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Jenny Skumsnes Moe,1,2 Jørgen G Bramness,1– 4 Ingeborg Bolstad,1,5 Jørg Gustav Mørland,3,6 Philip Gorwood,7,8 Nicolas Ramoz7,8 1Research Center for Substance Use Disorders and Mental Illness, Innlandet Hospital Trust, Brumunddal, Norway; 2Institute for Clinical Medicine, The Arctic University of Norway, Tromsø, Norway; 3Department of Alcohol, Tobacco, and Drugs, Norwegian Institute of Public Health, Oslo, Norway; 4Section for Clinical Addiction Research, Oslo University Hospital, Oslo, Norway; 5Department of Health and Social Science, Inland Norway University of Applied Sciences, Elverum, Norway; 6Institute of Clinical Medicine, University of Oslo, Oslo, Norway; 7Université Paris Cité, Inserm U1266, Institut de Psychiatrie et Neurosciences de Paris (IPNP), Team Vulnerability of Psychiatric and Addictive Disorders, Paris, France; 8GHU PARIS Psychiatrie & Neurosciences, Hôpital Sainte-Anne, CMME, Paris, FranceCorrespondence: Jenny Skumsnes Moe, Research Center for Substance Use Disorders and Mental Illness, Innlandet Hospital Trust, P.O. Box 104, Brumunddal, 2381, Norway, Email jenny.s.moe@uit.noPurpose: Alcohol use is a leading risk factor for preventable death, injury, and disease globally. Low sensitivity to the effects of alcohol is influenced by genes and predicts risk for harmful alcohol use and alcohol use disorder (AUD). Alcohol induces effects partly by modulation of gamma-aminobutyric acid receptors type A (GABAARs). This study investigates the relationship between genetic variation in GABAAR subunit genes and individual alcohol sensitivity among French university students.Patients and Methods: The study involved 1,409 French university students (34.5% women; mean age 20.3 years). Alcohol sensitivity was measured by the Self-Rating of the Effects of Alcohol Scale (SRE). SRE-scores from initial drinking, regular drinking, and heavy drinking were investigated for correlations with alcohol consumption and for associations with single nucleotide polymorphisms (SNPs) in GABAAR subunit genes (GABRA2, GABRG2, GABRA6).Results: We replicated correlations between low alcohol sensitivity and high alcohol consumption. We further found an association between the minor allele in rs211014 (GABRG2) and higher SRE-scores, linked to dizziness and motor incoordination. Genetic variation in GABRG2 has previously been associated with processes involving motor coordination (alcohol withdrawal, febrile- and epileptic seizures).Conclusion: The results from our study suggest that genetic variation in GABRG2 may influence alcohol sensitivity, which could inform strategies for assessing risk for harmful alcohol use and AUD.Keywords: alcohol use, GABRG2, self-rating of the effects of alcohol, genetic, AUD, AUDIT

Jørgen G Bramness,1– 3 Susmita Pandey,1 Jenny Skumsnes Moe,1,3 Helge Toft,4 Lars Lien,1,4 Fredrik A Walby,5 Martin Øverlien Myhre,5 Ingeborg Bolstad1,4 1Norwegian National Advisory Unit on Concurrent Substance Abuse and Mental Health Disorders, Innlandet Hospital Trust, Brumunddal, Norway; 2Norwegian Institute of Public Health, Department of Alcohol, Tobacco and Drugs, Oslo, Norway; 3Institute of Clinical Medicine, UiT – The Arctic University of Norway, Tromsø, Norway; 4Faculty of Social and Health Sciences, Inland Norway University of Applied Sciences, Elverum, Norway; 5National Centre for Suicide Research and Prevention, Institute of Clinical Medicine, University of Oslo, Oslo, NorwayCorrespondence: Jørgen G Bramness, Norwegian Institute of Public Health, P.O.Box 222, Oslo, 0213, Norway, Email jobr@fhi.noBackground: Patients with alcohol use disorder (AUD) have an increased risk of suicide. Neuroimmunological measures, such as cytokines, are shown to deviate in people with attempted suicide. Few studies have investigated this among AUD patients.Patients and Methods: One-hundred and fourteen patients undergoing residential treatment for AUD were interviewed on lifetime suicide attempts (SA) along with several other background variables and clinical characteristics. Serum blood samples were drawn for analysis of cytokines.Results: Thirty-one patients (27%) reported at least one SA. These patients had more symptoms of current affective disorders and more severe dependence. In bivariate analysis only IL-6 and IL-10 appeared to be associated with lifetime SA but without reaching statistical significance. In multivariate linear regression, adjusting for sex, nicotine use, somatic illness, and the use of anti-inflammatory drugs, IL-6 was associated to SA (p = 0.033).Conclusion: The cytokine IL-6 has repeatedly been found to be associated with suicidality. The present study concurs with this role of IL-6 in a naturalistic observational study of AUD patients.Keywords: alcohol use disorder, suicide attempted, cytokines, interleukins

Jørgen G Bramness,1– 3 Susmita Pandey,1 Jenny Skumsnes Moe,1,3 Helge Toft,1,4 Lars Lien,1,4 Ingeborg Bolstad1,4 1Norwegian National Advisory Unit on Concurrent Substance Abuse and Mental Health Disorders, Innlandet Hospital Trust, Brumunddal, Norway; 2Norwegian Institute of Public Health, Department of Alcohol, Tobacco and Drugs, Oslo, Norway; 3Institute Clinical of Medicine, UiT – The Arctic University of Norway, Tromsø, Norway; 4Department of Health Studies, Inland Norway University of Applied Sciences, Elverum, NorwayCorrespondence: Jørgen G Bramness, Norwegian Institute of Public Health, P.O.Box 222, Oslo, 0213, Norway, Email jobr@fhi.noIntroduction: Delirium tremens (DT) occurs after stopping prolonged, high alcohol intake and may be life-threatening if untreated. We need to know about clinical correlates of DT in order to provide the best clinical care.Methods: At admission to inpatient treatment a cohort of 114 alcohol use disorder (AUD) patients were interviewed and examined concerning psychiatric diagnosis and symptoms, trauma experiences and alcohol related measures and if they had experienced DT.Results: Twenty-four percent of the patients reported a life-time experience of DT. These patients were predominantly males and had lower educational level. More of the patients in the DT than the non-DT group reported at least one suicide attempt, were diagnosed with PTSD, and dropped out of treatment. Also, having parents with alcohol problems was more common among these patients, and they reported a longer duration of problematic drinking and a higher number of drinks needed to feel an effect of drinking. In the multivariable adjusted analysis only a diagnosis of PTSD (OR=5.71; 95% confidence interval (CI): 1.34– 24.31) and duration of problematic drinking with a 6% increase in risk for every year (OR=1.06; 95% CI: 1.01– 1.11) remained significant risk factors for having DT experience.Discussion and conclusion: Having experienced DT was more prevalent in the current investigation than in earlier studies. Patients that had experienced DT seemed to have more serious AUD, especially signified by a longer duration of drinking. These patients seemed to have many clinical disadvantages including more drop-out and higher suicide rate. PTSD could be a risk factor for DT but may also follow the DT experience.Keywords: alcohol use disorder, delirium tremens, treatment, PTSD

Susmita Pandey,1,2 Ingeborg Bolstad,1 Lars Lien,1,3 Jørgen G Bramness1,4,5 1Norwegian National Advisory Unit on Concurrent Substance Abuse and Mental Health Disorders, Innlandet Hospital Trust, Brumunddal, Norway; 2Institute of Clinical Medicine, University of Oslo, Oslo, Norway; 3Department of Health and Social Science, Innlandet University of Applied Science, Elverum, Norway; 4Department of Clinical Medicine, UiT – Norway’s Arctic University, Tromsø, Norway; 5Norwegian Institute of Public Health, Oslo, NorwayCorrespondence: Susmita Pandey Email susmita.research@gmail.comBackground: Patients with alcohol use disorders (AUD) vary significantly in many clinically important characteristics making them a heterogenous group. AUD patients with comorbid antisocial personality disorder (ASPD) form an important sub-group, and studies indicate that these patients may have poorer treatment outcomes. Therefore, we aimed to investigate the characteristics of AUD inpatients with comorbid ASPD and identify predictors of early relapse or treatment drop-out in these patients.Methods: In a longitudinal study of AUD patients (n = 113; 30 females; aged 27 to 72 years) in treatment at three residential rehabilitation clinics in Norway, we used interviews and self-report questionnaires to collect data on alcohol use, mental health, and trauma experience. In addition, we assessed biochemical parameters. The patients were followed up at 6 weeks to identify early relapse or drop-out.Results: Prevalence of ASPD among AUD patients was 15%. AUD patients with comorbid ASPD were exclusively male, of younger age, and reported more childhood trauma, and adult attention-deficit-hyperactivity-disorder symptoms. They reported more hazardous drinking behavior and more often had dependence on substances in addition to alcohol. The presence of ASPD did not predict early relapse or drop-out. However, early relapse or drop-out in ASPD patients was associated with childhood and adult trauma, younger age of drinking debut, and higher baseline prolactin levels.Conclusion: AUD patients with ASPD had different clinical characteristics to other AUD patients and they had specific predictors of early relapse or drop-out. Our findings indicate that the early relapse or drop-out among AUD patients with ASPD may be attributed to environmental and possibly biological vulnerability. However, further studies with larger sample size are warranted to confirm these preliminary associations.Keywords: alcohol use disorder, antisocial personality disorder, relapse, drop-out

Insomnia is prevalent among patients with alcohol use disorder (AUD), potentially undermining treatment and increasing the risk of relapse. Cognitive behavioral therapy for insomnia (CBT-I) is the recommended first-line treatment for insomnia, but its efficacy is not well-characterized in patients across the spectrum of AUD. The aim of this meta-analysis was to quantify the effectiveness of CBT-I in improving insomnia severity and alcohol-related outcomes in adults with heavy alcohol use and/or varying levels of AUD severity and comorbid insomnia. MEDLINE, Cochrane Library, PsycINFO and ClinicalTrials.gov were systematically searched (up to February 2024) to retrieve randomized controlled trials (RCTs). Multilevel meta-analyses were conducted to estimate mean differences over time in insomnia severity, measured using the Insomnia Severity Index (ISI), as well as in alcohol craving and alcohol-related psychosocial problems between CBT-I and control groups. For the number of heavy-drinking/abstinent days, incidence rate ratios were estimated. Risk of bias was assessed using the Risk of Bias 2 (RoB 2) tool. Eight RCTs encompassing 426 adults (68.78 % men) were included. Compared with control conditions, CBT-I resulted in a large reduction of insomnia severity post-treatment [estimated ISI reduction = -5.51, 95% CI (-7.13 to -3.90)], which was maintained at 1-to-3-month [7 studies; estimate = -4.39, 95% CI (-6.08 to -2.70)], and 6-month follow-up [4 studies; estimate = -4.55, 95% CI (-6.77 to -2.33)]. Alcohol-related outcomes were reported less consistently, and no significant differences were found. The included trials were judged to have a low or moderate overall risk of bias for the assessment of all outcomes. CBT-I effectively reduces insomnia severity across the spectrum of AUD, supporting wide implementation in AUD prevention and treatment settings. PROSPERO REGISTRATION NUMBER: CRD42023464612., Competing Interests: Conflict of interest disclosures Dr. Chakravorty has received research support from AstraZeneca Pharmaceuticals and Teva Pharma. The other authors have no conflicts of interest to declare., (Copyright © 2025 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Smoking is negatively related to mental health, but there is a paucity of research on the relationship between the use of smokeless tobacco, such as snus, and mental health outcomes, especially in people with alcohol use disorders (AUD). The aim of the present study was to examine the development of mental distress and quality of life (QoL) among AUD patients in treatment who did or did not use snus., Method: The study included 128 AUD patients (27% female) from three rehabilitation clinics in Eastern Norway who were interviewed at admission, at 6 weeks, and after 6 months. Patients were asked about their mental health-related problems, alcohol, and substance use, QoL, and physical activity. Information about tobacco use was gathered with the questions "Do you smoke cigarettes?" and "Do you use snus?", with follow-up questions "How often?"., Result: There were 39 current snus users (31%), of which 20 were also current smokers (dual users). Seventy-five patients (59%) were smokers only, and only 14 (11%) patients were abstainers. Those who used snus only had a lower severity of dependence score than the other groups (p < 0.05). The dual use group reported lower QoL than the no tobacco use group. In a regression model adjusted for sex and age, smokers and dual users, but not users of snus, had higher levels of mental distress and poorer QoL compared to nontobacco users (p < 0.05). There were no differences between tobacco groups at follow-ups., Conclusion: In this study, among AUD patients, snus users reported QoL and mental distress close to that of non-smokers, indicating a lower problem load among snus users compared to smokers., Implications: Previous studies have shown conflicting results regarding the potential harm reduction effect of snus use among patients with AUD who smoke regarding their tobacco use, quality of life and mental health problems. This study suggests that snus use could also be a viable alternative to smoking for patients with addictions., (© 2024. The Author(s).)

Background: Comorbid anxiety and depression are common and can make the problems more complex and sometimes resistant to pharmacological treatment. In existing research, the diagnoses are often studied separately, and physical activity, healthy nutrition, psychoeducation, and social support have shown good effects. The aim of the present study was to explore the longitudinal effects of a comprehensive treatment on patients with comorbid anxiety and depression in a clinical context., Method: Eighty inpatients (15 men and 65 women) in age range 23-65 years receiving psychiatric treatment in Norwegian clinic participated in the longitudinal study. Treatment was person-centered and was most frequently given for anxiety and depression, e.g., pharmacological treatment and psychotherapy, individually and in groups. In combination with this, physical activity, healthy nutrition, psychoeducation and social support in contacts with authorities and relatives were also a part of treatment. Depression and anxiety were assessed using the Beck Anxiety Inventory and Beck Depression Inventory at three points in time: baseline, at the end of treatment, and 3 months after treatment. The answers were categorized and combined into four groups according to severity of anxiety and depression to measure effects on comorbidity. Mann Whitney U test, Chi-square, Friedmans test, and McNemar test were used to analyze the data., Result: The results showed a significant increase of frequencies in the group with mild anxiety and depression 3 months past treatment compared to baseline., Conclusion: Through the comprehensive, person-centered treatment more patients had low levels of both anxiety and depression 3 months after treatment. We suggest that clinics working with comorbid depression and anxiety patients should add physical activity, nutrition advice, social support, and psychoeducation to the traditional treatment regimes. More research concerning comorbid anxiety and depression are urgent to further expand the treatment possibilities., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Svensén, Bolstad, Ødbehr and Larsson.)

FtsH, a AAA protease, associates with HflK/C subunits to form a megadalton complex that spans the inner membrane and extends into the periplasm of E. coli . How this complex and homologous assemblies in eukaryotic organelles recruit, extract, and degrade membrane-embedded substrates is unclear. Following overproduction of protein components, recent cryo-EM structures reveal symmetric HflK/C cages surrounding FtsH in a manner proposed to inhibit degradation of membrane-embedded substrates. Here, we present structures of native complexes in which HflK/C instead forms an asymmetric nautilus-like assembly with an entryway for membrane-embedded substrates to reach and be engaged by FtsH. Consistent with this nautilus-like structure, proteomic assays suggest that HflK/C enhances FtsH degradation of certain membrane-embedded substrates. The membrane curvature in our FtsH•HflK/C complexes is opposite that of surrounding membrane regions, a property that correlates with lipid-scramblase activity and possibly with FtsH's function in the degradation of membrane-embedded proteins., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.

Aims: Patients who have undergone some forms of bariatric surgery have increased risk of developing alcohol use disorder (AUD). In the present observational study, we compared patients with AUD who themselves reported to having undergone bariatric surgery with other patients in treatment for AUD., Materials: One-hundred-and-six consecutively enrolled patients in residential treatment for AUD were asked if they had undergone bariatric surgery. Sociodemographics, mental health-related, and alcohol use-related parameters were compared between those who had and those who had not undergone bariatric surgery., Results: Of the 106 patients with AUD, seven (6.6%; 95% confidence interval, 2.7%-13.1%) had undergone bariatric surgery. Six of seven patients had undergone such surgery were women (P < .001). The patients with AUD who had undergone bariatric surgery were similar to other patients with AUD on most other parameters, the exception being a larger number of alcohol units ingested to feel an effect of alcohol (adjusted odds ratio 7.1; 95% confidence interval 2.0-12.2; P = .007)., Conclusion: The high number of patients with AUD that reported having undergone bariatric surgery emphasizes the risks following such a procedure. The overrepresentation of women may reflect than more women undergo such procedures. The unexpected finding that patients with AUD having undergone bariatric surgery seemed to need more alcohol to feel intoxicated warrants further research., (© The Author(s) 2024. Medical Council on Alcohol and Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Smoking and alcohol use often co-occur, and the use of nicotine-containing products is particularly common among persons with alcohol use disorder (AUD). Recent evidence shows that chronic alcohol use leads to inflammation through increased gut permeability and dysregulated cytokine levels. While cigarette smoking also has detrimental health effects, nicotine has immune dampening effects in some settings. Preclinical evidence demonstrates that nicotine can dampen alcohol-induced inflammation, but inflammatory responses after nicotine use has not been studied in persons with AUD. This study compared the level of circulating cytokines in abstinent AUD inpatients who were non-tobacco users, smokers, users of Swedish snus, or dual tobacco users., Methods: We collected blood samples and information about somatic and mental health and tobacco habits from 111 patients in residential treatment for AUD and 69 healthy controls. Levels of interferon (IFN)-γ, interleukin (IL)-10, tumor necrosis factor (TNF)-α, IL-17a, IL-1β, IL-6, IL-8, IL-1 receptor antagonist (ra), and monocyte chemoattractant protein (MCP)-1 were examined using a multiplex assay., Results: Patients with AUD had higher levels of seven cytokines than healthy controls. Among the AUD patients, nicotine users had lower levels of IL-10, TNF-α, IL-17a, IL-1β, IL-8, and MCP-1 (all p < 0.05)., Conclusions: Our findings may indicate that nicotine has anti-inflammatory effects in patients with AUD. Nonetheless, nicotine use cannot be recommended as a viable therapeutic option to reduce alcohol-induced inflammation because of its other adverse effects. Additional studies of the effects of tobacco or nicotine products on cytokine patterns in relation to mental or somatic health conditions are warranted., (© 2023 The Authors. Alcohol: Clinical and Experimental Research published by Wiley Periodicals LLC on behalf of Research Society on Alcohol.)

Background: Posttraumatic stress disorder (PTSD) is associated with cardiometabolic diseases, concurrent anxiety, alcohol use disorder and depression. The relationship between PTSD and cardiometabolic diseases are still unclear, and less is known about the effects of socioeconomic status, comorbid anxiety, comorbid alcohol use disorder and comorbid depression. The study, therefore, aims to examine the risk of developing cardiometabolic diseases including type 2 diabetes mellitus over time in PTSD patients, and to what extent socioeconomic status, comorbid anxiety, comorbid alcohol use disorder and comorbid depression attenuate associations between PTSD and risk of developing cardiometabolic diseases., Method: A retrospective, register-based cohort study with 6-years follow-up of adult (> 18 years) PTSD patients (N = 7 852) compared with the general population (N = 4 041 366), was performed. Data were acquired from the Norwegian Patient Registry and Statistic Norway. Cox proportional regression models were applied to estimate hazard ratios (HRs) (99% confidence intervals) of cardiometabolic diseases among PTSD patients., Results: Significantly (p < 0.001) higher age and gender adjusted HRs were disclosed for all cardiometabolic diseases among PTSD patients compared to the population without PTSD, with a variation in HR from 3.5 (99% CI 3.1-3.9) for hypertensive diseases to HR = 6.5 (5.7-7.5) for obesity. When adjusted for socioeconomic status and comorbid mental disorders, reductions were observed, especially for comorbid depression, for which the adjustment resulted in HR reduction of about 48.6% for hypertensive diseases and 67.7% for obesity., Conclusions: PTSD was associated with increased risk of developing cardiometabolic diseases, though attenuated by socioeconomic status and comorbid mental disorders. Health care professionals should be attentive towards the burden and increased risk that low socioeconomic status and comorbid mental disorders may represent for PTSD patients' cardiometabolic health., (© 2023. The Author(s).)

Background: Alcohol and other substance use disorders and major depression often co-occur. A sedentary lifestyle is related to major depression and even moderate exercise may prevent and contribute to the treatment of depression. Studies have found an effect of physical activity on depression in alcohol and other substance use disorder patients even in clinical settings., Aim: To investigate the relationship between level of physical activity and depressive symptoms over time in alcohol and substance use disorder inpatients., Methods: Eighty-nine substance use disorder inpatients were followed for 6 months during treatment. The International Physical Activity Questionnaire was used to categorize 3 groups of low, moderate, or high level of physical activity. In addition to background variables and alcohol and drug use measures, data on biometric measures and on sleep were gathered. Becks Depression Inventory version II (BDI-II) measured depressive symptoms. A multilevel logistic regression was used to analyze the longitudinal relationship between physical activity and depressive symptoms., Results: Most patients (57%) reported low activity, while 24% reported moderate and 19% high activity. Few changed their activity level during treatment. Moderate physical activity was related to lower score on BDI-II ( P  = .029). Level of physical activity was closely related to insomnia ( P  = .024). In the multivariate analysis the relationship between depressive symptoms and physical activity did not withstand the adjustment for insomnia. However, in the multilevel logistic regression higher physical activity was related to lower BDI-II score in a dose dependent manner., Conclusions: Among these alcohol and other substance use disorders patients in treatment, there was a relationship between depressive symptoms and physical activity. The low level of physical activity identified among these patients was related to a high level of depressive symptoms. The level of depressive symptoms declined over time; but this change was not related to an increase in physical activity., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Insomnia is common among patients with AUD and can impair quality of life and cognitive functioning, as well as cause psycho-social problems and increased risk of relapse. Nonetheless, determinants of insomnia in patients with AUD have scarcely been studied. We aimed to examine prevalence and development of self-perceived insomnia among inpatients in treatment for AUD, and to examine factors in this group known to be associated with sleep disturbance in the general population. We examined self-reported information about sleep from 94 AUD inpatients in long-term treatment (up to 9 months) using a questionnaire identifying probable insomnia. Potential predictors identified in bivariate tests were used in binomial logistic regressions to examine the effect on sleep at baseline and at 6-week follow-up. Longitudinal multilevel analyses were used to examine factors affecting development of sleep quality during the treatment stay. At baseline, 54% of the patients reported sleep problems indicating insomnia. This was reduced to 35% at 6-week follow-up. In a cross-sectional analysis of sleep at baseline, we found that being male (OR 0.18, p = 0.042) and engaging in physical activity (OR 0.09, p < 0.001) were negatively associated with insomnia, while a high level of depressive symptoms (OR 1.10, p = 0.010) was positively associated after adjustment for age, history of trauma, and severity of dependence. Multilevel analyses of data over a 6-month period showed time interactions with physical activity, such that sleep improvement was greater in patients who initially had a low level of physical activity. This longitudinal study corroborates findings of high prevalence of insomnia among AUD patients and identifies factors in this group associated with insomnia, such as sex, depression, and physical activity. Future longitudinal studies are needed to examine the causal directions between sleep, depression, and physical activity and how these might be targeted in clinical settings., Competing Interests: Declaration of competing interest None., (Copyright © 2022. Published by Elsevier Inc.)

Introduction: Alcohol, tobacco and coffee are commonly used substances and use in adolescence has previously been linked to mood disorders. However, few large prospective studies have investigated adolescent use in relation to mental health outcomes in adulthood. The main aim of this study was to examine the prospective associations between alcohol use, cigarette smoking and coffee consumption at age 16 and subsequent mood disorders up to 33 years of age., Methods: Data from The Northern Finland Birth Cohort 1986 Study were used and a total of 7660 participants (49.9% male) were included. Associations between alcohol use, cigarette smoking and coffee consumption at age 16 and later diagnoses of major depression and bipolar disorder were examined using multinomial logistic regression analyses., Results: Mean number of cigarettes/day (OR, 1.23 [95% CI 1.01-1.50]) and mean volume of alcohol consumption (OR, 1.22 [95% CI 1.01-1.47]), but not frequency of excessive drinking, in adolescence were associated with increased risk for subsequent bipolar disorder after adjustment for sex, parental psychiatric disorders, family structure, illicit substance use, and emotional and behavioral problems at age 16. An association between cigarette smoking and major depression attenuated to statistically non-significant when adjusted for emotional and behavioral problems. No associations were observed between adolescent coffee consumption and subsequent mood disorders., Conclusions: This is the first study to report an association of adolescent cigarette smoking and subsequent bipolar disorder diagnosis providing grounds for further research and pointing to a place for preventive measures among adolescents., (© 2022 The Authors. Acta Psychiatrica Scandinavica published by John Wiley & Sons Ltd.)

Background: Patients with alcohol use disorder (AUD) are at high risk for suicide attempts. Mental health problems along with AUD-related factors may contribute to this increased risk. Studies have shown sex differences in rates and correlates of suicide attempts., Aims: The purpose of the study was to examine mental-health-related and AUD-related factors associated with suicide attempt separately in female and male AUD patients., Method: We collected information about lifetime suicide attempt and mental-health- and AUD-related factors for AUD in-patients ( n = 114; 32 females) receiving rehabilitative treatment., Results: The prevalence of lifetime suicide attempt was 27%, and the rate was similar in both sexes. Among females, current depressive symptoms and current post-traumatic stress disorder diagnosis were associated with suicide attempt. In male AUD patients, among the mental-health-related factors, lifetime major depression, panic disorder, social phobia, childhood sexual abuse and antisocial personality disorder were associated with suicide attempt. In addition, AUD-related factors including longer duration of drinking, history of delirium tremens, greater severity of AUD and lower levels of prolactin were associated with suicide attempt in males., Conclusions: Our results indicate that suicide attempts in female AUD patients were more mental-health-related, whereas those in males were also related to the severity of AUD. This suggests that a suicide prevention programme for AUD patients would benefit from a sex-based understanding of the risk factors.

Alcohol use disorder (AUD) and major depressive disorder (MDD) are prevalent disorders that often co-occur. The aim of the study was to investigate how the Beck Depression Inventory (BDI-II) and Hopkins Symptom Checklist (HSCL-10) perform as screening instruments for MDD in AUD patients in treatment. The study included 127 mainly AUD inpatients currently in treatment at rehabilitation clinics in Norway. Demographic and clinical variables were examined using questionnaires and clinical interviews. The factor structures of the BDI-II and HCSL-10 were examined, as well as internal consistency and receiver operating characteristic (ROC) curve analyses. The Mini International Neuropsychiatric Interview (M.I.N.I.) was used as standard for diagnosing MDD. In total, 14% of the participants were diagnosed with MDD. BDI-II factor analysis retrieved three factors; cognition, somatic complaints and affect, and factor analysis for the HSCL-10 retrieved two factors; depression and anxiety. The optimal cut-off for the BDI-II was 24.5 with sensitivity of 80% and specificity of 78%. For HSCL-10 the optimal cut-off was 2.35, giving sensitivity of 80% and specificity of 69%. Both the BDI-II and HSCL-10 may be clinically useful screening instruments for MDD in AUD patients. There was a tendency that the affect factor of the BDI-II and the depression factor of the HSCL-10 were slightly more suitable for identifying MDD than the other factors. Optimal cut-offs for both the BDI-II and the HSCL-10 in this patient group were higher than cut-offs commonly used in the general population., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Little is known about genetic influences on the relationship between alcohol consumption and mental distress in the general population, where the majority report consumption and distress far below diagnostic thresholds. This study investigated single nucleotide polymorphisms (SNPs) from candidate gene studies on alcohol use disorder and depressive disorders, for association with alcohol consumption and with mental distress in a population-based sample from the Cohort of Norway (n = 1978, 49% women). The relationship between alcohol consumption and mental distress was further examined for genotype modification. There was a positive correlation between mental distress and alcohol consumption in men, as well as an association between SNPs and mental distress in men (GABRG1, GABRA2, DRD2, ANKK1, MTHFR) and women (CHRM2, MTHFR) and between SNPs and alcohol consumption in women (GABRA2, MTHFR). No modification by SNP genotype was found on the relationship between alcohol consumption and mental distress. The association between mental distress and GABRG1 in men remained significant after correcting for multiple comparisons. The results indicate that alcohol consumption and mental distress are associated in the general population even at levels below clinical thresholds and point to SNPs in genes related to GABAergic signalling for level of mental distress in men., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: Cross-sectional data show that post-traumatic stress disorder (PTSD) patients often have increased levels of circulating inflammatory markers. There is, however, still a paucity of longitudinal studies with long follow-up times on levels of cytokines in such patients. The current study assesses patients with and without PTSD diagnosis 1 year after discharge from inpatient treatment., Methods: Patients in treatment for serious non-psychotic mental disorders were recruited at the beginning of their treatment stay at a psychiatric centre in Norway. Ninety patients submitted serum samples and filled out the Hopkins Symptom Checklist-90 Revised Global Severity Index (HSCL-90R GSI) questionnaire during their mainstay and at a follow-up stay 1 year after discharge. Of these patients, 33 were diagnosed with PTSD, 48 with anxiety, depression, or eating disorder, while 9 patients had missing data. The patients were diagnosed using the Mini-International Neuropsychiatric Interview (MINI)., Results: At the follow-up stay (T3), PTSD patients had higher levels of GSI scores than non-PTSD patients (p = 0.048). These levels were unchanged from the year before (T2) in both groups. The levels of circulating cytokines/chemokine did not differ between the PTSD and non-PTSD patients at T3. At T2, however, the PTSD and non-PTSD groups exhibited different levels of interleukin 1β (IL-1β) (p = 0.053), IL-1RA (p = 0.042), and TNF-α (p = 0.037), with the PTSD patients having the higher levels., Conclusion: Despite exhibiting different mental distress scores, the PTSD and non-PTSD patients did not differ regarding levels of circulating inflammatory markers at 1-year follow-up.

Background: Unhealthy changes in eating behavior among people experiencing trauma have been observed. There is, however, a lack of in-depth knowledge regarding the impact of the after effects of traumatic life experiences on eating behavior. Because eating behavior represents important components for promotion and maintenance of good health throughout life, this study aimed to explore inpatients' lived experiences of the impact of traumatic stress on eating behavior., Method: Thirteen female and two male inpatients (age range 28-62 years), recruited from a psychiatric clinic in Norway, participated in this qualitative explorative focus group study. The data analysis was performed using systematic text condensation., Results: The results in the present study describe the participants' experiences about the impact of traumatic stress on their eating behavior. Their discussions and descriptions disclosed problems that could be summarized into four main themes: "experiencing eating behaviors as coping strategies"; "experiencing being addicted to food and sweets"; "experiencing eating behaviors controlled by stress and emotions"; and "experiencing lack of appetite and reduced capacity to plan and prepare meals"., Conclusion: Traumatic stress can impact eating behavior in several complex ways that over time may cause adverse health consequences. The results add to an important understanding of changes in eating behavior that might appear in people struggling to cope with the after effects of traumatic life experiences to the existing literature. To better understand the complexity of how traumatic experiences may impact eating behavior, this knowledge is important and useful for health professionals offering support to those who experience struggling with eating behavior after traumatic experiences., (© 2021. The Author(s).)

Background: Prolactin mirrors the dopaminergic activity in the brain which is key to understanding alcohol use disorders (AUD). Still, patients with AUD are a heterogenous group and there seem to be gender differences in the relationship between alcohol use and the level of prolactin. In this study, we examined gender-wise relationship of alcohol use trait- and state-related factors with the level of prolactin among AUD inpatients in remission., Methods: This cross-sectional study examined the level of prolactin along with general patient characteristics and alcohol use trait- and state-related factors that could influence the level of prolactin in 112 AUD inpatients at three rehabilitation clinics in Norway. Logistic regression was performed to identify the gender-specific predictors of level of prolactin., Results: Male and female AUD patients had similar level of prolactin. Among females, younger age, early alcohol debut, and absence of parental drinking problem predicted higher level of prolactin. In males, presence of other substance dependence predicted a lower level of prolactin., Conclusions: There were gender differences in the factors associated with the level of prolactin among the AUD patients. Especially in the female AUD patients under remission, alcohol use trait-related factors were better predictors of the level of prolactin than the alcohol use state-related factors, indicating that individuals might characteristically have varying degree of dopamine reactivity., (© 2021 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of the Japanese Society of Neuropsychopharmacology.)

Attention deficit hyperactivity disorder (ADHD) and post-traumatic stress disorder (PTSD) are more common in alcohol use disorder (AUD) patients than in the general population. Still, there is a lack of knowledge about the relationship between the two conditions in these patients. The main objective of this study was to examine the prevalence of ADHD symptoms, and the relationship between ADHD symptoms and PTSD in AUD inpatients in treatment. Data from 85 AUD patients were collected. The Adult ADHD Self-Report Scale (ASRS) was used to measure ADHD symptoms in all patients. Differences between groups split by PTSD diagnosis and by ASRS clinical cut-off were described, and the relationship between ADHD symptom level and PTSD was tested in a multiple regression model. Almost half the patients scored above ASRS cut-off and 14% had PTSD. Of the patients whose score was above cut-off on the ASRS 23% had PTSD, versus 7% among those below cut-off. Higher ASRS score was associated with PTSD even when age, sex and trauma were adjusted for. This study confirms the high level of ADHD symptoms in AUD patients in treatment. Diagnostic evaluation of PTSD is recommended in patients with ADHD attending inpatient treatment programs for AUD., (Copyright © 2021. Published by Elsevier B.V.)

Background: Smoking is still prevalent among people with substance use disorders. The objective of this study was to investigate the prevalence of smoking among patients in treatment for substance use disorders and to analyze the effect of smoking both at baseline and follow-up on drop-out, mental health and quality of life., Methods: One hundred and twenty-eight inpatients (26% female), mainly with alcohol use disorder, staying at three different rehabilitation clinics in Eastern Norway, were interviewed at admission, and at 6 weeks and 6 months follow-up. The interview contained mental health-related problems, trauma, questions on alcohol and other substances and quality of life. Non-parametric tests were used to test group differences and unadjusted and adjusted linear regression to test the associations between smoking and the main outcome variables, while logistic regression was used to test the association between smoking and drop-out., Results: At admission, 75% were daily smokers. Compared to non-smokers at baseline, the smokers had higher drop-out rates (37% vs. 13%), more mental distress, and lower quality of life from baseline up to 6 months follow-up. Those quitting smoking while admitted improved in mental distress and quality of life at the same rate as non-smokers. Alcohol-related factors did not differ between smokers and non-smokers., Conclusions: Smoking was associated with mental distress, quality of life and treatment drop-out among patients in primary alcohol use disorder treatment. The results indicate that smoking cessation should be recommended as an integral part of alcohol use treatment both before and during inpatient treatment to reduce drop-out.

The left inferior frontal gyrus and the bilateral ventral striatum are thought to be involved in motivation-mediated decision-making. Antipsychotics may influence this relationship, and atypical antipsychotics improve secondary negative symptoms in schizophrenia, such as loss of motivation, although the acute effects of pharmacological medication on motivation are not fully understood. In this single-blinded, randomized controlled trial, 49 healthy volunteers were randomized into three groups to receive a single dose of haloperidol, aripiprazole or placebo. Between 4.0 and 5.6 h later, participant's brain blood-oxygen-level dependent (BOLD) activity was recorded using functional magnetic resonance imaging (fMRI) while completing a perceptual decision-making fMRI task consisting of one neutral and one motivated condition. Response bias, reflecting the participant's willingness to say that the target stimulus is present, was calculated using signal detection theory. Concurrent with widespread changes in BOLD signal in the motivated vs. neutral condition, a less conservative, mathematically optimal response bias was observed in the motivated condition across the whole sample. Within-group differences in BOLD signal in the left inferior frontal gyrus and bilateral ventral striatum were observed between conditions in the aripiprazole and haloperidol groups, but not in the placebo group. No robust between-group differences in brain activity in the left inferior frontal gyrus or the bilateral ventral striatum were found. Overall, we found no robust evidence for an effect of either aripiprazole or haloperidol on motivationally mediated behavior. An interesting pattern of correlations possibly related to pharmacologically induced alterations in the dopamine system was observed, although findings remain inconclusive and must be replicated in larger samples., (Copyright © 2020 IBRO. Published by Elsevier Ltd. All rights reserved.)

The atypical antipsychotic drug aripiprazole is a partial dopamine (DA) D2 receptor agonist, which differentiates it from most other antipsychotics. This study compares the brain activation characteristic produced by aripiprazole with that of haloperidol, a typical D2 receptor antagonist. Healthy participants received an acute oral dose of haloperidol, aripiprazole or placebo, and then performed an active aversive conditioning task with aversive and neutral events presented as sounds, while blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) was carried out. The fMRI task, targeting the mesolimbic motivational system that is thought to be disturbed in psychosis, was based on the conditioned avoidance response (CAR) animal model - a widely used test of therapeutic potential of antipsychotic drugs. In line with the CAR animal model, the present results show that subjects given haloperidol were not able to avoid more aversive than neutral task trials, even though the response times were shorter during aversive events. In the aripiprazole and placebo groups more aversive than neutral events were avoided. Accordingly, the task-related BOLD-fMRI response in the mesolimbic motivational system was diminished in the haloperidol group compared to the placebo group, particularly in the ventral striatum, whereas the aripiprazole group showed task-related activations intermediate of the placebo and haloperidol groups. The current results show differential effects on brain function by aripiprazole and haloperidol, probably related to altered DA transmission. This supports the use of pharmacological fMRI to study antipsychotic properties in humans., (Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.)

Background: Aripiprazole is an atypical antipsychotic drug that is characterized by partial dopamine D2 receptor agonism. Its pharmacodynamic profile is proposed to be beneficial in the treatment of cognitive impairment, which is prevalent in psychotic disorders. This study compared brain activation characteristics produced by aripiprazole with that of haloperidol, a typical D2 receptor antagonist, during a task targeting executive functioning., Methods: Healthy participants received an acute oral dose of haloperidol, aripiprazole or placebo before performing an executive functioning task while blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) was carried out., Results: There was a tendency towards reduced performance in the aripiprazole group compared to the two other groups. The image analysis yielded a strong task-related BOLD-fMRI response within each group. An uncorrected between-group analysis showed that aripiprazole challenge resulted in stronger activation in the frontal and temporal gyri and the putamen compared with haloperidol challenge, but after correcting for multiple testing there was no significant group difference., Conclusion: No significant group differences between aripiprazole and haloperidol in frontal cortical activation were obtained when corrected for multiple comparisons. This study is registered in ClinicalTrials.gov (identifier: 2009-016222-14).

Introduction: Impaired monitoring of internally generated information has been proposed to be one component in the development and maintenance of delusions. The present study investigated the neural correlates underlying the monitoring processes and whether they were associated with delusions., Methods: Twenty healthy controls and 19 patients with schizophrenia spectrum disorders were administrated a reality monitoring paradigm during functional magnetic resonance imaging. During encoding participants were instructed to associate a statement with either a presented (viewed condition) or an imagined picture (imagined condition). During the monitoring session in the scanner, participants were presented with old and new statements and their task was to identify whether a given statement was associated with the viewed condition, imagined condition, or if it was new., Results: Patients showed significantly reduced accuracy in the imagined condition with performance negatively associated with degree of delusions. This was accompanied with reduced activity in the left dorsolateral prefrontal cortex and left hippocampus in the patient group. The severity of delusions was negatively correlated with the blood-oxygenation-level dependent response in the left hippocampus., Conclusions: The results suggest that weakened monitoring is associated with delusions in patients with schizophrenia spectrum disorder, and that this may be mediated by a frontotemporal dysfunction.

Ability to anticipate aversive events is important for avoiding dangerous or unpleasant situations. The motivation to avoid an event is influenced by the incentive salience of an event-predicting cue. In an avoidance fMRI task we used tone intensities to manipulate salience in order to study the involvement of the orbitofrontal cortex in processing of incentive salience. In the task, cues predicting either aversive or neutral avoidable tones were presented. Ventral striatum, amygdala and anterior insula activations were significantly stronger during presentation of cues for aversive than neutral tones. A psychophysiological interaction analysis showed stronger connectivity between the ventral striatum and the orbitofrontal cortex during aversive than neutral conditions. The present study shows an interaction between the ventral striatum, a structure previously linked to negative incentive salience, and the orbitofrontal cortex supporting a role for this region in processing salience. In addition, this study replicates previous findings suggesting that the task is robust.

This study investigated the effect of arousal on short-term relational memory and its underlying cortical network. Seventeen healthy participants performed a picture by location, short-term relational memory task using emotional pictures. Functional magnetic resonance imaging was used to measure the blood-oxygenation-level dependent signal relative to task. Subjects' own ratings of the pictures were used to obtain subjective arousal ratings. Subjective arousal was found to have a dose-dependent effect on activations in the prefrontal cortex, amygdala, hippocampus, and in higher order visual areas. Serial position analyses showed that high arousal trials produced a stronger primacy and recency effect than low arousal trials. The results indicate that short-term relational memory may be facilitated by arousal and that this may be modulated by a dose-response function in arousal-driven neuronal regions.

Diffusion MRI (dMRI) is widely used to measure microstructural features of brain white matter, but commonly used dMRI measures have limited capacity to resolve the orientation structure of complex fiber architectures. While several promising new approaches have been proposed, direct quantitative validation of these methods against relevant histological architectures remains missing. In this study, we quantitatively compare neuronal fiber orientation distributions (FODs) derived from ex vivo dMRI data against histological measurements of rat brain myeloarchitecture using manual recordings of individual myelin stained fiber orientations. We show that accurate FOD estimates can be obtained from dMRI data, even in regions with complex architectures of crossing fibers with an intrinsic orientation error of approximately 5-6 degrees in these regions. The reported findings have implications for both clinical and research studies based on dMRI FOD measures, and provide an important biological benchmark for improved FOD reconstruction and fiber tracking methods.

The cerebral cortex conveys major input to the granule cell layer of the cerebellar hemispheres by way of the pontine nuclei. Cerebrocortical projections terminate in multiple, widely distributed clusters in the pontine nuclei. This clustered organization is thought to provide the transition between the different organizational principles of the cerebrum and cerebellum, and indicates that parallel processing occurs at multiple sites in the pontine nuclei. At a cellular level, however, it is unknown whether individual cerebropontine neurons target pontocerebellar cells located in different clusters or not. We have employed anterograde axonal tracing and 3D computerized reconstruction techniques to characterize the branching pattern and morphology of individual cerebropontine axons from the primary somatosensory cortex (SI). Our findings show that 43% of the cerebrobulbar fibers arising from SI whisker representations provide two or three fibers entering the pontine nuclei, whereas 39% have only one fiber, and the remaining 18% do not project to the pontine nuclei. Thus, it appears that a majority of cerebropontine axons originating in SI whisker representations diverge to contact multiple, separated pontocerebellar cells. Further, 84% of the somatosensory cerebropontine fibers are collateral branches from cerebrobulbar and/or cerebrospinal parent fibers, while 16% are direct cerebropontine projections without a further descending projection. A range of thicknesses of the fibers entering the pontine nuclei were observed, with collaterals of corticobulbar fibers having the smallest diameter. Taken together, these findings may be related to previously described separate cerebropontine transmission lines with different properties.

The major cortical-subcortical re-entrant pathways through the basal ganglia and cerebellum are considered to represent anatomically segregated channels for information originating in different cortical areas. A capacity for integrating unique combinations of cortical inputs has been well documented in the basal ganglia circuits but is largely undefined in the precerebellar circuits. To compare and quantify the amount of overlap that occurs in the first link of the cortico-ponto-cerebellar pathway, a dual tracing approach was used to map the spatial relationship between projections originating from the primary somatosensory cortex (SI), the secondary somatosensory cortex (SII), and the primary motor cortex (MI). The anterograde tracers biotinylated dextran amine and Fluoro-Ruby were injected into homologous whisker representations of either SI and SII, or SI and MI. The ensuing pontine labeling patterns were analyzed using a computerized three-dimensional reconstruction approach. The results demonstrate that whisker-related projections from SI and MI are largely segregated. At some locations, the two projections are adjoining and partly overlapping. Furthermore, SI contributes significantly more corticopontine projections than MI. By comparison, projections from corresponding representations in SI and SII terminate in similar parts of the pontine nuclei and display considerable amounts of spatial overlap. Finally, comparison of corticopontine and corticostriatal projections in the same experimental animals reveals that SI-SII overlap is significantly larger in the pontine nuclei than in the neostriatum. These structural differences indicate a larger capacity for integration of information within the same sensory modality in the pontocerebellar system compared to the basal ganglia., (Copyright 2004 Wiley-Liss, Inc.)