posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD). Childhood maltreatment is associated with negative psychosocial outcomes, including use of aggression during adulthood. Prior research has identified maladaptive cognitions as a key mediating variable in the association between early life trauma and aggression. Given the high rates of comorbid PTSD and AUD among veterans and the increased risk of aggression when these conditions co-occur, it is critical to examine malleable intervention targets, such as maladaptive cognitions, for this population. The current secondary analyses examined the mediating role of hostile cognitions on the associations between childhood maltreatment and adulthood aggression in a sample of dually diagnosed veterans. Participants were veterans with co-occurring PTSD and AUD (N = 73) who were enrolled in a larger randomized controlled laboratory trial. Participants completed self-report measures of childhood maltreatment, hostile cognitions, and aggressive behavior. Three models were tested to examine the mediating effect of hostility on the associations between childhood maltreatment, abuse, and neglect on aggression. Results indicated that hostility fully mediated the effect of maltreatment on aggression and partially mediated the effect of childhood abuse on aggression. The effect of childhood neglect on aggression was nonsignificant. Hostile cognitions may be a critical intervention target for veterans with co-occurring PTSD and AUD and history of childhood maltreatment, particularly for those who have experienced higher levels of childhood abuse.

Chronic ethanol consumption exacerbates future stress-enhanced fear learning, an effect mediated by dorsal hippocampal astrocytes.

Alcohol use disorder (AUD) and post-traumatic stress disorder (PTSD) are highly comorbid, yet there is a lack of preclinical research investigating how prior ethanol (EtOH) dependence influences the development of a PTSD-like phenotype. Furthermore, the neuroimmune system has been implicated in the development of both AUD and PTSD, but the extent of glial involvement in this context remains unclear. A rodent model was developed to address this gap in the literature. We used a 15-day exposure to the 5% w/v EtOH low-fat Lieber-DeCarli liquid diet in combination with the stress-enhanced fear learning (SEFL) paradigm to investigate the effects of chronic EtOH consumption on the development of a PTSD-like phenotype. Next, we used a reverse transcription quantitative real-time polymerase chain reaction to quantify mRNA expression of glial cell markers GFAP (astrocytes) and CD68 (microglia) following severe footshock stress in EtOH-withdrawn rats. Finally, we tested the functional contribution of dorsal hippocampal (DH) astrocytes in the development of SEFL in EtOH-dependent rats using astrocyte-specific Gi designer receptors exclusively activated by designer drugs (Gi -DREADD). Results demonstrate that chronic EtOH consumption and withdrawal exacerbate future SEFL. Additionally, we found significantly increased GFAP mRNA expression in the dorsal and ventral hippocampus and amygdalar complex following the severe stressor in EtOH-withdrawn animals. Finally, the stimulation of the astroglial Gi -DREADD during EtOH withdrawal prevented the EtOH-induced enhancement of SEFL. Collectively, results indicate that prior EtOH dependence and withdrawal combined with a severe stressor potentiate future enhanced fear learning. Furthermore, DH astrocytes significantly contribute to this change in behavior. Overall, these studies provide insight into the comorbidity of AUD and PTSD and the potential neurobiological mechanisms behind increased susceptibility to a PTSD-like phenotype in individuals with AUD.

Genetic overlap between mood instability and alcohol-related phenotypes suggests shared biological underpinnings.

Alcohol use disorder (AUD) is a pervasive and devastating mental illness with high comorbidity rates with other mental disorders. Understanding the genetic architecture of this comorbidity could be improved by focusing on intermediate traits that show positive genetic correlation with the disorders. Thus, we aimed to characterize the shared vs. unique polygenicity of AUD, alcohol consumption (AC) and mood instability (MOOD)-beyond genetic correlation, and boost discovery for jointly-associated loci. Summary statistics for MOOD (a binary measure of the tendency to report frequent mood swings), AC (number of standard drinks over a typical consumption week) and AUD GWASs (Ns > 200,000) were analyzed to characterize the cross-phenotype associations between MOOD and AC, MOOD and AUD and AC and AUD. To do so, we used a newly established pipeline that combines (i) the bivariate causal mixture model (MiXeR) to quantify polygenic overlap and (ii) the conjunctional false discovery rate (conjFDR) to discover specific jointly associated genomic loci, which were mapped to genes and biological functions. MOOD was highly polygenic (10.4k single nucleotide polymorphisms, SNPs, SD = 2k) compared to AC (4.9k SNPs, SD = 0.6k) and AUD (4.3k SNPs, SD = 2k). The polygenic overlap of MOOD and AC was twice that of MOOD and AUD (98% vs. 49%), with opposite genetic correlation (-0.2 vs. 0.23), as confirmed in independent samples. MOOD&AUD associated SNPs were significantly enriched for brain genes, conversely to MOOD&AC. Among 38 jointly associated loci, fifteen were novel for MOOD, AC and AUD. MOOD, AC and AUD were also strongly associated at the phenotypic level. Overall, using multilevel polygenic quantification, joint loci discovery and functional annotation methods, we evidenced that the polygenic overlap between MOOD and AC/AUD implicated partlyshared biological underpinnings, yet, clearly distinct functional patterns between MOOD&AC and MOOD&AUD, suggesting new mechanisms for the comorbidity of AUD with mood disorders.

A prospective study revealing a compounded burden of COVID-19, sex, and clinical diagnosis of alcohol use disorder and HIV infection on quality of life, anxiety, and alcohol use

The COVID-19 pandemic led to unprecedented restrictions to mitigate disease spread, leading to consequences affecting mental health. Many studies examining COVID-19 pandemic effects on well-being and mental health initiated inquiry after the pandemic onset, whereas we used self-report questionnaires obtained before the pandemic to re-assess the same functions during the pandemic. Participants were drawn from our ongoing longitudinal studies of people with HIV infection, alcohol use disorder (AUD), HIV + AUD comorbidity, and controls. We used phone or mail contact to invite all to participate in our COVID phone survey, which included three self-report questionnaires: Health-related Quality of Life (QoL), State-Trait Anxiety Inventory (STAI), and Alcohol Use Disorder Identification Test (AUDIT). Of 218 eligible participants, 86 responded (July 2020–March 2021): clinical (29 men, 23 women; 17 AUD, 21 HIV, 14 HIV + AUD); control (17 men, 17 women). QoL scores declined, and anxiety symptoms increased from pre-COVID surveys in all groups; clinical women reported greater negative changes than the other groups. QoL subscales revealed COVID-related declines in emotional well-being in all groups, with clinical women reporting additional declines in energy, physical and social functioning, health, and pain increase. Clinical men also reported health declines. Although AUDIT scores were stable in all groups between assessments, changes in AUDIT scores were inversely correlated with QoL scores in clinical women; in clinical men, changes in STAI scores were inversely correlated with QoL scores. Although all groups were adversely affected by the pandemic, the negative effects were greater in the clinical group regardless of diagnosis and greatest in clinical women.

Comorbid alcohol and cannabis use disorders increase mortality in patients with eating disorders

IntroductionAlcohol and cannabis use disorders are the most frequent comorbid substance use disorders (SUDs) among patients with eating disorders (EDs). EDs and SUDs involving alcohol and cannabis are independently associated with excess mortality.ObjectivesTo investigate the impact of comorbid alcohol use disorder (AUD) and cannabis use disorder (CUD) on mortality in anorexia nervosa (AN), bulimia nervosa (BN), and unspecified eating disorder (USED) compared with matched control subjects.MethodsThis retrospective cohort study was conducted using Danish nationwide registers. The risk of mortality among ED patients with/without AUD and/or CUD was compared to matched control subjects with/without AUD and/or CUD using hazard ratios (HRs).ResultsOf the 20,759 included ED patients, 4.7% and 4.3% had AUD and CUD, respectively. The corresponding figures for the 83,036 control subjects were 1.0% (AUD) and 1.3% (CUD). ED patients without SUDs exhibited an increased risk of mortality compared to control subjects without SUDs (adjusted HR 2.9, P&lt;.001). Mortality risk was higher among ED patients with AUD (adjusted HR 11.8, P&lt;.001) or CUD (adjusted HR 4.6, P&lt;.001) compared to control subjects without AUD/CUD. In addition, patients with AN, BN, and USED, who had comorbid AUD and/or CUD, exhibited an elevated risk of mortality compared to control subjects without AUD/CUD (AN: adjusted HR 11.3, P&lt;.001; BN: adjusted HR 5.9, P&lt;.001; USED: adjusted HR 10.9, P&lt;.001).ConclusionsComorbid AUD and/or CUD increase mortality risk in patients with EDs. In order to reduce mortality in ED patients, prevention and treatment of AUD and CUD is important.DisclosureNo significant relationships.

The pharmacotherapeutic management of co-morbid bipolar disorder and alcohol use disorder

Introduction Comorbidity of bipolar disorder (BD) and alcohol use disorder (AUD) is very frequent resulting in detrimental outcomes, including increased mortality. Diagnosis of AUD in BD and vice versa is often delayed as symptoms of one disorder mimic and obscure the other one. Evidence for pharmacotherapies for people with comorbid BD and AUD remains limited, and further proof-of-concept studies are urgently needed. Areas covered This paper explores the currently available pharmacotherapies for AUD, BD and their usefulness for comorbid BD and AUD. It also covers to some degree the epidemiology, diagnosis, and potential common neurobiological traits of comorbid BD and AUD. Expert opinion The authors conclude that more controlled studies are needed before evidence-based guidance can be drawn up for clinician’s use. Since there are no relevant pharmacological interactions, approved medications for AUD can also be used safely in BD. For mood stabilization, lithium should be considered first in adherent persons with BD and comorbid AUD. Alternatives include valproate, lamotrigine and some atypical antipsychotics, with partial D2/D3 receptor agonism possibly being beneficial in AUD, too.