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The maternal immune activation hypothesis has gained attention over the past two decades as a potential contributor to the etiology of autism. This hypothesis posits that maternal conditions associated with inflammation during pregnancy may increase the risk of autism in offspring. Autism is highly heritable, and causal environmental contributors to autism largely remain elusive. We review studies on maternal conditions during pregnancy, all associated with some degree of systemic inflammation; namely, maternal infections, autoimmunity, and high BMI. We additionally review studies of inflammatory markers in biological samples collected from the mother during pregnancy or from the neonate and their relationship with autism assessed in children later in life. Recent reports indicate familial clustering of autism, autoimmunity and infections, as well as genetic correlations between autism and aspects of immune function. In light of this literature, there is an apparent risk of confounding of the reported associations between inflammatory exposures and autism by familial genetic factors in both clinical and epidemiological cohort studies. We highlight recent studies that have attempted to address potential confounding to assess evidence of causal effects of inflammation during early life in autism., (Copyright © 2024. Published by Elsevier Inc.)

Objective: Exercise is increasingly used as adjunct treatment for alcohol use disorder (AUD). Evidence suggests that moderate-to-high-intensity exercise can ameliorate cravings. We explored the potential mediating effects of changes in mood states in the relationship between exercise intensity and alcohol cravings., Method: Secondary analyses of a nested single-arm trial within a randomized controlled trial (FitForChange). In total, 117 sedentary adults (68.4% female, M = 52 ± 12 years) with clinician diagnosed (Diagnostic and Statistical Manual of Mental Disorders, fifth edition ) AUD and indications of craving (Desire for Alcohol Questionnaire) completed a 12-min submaximal cardiorespiratory fitness test on a cycle ergometer. Assessments of craving, mood states (POMS), and state anxiety (STAI-Y1) were taken immediately before, after, and 30 min after exercise. Ratings of perceived exertion (RPE) were included as indirect measures of exercise intensity. The med4way command in Stata was used to explore mediating and interaction effects of improvements in total mood disturbance (TMD) and state anxiety., Results: Improvements in mood and anxiety did not mediate the effect of higher exercise intensity on reductions in alcohol craving. A significant reference interaction was found between "hard" (or greater) exertion and anxiety improvements (β = -1.06, 95% CI [-1.50, -0.61]). Participants whose anxiety reduced during exercise had two times higher odds of reduced cravings when exercising at a higher intensity than participants whose anxiety worsened ( OR = 2.04, 95% CI [1.12, 3.72])., Conclusions: Reductions in anxiety may partly explain the positive effect of higher exercise intensity on alcohol cravings. The findings are preliminary and require replication in future studies. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Background: Alcohol-attributable medical disorders are prevalent among individuals with alcohol use disorder (AUD). However, there is a lack of research on prescriptions of pharmacological treatment for AUD in those with comorbid conditions. This study aims to investigate the utilization of pharmacological treatment (acamprosate, disulfiram and naltrexone) in specialist care among patients with AUD and comorbid medical diagnoses., Methods: This was a descriptive register-based Swedish national cohort study including 132,728 adults diagnosed with AUD (N = 270,933) between 2007 and 2015. The exposure was alcohol-attributable categories of comorbid medical diagnoses. Odds ratios (OR) were calculated using mixed-effect logistic regression analyses for any filled prescription of acamprosate, disulfiram or oral naltrexone within 12 months post AUD diagnosis., Results: Individuals with comorbid alcohol-attributable medical diagnoses had lower odds of filling prescriptions for any type of AUD pharmacotherapy compared to those without such comorbidities. Cardiovascular (OR = 0.41 [95% CI: 0.39-0.43]), neurological (OR = 0.52 [95% CI: 0.48-0.56]) and gastrointestinal (OR = 0.57 [95% CI: 0.54-0.60]) diseases were associated with the lowest rates of prescription receipt. The presence of diagnoses which are contraindications to AUD pharmacotherapy did not fully explain the low prescription rate., Conclusion: There is a substantial underutilization of AUD pharmacotherapy in patients with AUD and comorbid medical disorders in specialist care. Increasing the provision of pharmacotherapy to this group of patients is essential and may prevent morbidity and mortality. There is a need to further understand barriers to medical treatment both from the patient and prescriber perspective., (© 2024. The Author(s).)

Importance: Several studies suggest that acetaminophen (paracetamol) use during pregnancy may increase risk of neurodevelopmental disorders in children. If true, this would have substantial implications for management of pain and fever during pregnancy., Objective: To examine the associations of acetaminophen use during pregnancy with children's risk of autism, attention-deficit/hyperactivity disorder (ADHD), and intellectual disability., Design, Setting, and Participants: This nationwide cohort study with sibling control analysis included a population-based sample of 2 480 797 children born in 1995 to 2019 in Sweden, with follow-up through December 31, 2021., Exposure: Use of acetaminophen during pregnancy prospectively recorded from antenatal and prescription records., Main Outcomes and Measures: Autism, ADHD, and intellectual disability based on International Classification of Diseases, Ninth Revision and International Classification of Diseases, Tenth Revision codes in health registers., Results: In total, 185 909 children (7.49%) were exposed to acetaminophen during pregnancy. Crude absolute risks at 10 years of age for those not exposed vs those exposed to acetaminophen were 1.33% vs 1.53% for autism, 2.46% vs 2.87% for ADHD, and 0.70% vs 0.82% for intellectual disability. In models without sibling control, ever-use vs no use of acetaminophen during pregnancy was associated with marginally increased risk of autism (hazard ratio [HR], 1.05 [95% CI, 1.02-1.08]; risk difference [RD] at 10 years of age, 0.09% [95% CI, -0.01% to 0.20%]), ADHD (HR, 1.07 [95% CI, 1.05-1.10]; RD, 0.21% [95% CI, 0.08%-0.34%]), and intellectual disability (HR, 1.05 [95% CI, 1.00-1.10]; RD, 0.04% [95% CI, -0.04% to 0.12%]). To address unobserved confounding, matched full sibling pairs were also analyzed. Sibling control analyses found no evidence that acetaminophen use during pregnancy was associated with autism (HR, 0.98 [95% CI, 0.93-1.04]; RD, 0.02% [95% CI, -0.14% to 0.18%]), ADHD (HR, 0.98 [95% CI, 0.94-1.02]; RD, -0.02% [95% CI, -0.21% to 0.15%]), or intellectual disability (HR, 1.01 [95% CI, 0.92-1.10]; RD, 0% [95% CI, -0.10% to 0.13%]). Similarly, there was no evidence of a dose-response pattern in sibling control analyses. For example, for autism, compared with no use of acetaminophen, persons with low (<25th percentile), medium (25th-75th percentile), and high (>75th percentile) mean daily acetaminophen use had HRs of 0.85, 0.96, and 0.88, respectively., Conclusions and Relevance: Acetaminophen use during pregnancy was not associated with children's risk of autism, ADHD, or intellectual disability in sibling control analysis. This suggests that associations observed in other models may have been attributable to familial confounding.

Background: Intrahepatic cholestasis of pregnancy (ICP) is the most common obstetric liver disorder and is associated with an increased risk of iatrogenic preterm birth and adverse infant outcomes. Hence, there are several plausible pathways through which ICP could affect offspring neurodevelopment. However, to the best of our knowledge, no studies have investigated these associations. Thus, we aimed to determine whether ICP is associated with offspring neurodevelopmental conditions., Methods and Findings: In this Swedish register-based cohort study, we included singleton non-adopted children born in Sweden between the 1st of January 1987 and the 31st of December 2010, who were resident in Sweden >5 years, with no missing covariate information, which we followed until the 31st of December 2016. Maternal ICP diagnosis and the date of the initial diagnosis during pregnancy were obtained from the National Patient Register. Offspring diagnoses of attention deficit/hyperactivity disorder (ADHD), autism, or intellectual disability were obtained from the National Patient Register, and the dispensation of ADHD medications were obtained from the Prescribed Drug Register. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression while controlling for observed confounders and unobserved confounders shared among full siblings and maternal full cousins. A total of 2,375,856 children were included in the study; 81.6% of them were of Nordic origin, and 51.4% were male. Of these, 10,378 (0.44%) were exposed to ICP. During a median of 18 years follow-up (interquartile range 11 to 24), 143,746 (6.05%) of children were diagnosed with a neurodevelopmental condition. After adjusting for child's sex, birth year, birth month, maternal age, highest parental education level, maternal birth country, birth order, maternal psychiatric history, ICP was associated with increased odds of offspring neurodevelopmental conditions (OR 1.22, 95% CI 1.13 to 1.31), particularly among those exposed to early-onset ICP (OR 2.38, 95% CI 1.71 to 3.30) as compared to ICP diagnosed after reaching term (≥37 weeks of gestation) (OR 1.08, 95% CI 0.97 to 1.20). The findings of early-onset ICP were consistent in family-based analyses. Within-family comparisons of full maternal cousins yielded an OR of 2.99 (95% CI 1.48 to 6.04), and comparisons of full siblings showed an OR of 1.92 (95% CI 0.92 to 4.02), though the latter was less precise. The findings were consistent across specific neurodevelopmental conditions and different analytical approaches. The primary limitations of this study included its observational design, the absence of data on ICP therapeutics, and the lack of bile acid measures., Conclusions: In this study, we observed that exposure to ICP during gestation is associated with an increased likelihood of neurodevelopmental conditions in offspring, particularly in cases of early-onset ICP. Further studies are warranted to better understand the role of early-ICP in offspring neurodevelopment., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Chen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: To investigate the associations between low education and risk of mental disorders, substance use disorders and self-harm in different age-groups., Methods: All subjects in Stockholm born between 1931 and 1990 were linked to their own or their parent's highest education in 2000 and followed-up for these disorders in health care registers 2001-2016. Subjects were stratified into four age-groups: 10-18, 19-27, 28-50, and 51-70 years. Hazard Ratios with 95% Confidence Intervals (CIs) were estimated with Cox proportional hazard models., Results: Low education increased the risk of substance use disorders and self-harm in all age-groups. Males aged 10-18 with low education had increased risks of ADHD and conduct disorders, and females a decreased risk of anorexia, bulimia and autism. Those aged 19-27 years had increased risks of anxiety and depression, and those aged 28-50 had increased risks of all mental disorders except anorexia and bulimia in males with Hazard Ratios ranging from 1.2 (95% CIs 1.0-1.3) for bipolar disorder to 5.4 (95% CIs 5.1-5.7) for drug use disorder. Females aged 51-70 years had increased risks of schizophrenia and autism., Conclusion: Low education is associated with risk of most mental disorders, substance use disorders and self-harm in all age-groups, but especially among those aged 28-50 years., (© 2023 The Authors. International Journal of Methods in Psychiatric Research published by John Wiley & Sons Ltd.)

Background: Early studies of common mental disorders (CMDs) during the COVID-19 pandemic mainly report increases; however, more recent findings have been mixed. Also, studies assessing the effects of restriction measures on CMDs show varied results. The aim of this meta-analysis was to assess changes in levels of CMDs from pre-/early to during the pandemic and the effects of restriction policies in the European population., Methods: We searched for studies assessing both pre-pandemic and peri-pandemic self-reported emotional distress and symptoms of depression or anxiety among nationally/regionally representative samples in Europe and collected microdata from those studies. Estimates of corona containment index were related to changes in CMDs using random-effects meta-regression., Results: Our search strategy resulted in findings from 15 datasets drawn from 8 European countries being included in the meta-analysis. There was no evidence of change in the prevalence of emotional distress, anxiety, or depression from before to during the pandemic; but from early pandemic periods to later periods, there were significant decreases in emotional distress and anxiety. Increased school restrictions and social distancing were associated with small increases in self-reported emotional distress., Conclusions: Despite initial concerns of increased emotional distress and mental illness due to the COVID-19 pandemic, the results from this meta-analysis indicate that there was a decrease in emotional distress and no change in anxiety or depression in the general population in Europe. Overall, our findings support the importance of strong governance when implementing periodic and robust restriction measures to combat the spread of COVID-19.

Background: Substance use problems have been associated with poor labour market outcomes. This study investigated whether substance use disorders (SUD) in emerging adulthood increase the likelihood of later being not in employment, education or training (NEET)., Methods: A national cohort study of 23 5295 males and 227 792 females born between 1981 and 1987. SUD was assessed between ages 17 and 24 years. Logistic regression models were used to estimate the odds ratios (ORs) of NEET, between ages 25-34. Sibling-comparison analysis was performed to account for potential shared genetic and environmental factors., Results: Having been diagnosed with a SUD was associated with the likelihood of being NEET among males [OR = 1.37, 95% confidence interval (CI), 1.25-1.49] and females (1.19, 1.13-1.27) after adjusting for domicile, origin, psychiatric diagnosis and parental psychiatric diagnosis. Early SUD was also associated with a gradual increase in the ORs of accumulation of years being NEET. This was more evident among females. In the sibling-comparison analysis, we found a higher OR of NEET among same-sex sibling males 1.39 (1.06-1.82) and females 1.28 (0.99-1.66) with SUD. These risks were fully attenuated when another psychiatric diagnosis was adjusted for., Conclusion: Early SUD was associated with an increased likelihood of being NEET in both males and females. Neither origin, domicile, psychiatric diagnoses nor parental psychiatric diagnoses did fully explain the association. The combination of unmeasured familial factors and having other psychiatric disorders largely explained these associations., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Public Health Association.)

Background and Aim: Cannabis use disorder (CUD) is one of the main reasons for seeking substance treatment in the Nordic countries, but there are few studies on readmission to care. We aimed to characterize CUD readmission and estimate the magnitude of how socio-economic factors and psychiatric comorbidity influence the risk of CUD readmission., Design, Setting and Participants: This was a nation-wide cohort study carried out between 2001 and 2016 in Sweden. The participants were individuals with CUD, aged 17 years and above (n = 12 143)., Measurements: Information on predictors was obtained from registers and included education, income and psychiatric comorbidity assessed by six disease groups. The outcome measure was readmission, defined as a CUD visit to health-care at least 6 months after initial CUD diagnosis. Hazard ratios (HR) were estimated using Cox survival analyses and flexible parametric survival analyses to assess risk of readmission and how the risk varied with age., Findings: The vast majority of CUD visits took place in outpatient care (~80%). Approximately 23% of the included individuals were readmitted to care during follow-up. The fully adjusted model showed an increased risk of readmission among those with schizophrenia and other psychotic disorders [HR = 1.54, 95% confidence interval (CI) = 1.29-1.84], low education (HR = 1.40, 95% CI = 1.24-1.57), personality disorders (HR = 1.27, 95% CI = 1.05-1.54) or mood disorders (HR = 1.27, 95% CI = 1.12-1.45). Flexible parametric modeling revealed increased risk of readmission mainly in individuals aged 18-35 years., Conclusions: The risk of readmission was highest among those with low education, schizophrenia and other psychotic disorders, mood-related disorders or personality disorders. Individuals aged 18-35 years showed the highest risk of readmission. Our findings highlight individuals with complex health-care needs., (© 2023 The Authors. Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

Background: Previous studies suggest a protective effect of parenthood on suicide, but little is known about how the association may change across the lifespan, or in relation to sex, marital status or occurrence of psychiatric disorders., Methods: We followed a cohort of over 5 million Swedish women and men, from 1991 to 2011, up to max. age 75, for death by suicide using national registers. Information on childbirths/adoptions, potential confounders and modifying factors were obtained from national registers. We assessed the associations between parenthood and suicide across adulthood using within time-stratified Cox regression models, with parenthood as a time-dependent exposure., Results: Parents had a lower risk of suicide than non-parents across the lifespan, after adjusting for sociodemographic factors. The association was most pronounced in young adults, especially young women, but attenuated with increasing age and converged between sexes in older age groups. The lower risk of suicide over the life course was similar whether parents were married, unmarried or divorced, apart from married men; among them, parents only had a lower risk above age 55. The lower risk in parents was also evident in people with a history of psychiatric hospitalizations, but disappeared from age 55 in this population., Conclusion: The lower risk of suicide was present in both parents, was most pronounced in young adulthood and weakened with increasing age. Our results are consistent with a plausible mechanism where feelings of responsibility and connectedness are protective against suicide in parents., (© 2022. The Author(s).)

Background: Maternal infections during pregnancy are associated with intellectual disability and autism in exposed children. Whether these associations are causal, and therefore should be targets of preventive strategies, remains unknown. We aimed to investigate these associations, to determine whether there is a causal role of maternal infection during pregnancy for children's risk of autism and intellectual disability, by accounting for unmeasured familial factors., Methods: We used a register-based cohort study design, and included children living in Stockholm County, Sweden, who were born in 1987-2010. We excluded children not born in Sweden, adopted children, and children with unknown biological mothers or fathers. Maternal infections during pregnancy, defined by ICD-8, ICD-9, and ICD-10 codes, were identified in the National Patient Register and Medical Birth Register. Children were followed up from birth to an outcome or a censoring event (death, migration from Stockholm, age 18 years, or Dec 31, 2016, whichever occurred first). The primary outcomes were diagnosis of autism or diagnosis of intellectual disability. We did a survival analysis to examine the association between inpatient and outpatient specialised care for any infection during pregnancy and likelihood of autism or intellectual disability in the child. To address potential residual confounding, we also estimated the relationship between maternal infection in the year preceding pregnancy as a negative control exposure and conducted a matched sibling analysis of sibling pairs who were discordant for autism or intellectual disability., Findings: 647 947 children living in Stockholm County were identified and, after excluding 97 980 children, we included 549 967 in the study (267 995 [48·7%] were female and 281 972 [51·3%] were male; mean age at censoring 13·5 years [SD 5·0; range <1 to 18]; 142 597 [25·9%] had a mother who was not born in Sweden). 445 (1·3%) of 34 013 children exposed to maternal infection during pregnancy were diagnosed with intellectual disability and 1123 (3·3%) with autism. 5087 (1·0%) of 515 954 unexposed children were diagnosed with intellectual disability and 13 035 (2·5%) with autism. Maternal infection during pregnancy was associated with autism (hazard ratio [HR] 1·16, 95% CI 1·09-1·23) and intellectual disability (1·37, 1·23-1·51) in exposed children compared with unexposed children. Maternal infection in the year before pregnancy (negative control exposure) was also associated with autism (HR 1·25, 95% CI 1·14-1·36), but was not associated with intellectual disability (1·09, 0·94-1·27). In sibling comparisons, the associations with maternal infection during pregnancy were attenuated for autism (HR 0·94, 95% CI 0·82-1·08; n=21 864), but not to the same extent for intellectual disability (1·15, 0·95-1·40; n=9275)., Interpretation: Although infections in pregnant women are associated with both autism and intellectual disability in their children, the association with autism does not appear to reflect a causal relationship, but is more likely to be explained by factors shared between family members such as genetic variation or aspects of the shared environment. Thus, infection prevention is not expected to reduce autism incidence. For intellectual disability, unmeasured familial factors might not fully explain the observed associations, and a causal role of maternal infections cannot be excluded. Causal effects of specific but rare infections or infections not requiring health care contact cannot be excluded in either autism or intellectual disability., Funding: Swedish Research Council, Stanley Medical Research Institute, and Autism Speaks., Translation: For the Swedish translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Previous studies indicate a role of immune disturbances during early development in the etiology of autism spectrum disorders (ASD). Any potential disturbances during fetal development are best addressed by prospective evaluation of maternal markers of inflammation. Previous studies have investigated maternal cytokines, a group of powerful effectors of the immune system, with inconsistent results. In this study, we aimed to clarify the relationship between maternal cytokines and ASD by evaluating levels of 17 cytokines in first trimester maternal serum samples, from 318 mothers to ASD-cases and 429 mothers to ASD-unaffected controls, nested within the register-based Stockholm Youth Cohort. Overall, we observed no consistent associations between levels of maternal cytokines and ASD. While we observed a number of individual associations, the patterns varied across the diagnostic sub-groups. Levels above the 90th percentile of IL-1β (OR = 2.31, 95% CI 1.16-4.60), IL-7 (OR = 2.28, 95% CI 1.20-4.33), IL-13 (OR = 2.42, 95% CI 1.29-4.55), and MCP-1 (OR = 2.09, 95% CI 1.03-4.24) were associated with increased odds of ASD with co-occurring intellectual disability (ID), whereas GMCSF (OR = 2.06, 95% CI 1.03-4.11) and TNF-α (OR = 2.31, 95% CI 1.18-4.50) were associated with increased odds of ASD with ADHD but none survived correction for multiple comparisons. Also, none of the measured maternal cytokines were associated with ASD without co-occurring ID or ADHD. Implementing a data-driven approach using machine learning (Random Forest's Variable Importance measurement), we found no evidence to suggest that adding these cytokines and other markers of maternal immunity, to register-based maternal factors (e.g., psychiatric history) improves prediction of ASD. In summary, we found no robust evidence of an association between maternal immune markers during early pregnancy and ASD., 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 © 2022 Brynge, Gardner, Sjöqvist, Lee, Dalman and Karlsson.)

Aims: Underutilisation of mental health services among migrant youth has been demonstrated repeatedly, but little is known about potential discrepancies in terms of treatment receipt for those who do reach services. This study examines the type and level of care received among migrant children and descendants of migrants, particularly investigating disparities in treatment receipt given a specific diagnosis., Methods: We used register data of the total population aged 6-17 years in Stockholm, followed from 2006 to 2015, comprising 444 196 individuals, categorised as refugees, non-refugee migrants, descendants of migrants and Swedish-born. To identify recommended treatments for specific diagnoses we used official clinical guidelines. We report logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CIs) of diagnosis receipt, treatment provision and level of care where a diagnosis was first registered., Results: Migrant children had a lower likelihood of receiving a wide range of psychiatric diagnoses, including mood disorder (OR 0.58; 95% CI 0.52-0.64), anxiety disorder (OR 0.62; 95% CI 0.57-69) and neurodevelopmental disorder (OR 0.59; 95% CI 0.55-0.63). Moreover, when these diagnoses were set, migrant children had a lower likelihood of receiving the recommended treatments for these conditions compared to the majority individuals with the same diagnosis (OR of receiving psychotherapy for anxiety disorder and depression: 0.71; 95% CI 0.62-0.95 and 0.50; 95% CI 0.33-0.75, respectively; OR for receiving ADHD-medication: 0.49; 95% CI 0.43-0.54)., Conclusions: Migrant children risk underdiagnosis of various mental health conditions, and, when reaching mental health services, risk not receiving the optimal care available.

Previous research supports a contribution of early-life immune disturbances in the etiology of autism spectrum disorders (ASD). Biomarker studies of the maternal innate (non-adaptive) immune status related to ASD risk have focused on one of the acute phase proteins (APP), C-reactive protein (CRP), with conflicting results. We evaluated levels of eight different APP in first-trimester maternal serum samples, from 318 mothers to ASD cases and 429 mothers to ASD-unaffected controls, nested within the register-based Stockholm Youth Cohort. While no overall associations between high levels of APP and ASD were observed, associations varied across diagnostic sub-groups based on co-occurring conditions. Maternal levels of CRP in the lowest compared to the middle tertile were associated with increased risk of ASD without ID or ADHD in offspring (OR = 1.92, 95% CI 1.08-3.42). Further, levels of maternal ferritin in the lowest (OR = 1.78, 95% CI 1.18-2.69) and highest (OR = 1.64, 95% CI 1.11-2.43) tertiles were associated with increased risk of any ASD diagnosis in offspring, with stronger associations still between the lowest (OR = 3.81, 95% CI 1.91-7.58) and highest (OR = 3.36, 95% CI 1.73-6.53) tertiles of ferritin and risk of ASD with ID. The biological interpretation of lower CRP levels among mothers to ASD cases is not clear but might be related to the function of the maternal innate immune system. The finding of aberrant levels of ferritin conferring risk of ASD-phenotypes indicates a plausibly important role of iron during neurodevelopment., (© 2022. The Author(s).)

Background: Being not in education, employment, or training (NEET) has been associated with poor health outcomes. This study aimed to investigate the association between NEET during emerging adulthood and later drug use disorder (DUD) among males and females., Method: A national cohort comprising 383,116 Swedish males and 362,002 females born between 1984 and 1990. NEET exposure was assessed annually between the ages 17 and 24 years, and follow-up for DUD between ages 25-33. Trajectories of NEET were estimated using group-based trajectory analysis. Cox regression analysis was used to estimate hazard ratios (HR) of DUD. Sibling-comparison model was performed to account for potential shared genetic and environmental factors., Results: Four trajectories of NEET were identified: "constant low", "transient peak", "late increase", and "constant high". Compared with the "constant low", all other trajectories were associated with increased HRs of DUD. HR was highest among males and females in the "late increase trajectory"; HR = 4.10 (3.79-4.44, 95% CI) and HR = 3.73 (3.29-4.24, 95% CI), after adjusting for domicile, origin, birth year, psychiatric diagnoses, and parental psychiatric diagnoses. This association was reduced to about a twofold increased risk in the sibling comparison analysis., Conclusion: Being NEET during emerging adulthood was associated with later DUD for both males and females. Neither origin, psychiatric diagnoses, parental psychiatric diagnoses, nor shared familial factors did fully explain the association. Males and females belonging to the late increase NEET trajectory had about a twofold increased risk of DUD., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: To explore the associations between childhood infections and subsequent diagnoses of autism spectrum disorder (ASD), intellectual disability (ID), and their co-occurrence., Methods: The association between specialized care for any infection, defined by ICD-codes, and later ASD or ID was investigated in a register-based cohort of 556,732 individuals born 1987-2010, resident in Stockholm County, followed from birth to their 18th birthday or December 31, 2016. We considered as potential confounders children's characteristics, family socioeconomic factors, obstetric complications, and parental histories of treatment for infection and psychiatric disorders in survival analyses with extended Cox regression models. Residual confounding by shared familial factors was addressed in sibling analyses using within-strata estimation in Cox regression models. Sensitivity analyses with the exclusion of congenital causes of ASD/ID and documented risk for infections were also performed., Results: Crude estimates indicated that infections during childhood were associated with later ASD and ID with the largest risks observed for diagnoses involving ID. Inclusion of covariates, exclusion of congenital causes of ASD/ID from the population, and sibling comparisons highlighted the potential for confounding by both heritable and non-heritable factors, though risks remained in all adjusted models. In adjusted sibling comparisons, excluding congenital causes, infections were associated with later "ASD without ID" (HR 1.24, 95%CI 1.15-1.33), "ASD with ID" (1.57, 1.35-1.82), and "ID without ASD" (2.01, 1.76-2.28). Risks associated with infections varied by age at exposure and by age at diagnosis of ASD/ID., Conclusions: Infections during childhood may contribute to a later diagnosis of ID and ASD., (© 2022. The Author(s).)

Objective: To investigate whether patients with clozapine treatment are at an increased risk of a more severe COVID-19 infection as compared with patients on other antipsychotic drugs., Methods: In this register-based cohort study, all residents (age 18 or older) in the Stockholm Region with a psychotic disorder diagnosis and antipsychotic treatment were included (N = 8 233) and followed from 1 March 2020 to 14 January 2021. The exposure was defined as clozapine treatment and the outcome measures (indicating a more severe COVID-19 infection) were: inpatient care, care within intensive care unit or death due to COVID-19 infection. Differences in outcome rates between exposed (n = 966) and unexposed (other antipsychotics; n = 7 267) were examined using Cox proportional hazards models and expressed as hazard ratios (HR) with 95% confidence intervals (CI)., Results: No statistically significant differences in outcome rates were found between the two groups of patients after adjusting for age, sex and residence in retirement homes. The adjusted HR for the exposed compared to the unexposed was 0.96 (95% CI: 0.54, 1.70) for inpatient care; 1.69 (0.48, 5.93) for care in intensive care unit (ICU); and 0.86 (0.26, 2.80) for death. Regarding inpatient care, additional adjusting for country of birth, living in socioeconomically vulnerable areas, number of care visits during the previous year, and comorbid medical illnesses did not alter the results., Conclusions: Our results may add support to the present guidelines, recommending sustained clozapine treatment during the current COVID-19 pandemic with careful monitoring and readiness to alter drug doses as needed., (© 2021 The Authors. Acta Psychiatrica Scandinavica published by John Wiley & Sons Ltd.)

Purpose: Migrant children underutilize mental health services (MHS), but differences according to age, reason for migration, type of problem, and time have not been thoroughly analyzed. We aimed to explore utilization of MHS among migrant children and youth and to study if the hypothesized lower utilization could be explained by fewer neurodevelopmental assessments., Methods: A cohort of the population aged 0-24 years in Stockholm, comprising 472,129 individuals were followed for maximum 10 years, between January 1, 2006 and December 31, 2015. We categorized individuals as accompanied refugee migrants, unaccompanied refugee migrants and non-refugee migrants, or Swedish-born. We used survival and logistic analyses to estimate rates of utilization of MHS., Results: Migrant children and youth utilized less MHS than the majority population, with hazard ratios ranging from 0.62 (95% CI: 0.57; 0.67) to 0.72 (95% CI: 0.69; 0.76). Refugee and non-refugee children utilized less mental health care than their Swedish peers, apart from the youngest refugees (0-10 years) who had similar utilization as Swedish-born. The lower rates were partly explained by all migrant youths' lower risk of being diagnosed with a neurodevelopmental condition. Time in Sweden had a major impact, such that unaccompanied refugee minors had a higher utilization in their first 2 years in Sweden (OR: 3.39, 95% CI: 2.96; 3.85)., Conclusion: Migrant youth use less MHS compared with native-born peers, and this is partly explained by fewer neurodevelopmental diagnoses. Strengthening the awareness about unmet needs, and the referring capacity by professionals in contact with migrant children could help reduce barriers to care., (© 2021. The Author(s).)

Background: Pharmacotherapy for alcohol use disorders (AUD) is effective. However, knowledge about utilization of, and patient characteristics associated with prescriptions is scarce. The aim is to investigate prescriptions of pharmacotherapy for AUD in Sweden across time, sociodemographics, domicile and comorbid conditions., Method: This is a national cohort study, comprising 132 733 adult patients with AUD diagnosis between 2007 and 2015. The exposure variables were age, sex, income, education, family constellation, domicile, origin, concurrent psychiatric and somatic co-morbid diagnoses. Logistic regression analyses were used to obtain odds ratios (OR) for any filled prescription of AUD pharmacotherapy; Acamprosate, Disulfiram, Naltrexone or Nalmefene during 12 months after AUD diagnosis., Results: During the study period, the proportion of individuals who received pharmacotherapy ranged between 22.80 and 23.94 % (χ2(64) = 72.00, p = .23). Female sex, age 31-45, higher education and income, living in a big city, co-habiting and born in Sweden, bar Norway, Denmark and Iceland, were associated with higher odds of pharmacotherapy. Concurrent somatic diagnosis was associated with lower odds of pharmacotherapy but psychiatric diagnosis higher (aOR = 0.61 95 % CI 0.59-0.63 and aOR = 1.61 95 % CI 1.57-1.66 respectively)., Conclusions: Pharmacotherapy for AUD is underutilized. The proportion of individuals with a prescription did not change between 2007 and 2015. Provision of treatment is unequal across different groups in society, where especially older age, lower income and education, and co-morbid somatic diagnosis were associated with lower odds of prescription. There is a need to develop treatment provision, particularly for individuals with co-morbid somatic conditions., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Doxycycline has been hypothesized to prevent development of severe mental illness (SMI) through the suppression of microglia, especially if administered during the intense synaptic pruning period of adolescence. However, results from register studies on potential benefits differ considerably. The aim of the present study was to determine whether doxycycline exposure during adolescence is associated with reduced SMI risk, and to investigate if a direct and specific causality is plausible. This is a Swedish national population register-based cohort study of all individuals born from 1993 to 1997, followed from the age of 13 until end of study at the end of 2016. The primary exposure was cumulative doxycycline prescription ≥3000 mg and outcomes were first diagnosis of non-affective psychosis (F20-F29) and first diagnosis of bipolar disorder (F30-F31). Causal effects were explored through Cox regressions with relevant covariates and secondary analyses of multilevel exposure and comparison to other antibiotics. We found no association between doxycycline exposure and risk of subsequent non-affective psychosis (adjusted hazard ratio (HR) 1.15, 95% CI 0.73-1.81, p = 0.541) and an increased risk of subsequent bipolar disorder (adjusted HR 1.95, 95% CI 1.49-2.55, p < 0.001). We do not believe the association between doxycycline and bipolar disorder is causal as similar associations were observed for other common antibiotics., (© 2021. The Author(s).)

While individuals diagnosed with autism spectrum disorders (ASD) have higher levels of antibodies directed towards gliadin, a component of wheat gluten, no study has examined anti-gliadin antibodies (AGA) in etiologically relevant periods before diagnosis. The objective of this study was to investigate if maternal levels of AGA, during pregnancy and at the time of birth, are associated with ASD in offspring. We analyzed AGA in archived neonatal dried blood spots (NDBS) for 921 ASD cases and 1090 controls, and in paired maternal sera collected earlier in pregnancy for a subset of 547 cases and 428 controls. We examined associations with ASD diagnoses as a group and considering common comorbidities (intellectual disability [ID] and attention-deficit/hyperactivity disorder). We compared 206 cases to their unaffected siblings to examine the potential for confounding by shared familial factors. Odds of ASD tended to be lower among those with the highest levels (≥90th percentile) of AGA compared to those with low levels (<80th percentile; OR 0.78, 95% CI 0.56-1.09, measured in NDBS). This pattern was more apparent for ASD with comorbid ID when measured in NDBS (0.51, 0.30-0.87), with a similar trend in maternal sera (0.55, 0.24-1.29). High levels of AGA were similarly associated with lower odds of ASD in the sibling comparison. In summary, we found little association between maternal antibodies raised against components of gluten and risk of ASD in general. Exposure to high levels of AGA in the pre- and perinatal periods may be protective in terms of risk for ASD with ID. LAY SUMMARY: There is a debate among both scientists and community members as to whether an immune reaction to gluten exposure could be considered a cause of autism. We examined antibodies that are directed against gliadin, a part of gluten, in samples collected from pregnant mothers and their newborn babies. We did not see any major differences in the antibody level among those children diagnosed with ASD or their mothers compared to children who were not diagnosed with ASD. High levels of the antibodies were in fact associated with a somewhat lower risk of ASD with co-occurring intellectual disabilities, though we cannot tell from this study why that might be the case., (© 2021 The Authors. Autism Research published by International Society for Autism Research and Wiley Periodicals LLC.)

Background: Immune signaling pathways influence neurodevelopment and are hypothesized to contribute to the etiology of autism spectrum disorder (ASD). We aimed to assess risk of ASD in relation to levels of neonatal acute phase proteins (APPs), key components of innate immune function, measured in neonatal dried blood spots., Methods: We included 924 ASD cases, 1092 unaffected population-based controls, and 203 unaffected siblings of ASD cases in this case-control study nested within the register-based Stockholm Youth Cohort. Concentrations of 9 different APPs were measured in eluates from neonatal dried blood spots from cases, controls, and siblings using a bead-based multiplex assay., Results: Neonatal C-reactive protein was consistently associated with odds of ASD in case-control comparisons, with higher odds associated with the highest quintile compared with the middle quintile (odds ratio [OR] = 1.50, 95% confidence interval [CI] = 1.10-2.04) in adjusted analyses. In contrast, the lowest quintiles of α-2-macroglobulin (OR = 3.71, CI = 1.21-11.33), ferritin (OR = 4.20, CI = 1.40-12.65), and serum amyloid P (OR = 3.05, CI = 1.16-8.01) were associated with odds of ASD in the matched sibling comparison. Neonatal APPs varied with perinatal environmental factors and maternal/fetal phenotypes. Significant interactions in terms of risk for ASD were observed between neonatal APPs and maternal infection during late pregnancy, maternal anemia, and maternal psychiatric history., Conclusions: Indicators of the neonatal innate immune response are associated with risk of ASD, although the nature of these associations varies considerably with factors in the perinatal environment and the genetic background of the comparison group., (Copyright © 2020 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: To determine whether parenthood among 25- to 44-year-olds is associated with a lower suicide rate in men and women in Sweden, and whether this is explained by selection into parenthood., Methods: In total, 1,582,360 Swedish women and men, born between 1967 and 1985, and childless at their 25 th birthday, were followed from 1992 to 2011. All data originated from linkage to national Swedish registers. Cox regression models were used with time-varying parenthood status to estimate adjusted hazard ratios and 95% confidence intervals (aHR;CI) for suicide., Results: Having one, two, three or more children was associated with 64%, 79% and 78% lower suicide rate, respectively, compared with having no children, in models with basic adjustments. When a wide range of indicators of selection into parenthood were taken into account, the suicide rate was 58% lower in parents with one child and 70% lower in parents with two or more children compared with childless individuals (aHR 0.42 [95% CI 0.36-0.48]; 0.30 [95% CI 0.25-0.35]; 0.30 [95% CI 0.21-0.42]). In fathers with one, two, three or more children suicide rate was 54%, 64% and 59% lower, respectively, compared with non-fathers whereas in mothers was 70%, 83% and 93% lower, respectively, compared with non-mothers., Conclusion: Parenthood among 25-to 44-year-olds is associated with a lower suicide risk in both men and women but to a larger extent among women, and particularly in parents with two or more children. Although selection into parenthood is possible, a protective effect of parenthood on suicide is likely in both men and women., (© 2020 The Authors. Acta Psychiatrica Scandinavica published by John Wiley & Sons Ltd.)

Background: It has been hypothesised that refugees have an increased risk of suicide., Aims: To investigate whether risk of suicide is higher among refugees compared with non-refugee migrants from the same areas of origin and with the Swedish-born population, and to examine whether suicide rates among migrants converge to the Swedish-born population over time., Method: A population-based cohort design using linked national registers to follow 1 457 898 people born between 1 January 1970 and 31 December 1984, classified by migrant status as refugees, non-refugee migrants or Swedish-born. Participants were followed from their 16th birthday or date of arrival in Sweden until death, emigration or 31 December 2015, whichever came first. Cox regression models estimated adjusted hazard ratios for suicide by migrant status, controlling for age, gender, region of origin and income., Results: There were no significant differences in suicide risk between refugee and non-refugee migrants (hazard ratio 1.28, 95% CI 0.93-1.76) and both groups had a lower risk of suicide than Swedish born. During their first 5 years in Sweden no migrants died by suicide; however, after 21-31 years their suicide risk was equivalent to the Swedish-born population (hazard ratio 0.94, 95% CI 0.79-1.22). After adjustment for income this risk was significantly lower for migrants than the Swedish-born population., Conclusions: Being a refugee was not an additional risk factor for suicide. Our findings regarding temporal changes in suicide risk suggest that acculturation and socioeconomic deprivation may account for a convergence of suicide risk between migrants and the host population over time., Declaration of Interest: None.

Background: Endometriosis is a common gynecologic condition affecting women of reproductive age. It has been linked with greater rates of depression and anxiety in small, cross-sectional, and clinical studies. Other studies have reported that women with endometriosis have increased risk of bipolar disorder. These reports suggest that psychiatric disorders might be more common among women with endometriosis, contributing to increased burden of mental ill-health in this population of women. However, this hypothesis has not been adequately studied., Objectives: In this population-based study, we investigated the overall psychiatric comorbidity among women with endometriosis, and the role of familial liability., Study Design: Several Swedish national registers were linked and used to follow all women born in Sweden in 1973-1990 for diagnosed psychiatric disorders and endometriosis from age 14 years until year 2016. Sibling comparison analyses were performed in a subsample of 173,650 families., Results: After adjustment for birth characteristics and education, women with endometriosis had an increased risk of being later diagnosed with depressive-, anxiety and stress-related disorders, alcohol/drug dependence, and attention-deficit hyperactivity disorder compared with the general population and with their sisters without endometriosis. The adjusted hazard ratios ranged from 1.56 (95% confidence interval, 1.29-1.88) for depressive disorders to 1.98 (95% confidence interval, 1.34-2.93) for attention-deficit hyperactivity disorder in the sibling analysis. Also, women with previous affective psychotic disorders, depressive-, anxiety and stress-related disorders, eating disorders, personality disorders, and attention-deficit hyperactivity disorder were more likely to be later diagnosed with endometriosis. The adjusted hazard ratios ranged from 1.51 (95% confidence interval, 1.30-1.76) for depressive disorders to 1.93 (95% confidence interval, 1.47-2.52) for personality disorders., Conclusion: These findings reveal a high degree of comorbidity between endometriosis and many psychiatric disorders that was not entirely explained by shared familial confounding. Clinical practice may consider psychosocial support to women with endometriosis and treating them from a multidisciplinary perspective., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: To investigate differences in psychiatric care use over time between Swedish born and those born abroad who migrate to Sweden., Methods: Population-based cohort study analysing linked population and health registers, following individuals born 1944-1990 from 1 January 2005 to 31 December 2016. Time-stratified survival analysis using Cox regression estimated time to psychiatric care use. Population included 5 150 753 individuals with 78.1% Swedish born. Migrant status was coded as Swedish born or migrant. Migrants were grouped by year of immigration and region of origin. The main outcome: psychiatric care use, defined as any psychiatric care; psychiatric inpatient or outpatient care; or use of psychotropics., Results: Migrants arriving before 2005 had a higher use of any psychiatric care relative to Swedish born but migrants arriving 2005 onwards had lower use. Migrants from sub-Saharan Africa and Asia had a lower use of any psychiatric care during the first decade in Sweden whereas migrants from Middle East and North Africa had a higher use, driven by use of psychotropics., Conclusions: The lower use of psychiatric care during the first decade contrasts with higher use among migrants with a longer duration of stay. Psychiatric care use among migrants should be analysed multi-dimensionally, taking duration of stay, region of origin and type of care into account., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Background: To evaluate the association of acne in late adolescence with the risk for subsequent malignant melanoma (MM) in men., Methods: Swedish register-based cohort study of 242,096 males born between 1952 and 1956, who took part in compulsory assessments for Swedish military conscription in late adolescence between 1969 and 1975, with subsequent diagnoses of MM (n=1,058) up to December 31, 2009. Covariates included measures of childhood circumstances and information from adolescence on presence of acne, physical fitness, cognitive function, body mass index (BMI), and a summary of diagnoses. Cox regression was used for the analysis., Results: In total 1,058 men were diagnosed with MM. Acne was not associated with subsequent MM, with an adjusted hazard ratio (and 95% confidence interval) of 0.95 (0.61 to 1.49). Men with parents who were agricultural workers, and men who lived in northern Sweden, had lower physical fitness, or lower cognitive function had a lower risk of MM. Overweight and obesity was associated with a raised risk, with an adjusted hazard ratio of 1.39 (1.14, 1.71)., Conclusions: Acne in late adolescence is unlikely to represent a raised risk for subsequent MM in men. Overweight or obesity was identified as a raised risk for MM, possibly due to the associated increased skin surface area., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background Severe infections in adulthood are associated with subsequent short-term cardiovascular disease. Whether hospital admission for sepsis or pneumonia is associated with persistent increased risk (over a year after infection) is less well established. Design The design of this study was as a register-based cohort study. Methods Some 236,739 men born between 1952-1956 were followed from conscription assessments in adolescence to 2010. All-cause cardiovascular disease ( n = 46,754), including coronary heart disease ( n = 10,279) and stroke ( n = 3438), was identified through national registers 1970-2010 (at ages 18-58 years). Results Sepsis or pneumonia in adulthood (resulting in hospital admission) are associated with increased risk of cardiovascular disease in the years following infection. The risk is highest during the first year after the infection, with an adjusted hazard ratio (and 95% confidence intervals) of 6.33 (5.65-7.09) and a notably increased risk persisted with hazard ratios of 2.47 (2.04-3.00) for the second and 2.12 (1.71-2.62) for the third year after infection. The risk attenuated with time, but remained raised for at least five years after infection; 1.87 (1.47-2.38). The results are adjusted for characteristics in childhood, cardiovascular risk factors and medical history in adolescence. Similar statistically significant associations were found for coronary heart disease and stroke. Conclusions Raised risks of cardiovascular disease following hospital admission for sepsis or pneumonia were increased for more than five years after the infection, but with the highest magnitude during the first three years following infection, suggesting a period of vulnerability when health professionals and patients should be aware of the heightened risk for cardiovascular disease.

Background: Although the estimated contribution of genetic factors is high in bipolar disorder, environmental factors may also play a role. This Swedish register-based cohort study of men examined if physical and psychological characteristics in late adolescence, including factors previously linked with bipolar disorder (body mass index, asthma and allergy), are associated with subsequent bipolar disorder in adulthood. Unipolar depression and anxiety are analysed as additional outcomes to identify bipolar disorder-specific associations., Methods: A total of 213,693 men born between 1952 and 1956, who participated in compulsory military conscription assessments in late adolescence were followed up to 2009, excluding men with any psychiatric diagnoses at baseline. Cox regression estimated risk of bipolar disorder, depression and anxiety in adulthood associated with body mass index, asthma, allergy, muscular strength stress resilience and cognitive function in adolescence., Results: BMI, asthma and allergy were not associated with bipolar disorder. Higher grip strength, cognitive function and stress resilience were associated with a reduced risk of bipolar disorder and the other disease outcomes., Limitations: The sample consisted only of men; even though the characteristics in adolescence pre-dated disease onset, they may have been the consequence of prodromal disease., Conclusions: Associations with body mass index and asthma found by previous studies may be consequences of bipolar disorder or its treatment rather than risk factors. Inverse associations with all the outcome diagnoses for stress resilience, muscular strength and cognitive function may reflect general risks for these psychiatric disorders or intermediary factors., (Copyright © 2017 Elsevier B.V. All rights reserved.)