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Summary Background To examine the risk of schizophrenia in a Danish population after exposure to early life stress, and whether this risk is modified by DNA sequence variation, specifically two single nucleotide polymorphisms (SNPs) (rs5479 and rs56303414) from the gene HSD11B2 . This gene encodes the enzyme 11-β hydroxysteroid dehydrogenase type 2 which converts active cortisol into inactive cortisone. Methods A two-stage analysis involving (1) a population-based cohort study, and (2) a nested case-control study using genotype information. Stage 1 included 1,141,447 people; here, we calculated incidence rate ratios (IRR) for the risk of schizophrenia among children of mothers who experienced loss or serious illness of close relatives before, during, and after pregnancy. In stage 2, we genotyped rs5479 and rs56303414 among 1275 schizophrenia cases and 1367 controls, and investigated interactions between genotypes and early life stress on the risk of schizophrenia. Results In stage 1, no increased risk of schizophrenia was found in offspring after exposure during pregnancy, but offspring exposed to early life stress at age 0–2 years had a significantly increased risk of schizophrenia (adjusted IRR 1.18, 95% confidence interval 1.07–1.31). For rs5479, the minor allele was nucleotide A, and the major allele was nucleotide C. No interaction was found between rs5479 and exposure during pregnancy. Individuals with the minor A allele of rs5479, however, had a significantly increased risk of schizophrenia after exposure to early life stress at age 3–9 years (adjusted IRR 2.06, 1.04–4.06). No interaction was found between rs56303414 and exposure in any of the time periods. Conclusion No association was found between exposure to early life stress during pregnancy and schizophrenia in the offspring investigated, whereas individuals exposed to early life stress within the first two years of life had an increased risk. No interaction was found between HSD11B2 and exposure during pregnancy, but individuals with the A allele of rs5479 had an increased risk of schizophrenia after exposure at age 3–9 years. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: Genetic factors have been found to influence the risk of suicide. It is less clear if this also applies to attempted suicide. We have investigated genetic and familial environmental factors by studying the occurrence of suicide attempts in biological and adoptive siblings of adoptees who attempted suicide compared to siblings of adoptees with no suicide attempts. Method: We used a random sample of 1933 adoptees from the Danish Adoption Register, a register of non-familial adoptions of Danish children, i.e. the adoptive parents are biologically unrelated to the adoptee. Analyses were conducted on incidence rates of attempted suicide in biological and adoptive siblings given occurrence of attempted suicide in the adoptees while also taking into account psychiatric disorders. Information about suicidal attempt and history of psychiatric disorder was based on hospital admissions. Results: The rate of attempted suicide in full siblings of adoptees who attempted suicide before age 60 years was higher than in full siblings of adoptees who had not attempted suicide (incidence rate ratios (IRR)=3.45; 95% confidence interval [CI]=0.94–12.7). After adjustment for history of psychiatric admission of siblings the increased rate was statistically significant (IRR=3.88; 95% CI—1.42–10.6). Limitations: Information on attempted suicide and psychiatric history was limited to that which involved hospitalisation. Conclusions: Genetic factors influence risk of suicide attempts. [Copyright &y& Elsevier]

Introduction: Prenatal antidepressant exposure has been associated with lower gestational age and birthweight. Yet, unmeasured residual confounding may inflate this association. We explored if maternal genetic liability for major depression explains part of the association of antidepressant use in pregnancy with lower gestational age and birthweight. Material and Methods: We employed the maternal polygenic score (PGS) for major depression as a measure of genetic liability. We used generalised linear models to estimate the differences in gestational age and birthweight at each PGS quintile between children whose mothers continued antidepressant use during pregnancy (continuation group), children whose mothers discontinued antidepressant use during pregnancy (discontinuation group) and unexposed children. Results: After adjusting for confounders, we found significant differences in birthweight between PGS quintiles in the continuation and unexposed group. Yet, this relationship was not linear. Furthermore, at the lowest and highest PGS quintiles, the continuation group had significantly reduced mean gestational ages (adjusted β ranges: 1.7–4.5 days, p < 0.001–0.008) and lower mean birthweights (adjusted β ranges: 58.6–165.4 g, p = 0.001–0.008) than the discontinuation and unexposed groups. Conclusion: We confirmed that antidepressant use in pregnancy was associated with small reductions in gestational age and birthweight but found that genetic liability for depression was not linearly associated with this risk. The causality of the observed associations could not be established due to the observational nature of the study. Residual confounding linked to the underlying disease was likely still present. [ABSTRACT FROM AUTHOR]

Background: We quantified relative and absolute risks of postpartum psychiatric episodes (PPE) following risk factors: Young age, past personal or family history of psychiatric disorders, and genetic liability. Methods: We conducted a register‐based study using the iPSYCH2012 case‐cohort sample. Exposures were personal history of psychiatric episodes prior to childbirth, being a young mother (giving birth before the age of 21.5 years), having a family history of psychiatric disorders, and a high (highest quartile) polygenic score (PGS) for major depression. PPE was defined within 12 months postpartum by prescription of psychotropic medication or in‐ and outpatient contact to a psychiatric facility. We included primiparous women born 1981–1999, giving birth before January 1st, 2016. We conducted Cox regression to calculate hazard ratios (HRs) of PPE, absolute risks were calculated using cumulative incidence functions. Results: We included 8174 primiparous women, and the estimated baseline PPE risk was 6.9% (95% CI 6.0%–7.8%, number of PPE cases: 2169). For young mothers with a personal and family history of psychiatric disorders, the absolute risk of PPE was 21.6% (95% CI 15.9%–27.8%). Adding information on high genetic liability to depression, the risk increased to 29.2% (95% CI 21.3%–38.4%) for PPE. Conclusions: Information on prior personal and family psychiatric episodes as well as age may assist in estimating a personalized risk of PPE. Furthermore, additional information on genetic liability could add even further to this risk assessment. [ABSTRACT FROM AUTHOR]

An amendment to this paper has been published and can be accessed via the original article. [ABSTRACT FROM AUTHOR]

Background: Bullous pemphigoid (BP) is an autoimmune blistering skin disease that takes a profound physical and mental toll on those affected. The aim of the study was to investigate the bidirectional association between BP and all bullous disorders (ABD) with a broad array of psychiatric disorders, exploring the influence of prescribed medications. Methods: This nationwide, register-based cohort study encompassed 6,470,450 individuals born in Denmark and alive from 1994 to 2016. The hazard ratios (HRs) of a subsequent psychiatric disorder in patients with BP/ABD and the reverse exposure and outcome were evaluated. Results: Several psychiatric disorders were associated with increased risk of subsequent BP (4.18-fold for intellectual disorders, 2.32-fold for substance use disorders, 2.01-fold for schizophrenia and personality disorders, 1.92–1.85-1.49-fold increased risk for organic disorders, neurotic and mood disorders), independent of psychiatric medications. The association between BP and subsequent psychiatric disorders was not significant after adjusting for BP medications, except for organic disorders (HR 1.27, CI 1.04–1.54). Similar results emerged with ABD. Conclusion: Psychiatric disorders increase the risk of a subsequent diagnosis of BP/ABD independent of medications, whereas medications used for the treatment of BP/ABD appear to account for the subsequent onset of psychiatric disorders. Clinically, an integrated approach attending to both dermatological and psychiatric symptoms is recommended, and dermatologists should remain vigilant for early symptoms of psychiatric disorders to decrease mental health comorbidity. [ABSTRACT FROM AUTHOR]

Education is essential for socioeconomic security and long-term mental health; however, mental disorders are often detrimental to the educational trajectory. Genetic correlations between mental disorders and educational attainment do not always align with corresponding phenotypic associations, implying heterogeneity in the genetic overlap. We unraveled this heterogeneity by investigating associations between polygenic risk scores for 6 mental disorders and fine-grained school outcomes: school grades in language and mathematics in ninth grade and high school, as well as educational attainment by age 25, using nationwide-representative data from established cohorts (N = 79,489). High polygenic liability of attention-deficit/hyperactivity disorder was associated with lower grades in language and mathematics, whereas high polygenic risk of anorexia nervosa or bipolar disorder was associated with higher grades in language and mathematics. Associations between polygenic risk and school grades were mixed for schizophrenia and major depressive disorder and neutral for autism spectrum disorder. Polygenic risk scores for mental disorders are differentially associated with language and mathematics school grades. [ABSTRACT FROM AUTHOR]

Background: Although several types of risk factors for anorexia nervosa (AN) have been identified, including birth-related factors, somatic, and psychosocial risk factors, their interplay with genetic susceptibility remains unclear. Genetic and epidemiological interplay in AN risk were examined using data from Danish nationwide registers. AN polygenic risk score (PRS) and risk factor associations, confounding from AN PRS and/or parental psychiatric history on the association between the risk factors and AN risk, and interactions between AN PRS and each level of target risk factor on AN risk were estimated. Methods: Participants were individuals born in Denmark between 1981 and 2008 including nationwide-representative data from the iPSYCH2015, and Danish AN cases from the Anorexia Nervosa Genetics Initiative and Eating Disorder Genetics Initiative cohorts. A total of 7003 individuals with AN and 45 229 individuals without a registered AN diagnosis were included. We included 22 AN risk factors from Danish registers. Results: Risk factors showing association with PRS for AN included urbanicity, parental ages, genitourinary tract infection, and parental socioeconomic factors. Risk factors showed the expected association to AN risk, and this association was only slightly attenuated when adjusted for parental history of psychiatric disorders or/and for the AN PRS. The interaction analyses revealed a differential effect of AN PRS according to the level of the following risk factors: sex, maternal age, genitourinary tract infection, C-section, parental socioeconomic factors and psychiatric history. Conclusions: Our findings provide evidence for interactions between AN PRS and certain risk-factors, illustrating potential diverse risk pathways to AN diagnosis. [ABSTRACT FROM AUTHOR]

Background: The age of onset (AOO), incidence and cumulative incidence of mental disorders are critical epidemiological measures, providing essential insights into the development and course of these disorders across the lifespan. This study aims to provide up‐to‐date estimates of the AOO, age‐specific incidence, and cumulative incidence for a comprehensive range of mental disorders using data from Danish registers. Methods: We conducted a follow‐up study encompassing all Danish residents from January 1, 2004, to December 31, 2021, totaling 91,613,465 person‐years. Data were sourced from the Danish Psychiatric Central Research Register, identifying individuals treated for various mental disorders in psychiatric hospitals, outpatient departments, and accident/emergency departments, that is, treated in secondary care settings. We investigated specific categories of mental disorders, including substance abuse disorders, schizophrenia, mood disorders, anxiety, eating disorders, borderline personality disorders, intellectual disabilities, pervasive developmental disorders, and behavioral and emotional disorders. Age‐sex‐specific incidence rates were estimated using Poisson generalized linear models, and cumulative incidence was calculated using Aalen–Johansen's competing risks model. The study provides estimates of AOO, incidence, and cumulative incidence for various mental disorders, including their age and sex distributions. Results: The cumulative incidence by age 80 years for any mental disorder was 30.72% (95% confidence interval: 30.62%–30.83%) for males and 34.46% (34.35%–34.57%) for females. The most common types of mental disorders were anxiety‐related disorders 16.27% (16.19%–16.36%) for males and 23.39% (23.29%–23.50%) for females, and followed by mood disorder 10.34% (10.27%–10.41%) for males and 16.67% (16.58%–16.77%) for females. For those who develop mental disorder, half will have developed their disorder by approximately age 22 years (median and interquartile range: males 21.37 (11.85–36.00); females 22.55 (16.31–36.08)). Conclusions: Approximately one in three individuals will seek treatment for at least one mental disorder in a secondary care setting by age 80. Given that half of these individuals develop mental disorders before age 22, it is crucial to tailor service planning to meet the specific needs of young individuals. Web‐based interactive data‐visualization tools are provided for clinical utility. [ABSTRACT FROM AUTHOR]

Depression is associated with general medical conditions (GMCs), but it is not known if treatment-resistant depression (TRD) affects GMC risk and vice versa. We estimated bidirectional associations between TRD and GMCs (prior and subsequent). All individuals aged 18–69 years, born and living in Denmark, with a first-time prescription for an antidepressant between 2005 and 2012 were identified in the Danish Prescription Registry (N = 154,513). TRD was defined as at least two shifts in treatment regimes. For prior GMCs, we estimated odds ratios (ORs) using conditional logistic regression comparing TRD patients with matched non-TRD controls adjusted for other GMCs and number of other GMCs. For subsequent GMCs, we used Cox regression to calculate hazard ratios (HRs) in TRD vs. non-TRD patients adjusted for age at first prescription, calendar time, other GMCs and number of other GMCs. Patients with TRD had higher prevalence of prior GMCs related to the immune or neurological systems; musculoskeletal disorders (women aOR: 1.35, 95% CI: 1.26–1.46, men aOR: 1.30, 95% CI: 1.19–1.42) and migraine (women aOR: 1.22, 95% CI: 1.09–1.36, men aOR: 1.25, 95% CI: 1.00–1.56). Subsequent GMCs were related to a broader spectrum; cardiovascular (women aHR: 1.43, 95% CI: 1.32–1.54, men aHR: 1.31, 95% CI: 1.19–1.43), endocrine (women aHR: 1.52, 95% CI: 1.37–1.67, men aHR: 1.24, 95% CI: 1.07–1.44), and neurological disorders (women aHR: 1.24, 95% CI: 1.13–1.35, men aHR: 1.19, 95% CI: 1.07–1.34). Our study presents a broad overview of comorbid medical conditions in patients with TRD and further studies are needed to explore the associations in detail. [ABSTRACT FROM AUTHOR]

Background: Chronic stress in childhood may increase the risk of overweight and obesity in young people. Erik Hemmingsson has suggested a new obesity causation model which focuses on psychosocial stress. The aim was to examine the associations between socioeconomic disadvantage and overweight and obesity and examine if these associations attenuate, when the effect of the different domains from Eric Hemmingsson's obesity causation model were taken into account.Methods: A longitudinal study using data from The West Jutland Cohort Study (N = 2879). Outcome was overweight and obesity combined derived from self-reported weight and height at age 15, 18, 21 and 28 years. Exposure variables were equivalised household income, educational level and labour market participation of the mother derived from registers and psychosocial variables derived from questionnaires. A three-step adjustment model using logistic regression and stratified by gender was applied.Results: Mother's low educational level was associated with a 3-fold increased odds of obesity in 18 year-old-girls, which attenuated when adjusting for the domains adult distress, disharmonious family environment and offspring distress. In 28 year-old girls, a 2.5-fold increased odds of obesity was observed, which attenuated when mutual adjusted for other socioeconomic variables and attenuated even further when adjusting for all the domains. In 18-year-old boys, a 3-fold increased odds of obesity was observed which attenuated after adjustments for adult distress, disharmonious family environment and offspring distress. In 21-year old boys, a four-fold increased odds of obesity was observed that attenuated after adjustments. At age 28 years, a three-fold increased odds of obesity was observed, which vanished in the fully adjusted model.Conclusions: Our study confirms to some extent that the associations between socioeconomic disadvantage and overweight and obesity can be explained by the domains included in Erik Hemmingsson's model, although our results should be interpreted with caution. Adult distress, disharmonious family environment and offspring distress accounted for some of the association in girls, whereas in boys it was primarily offspring distress, which had the greatest impact. Young people's educational attainment can act as a buffer in the relationship between mother's lower educational level and obesity at age 28 years. [ABSTRACT FROM AUTHOR]

There are established associations between advanced paternal age and offspring risk for psychiatric and developmental disorders. These are commonly attributed to genetic mutations, especially de novo single nucleotide variants (dnSNVs), that accumulate with increasing paternal age. However, the actual magnitude of risk from such mutations in the male germline is unknown. Quantifying this risk would clarify the clinical significance of delayed paternity. Using parent-child trio whole-exome-sequencing data, we estimate the relationship between paternal-age-related dnSNVs and risk for five disorders: autism spectrum disorder (ASD), congenital heart disease, neurodevelopmental disorders with epilepsy, intellectual disability and schizophrenia (SCZ). Using Danish registry data, we investigate whether epidemiologic associations between each disorder and older fatherhood are consistent with the estimated role of dnSNVs. We find that paternal-age-related dnSNVs confer a small amount of risk for these disorders. For ASD and SCZ, epidemiologic associations with delayed paternity reflect factors that may not increase with age. Advanced paternal age associates with increased risk for psychiatric and developmental disorders in offspring. Here, Taylor et al. utilize parent-child trio exome sequencing data sets to estimate the contribution of paternal age-related de novo mutations to multiple disorders, including heart disease and schizophrenia. [ABSTRACT FROM AUTHOR]

Objective: Anorexia nervosa (AN) is associated with increased risk of mortality, but little is known about the risk of inpatient admissions and mortality outcomes in individuals with diagnoses of both AN and other psychiatric and somatic conditions. We aimed to investigate the inpatient admissions and mortality among people with AN and other diagnosed conditions using Danish national registers. Method: This retrospective cohort study included individuals diagnosed with AN in Denmark, born 1977–2010. We identified other mental and somatic conditions in this population. We used Cox proportional hazards regression to estimate the risk of inpatient admission and mortality, focusing on (i) the number of other diagnosed conditions, and (ii) specific combinations of conditions diagnosed prior to the AN diagnosis. Categories of inpatient admissions considered were due to: (i) AN, (ii) any psychiatric disorder, and (iii) any somatic disorder. Additionally, competing risks survival analysis was used to calculate the cumulative incidence of inpatient admission and all‐cause mortality over the follow‐up period. Results: The study population included 11,489 individuals. The most common conditions individuals had prior to their AN diagnosis were other eating disorders (34.5%) and anxiety disorders (32.7%). During the follow‐up, 3184 (27.7%), 4604 (40.1%), and 6636 (57.8%) individuals were admitted for AN, any psychiatric disorder, and any somatic disorder, respectively; and in total 106 (0.9%) died. The risk of all outcomes was highest among those who had received a higher number of other diagnoses. For most combinations, the risks of admission and mortality were increased. Discussion: Our study presents the prevalence of other conditions in patients with AN in Denmark and elucidates their association with higher rates of inpatient admission and mortality. Our findings highlight the need for comprehensive, multidisciplinary care of patients with AN considering the spectrum of other diagnosed conditions to improve health outcomes. [ABSTRACT FROM AUTHOR]

Background: Adverse early life experience and development may have long-term health consequences, but later environmental conditions may perhaps protect against the effects of such early life adversities. The aim was to investigate whether cause-specific and overall mortality rates among adoptees are associated with the age at which they were transferred to the adoptive family and whether the social class of the adoptive family modifies this association.Methods: A cohort of 10,592 non-familial adoptions (biologically unrelated adoptee and adoptive parents) of Danish-born children formally granted in 1924-47 and with follow-up of total and cause-specific mortality through ages up to 85 years. The rates of death after the age of 16 from all causes combined, all natural causes, all external causes, and suicide were compared according to the age at which adoptees were transferred to their adoptive family by estimating hazard ratios in Cox regression models.Results: Death rates from all causes were significantly higher in adoptees transferred between age 1 month and 4 years compared to those transferred immediately after birth with the hazard ratio peaking at 1.19 (95% confidence limit: 1.08 to 1.32) for adoptees transferred between 6 and 11 months. This result was primarily driven by a similar pattern for natural causes of death. For death from external causes and for suicide the hazard ratios were increasing with increasing age at transfer, and tests for trend were statistically significant. The social class of the adoptive family did not significantly modify these associations.Conclusions: Transfer to an adoptive family later than at the time of birth may have adverse long-term consequences affecting overall and cause-specific mortality. These effects were not modified by the environment provided by the adoptive family as indicated by the social class of these families. [ABSTRACT FROM AUTHOR]

Abstract Background Evidence links infections to mental disorders and suicidal behavior. However, knowledge is sparse regarding less severe infections, anti-infective treatment, and deliberate self-harm. Using nationwide Danish longitudinal registers, we estimated associations between infections treated with anti-infective agents and infections requiring hospitalization with the risk of deliberate self-harm. Methods A total of 1.3 million people born between 1977 and 2002 were followed during the period from 1995 to 2013. In total, 15,042 individuals were recorded with deliberate self-harm (92% had been treated with anti-infective agents and 19% had been hospitalized for infections) and 114 died by suicide (64% had been treated with anti-infective agents and 13% had been hospitalized for infections). Hazard rate ratios were obtained while adjusting for age, gender, calendar period, education, hospitalizations with infections, prescribed anti-infective agents during childhood, parental mental disorders, and parental deliberate self-harm. Results Individuals with infections treated with anti-infective agents had an increased risk of deliberate self-harm with a hazard rate ratio of 1.80 (95% confidence interval = 1.68–1.91). The associations fitted a dose–response relationship (p <.001) and remained significant up to 5 years after last infection. An additive effect was found for individuals with an additional hospitalization for infections with an increased hazard rate ratio of 3.20 (95% confidence interval = 2.96–3.45) for deliberate self-harm. Conclusions An increased risk of deliberate self-harm was found among individuals with infections treated with anti-infective agents in temporal and dose–response associations. These results add to the growing literature on a possible link between infections and the pathophysiological mechanisms of suicidal behavior. [ABSTRACT FROM AUTHOR]

Objective: To examine gender differences in the association between attention-deficit/hyperactivity disorder (ADHD) and substance use disorder (SUD), and to explore the impact of comorbid psychiatric conditions.Method: This was a cohort study of all children born in Denmark in 1990 to 2003 (n = 729,560). By record linkage across nationwide registers, we merged data on birth characteristics, socioeconomic status, familial psychiatric history, and diagnoses of ADHD (N = 19,645), comorbidities, and SUD. Hazard ratios (HR) with 95% CIs were estimated by Cox regression and adjusted for a range of variables.Results: ADHD increased the risk of alcohol abuse (HRfemales = 1.72 [95% CI = 1.42-2.08], HRmales = 1.57 [1.37-1.79]), cannabis abuse (HRfemales = 2.72 [2.12-3.47], HRmales = 2.24 [1.86-2.70]), and other illicit substance abuse (HRfemales = 2.05 [1.54-2.73], HRmales = 2.42 [1.98-2.96]), compared to individuals without ADHD. In the overall estimates, no gender differences were found. Among individuals with ADHD without comorbidities, females had a higher SUD risk than males, as did females with ADHD and conduct disorder (CD). Comorbid CD, depression, bipolar disorder, and schizophrenia further increased the risk of SUD in ADHD, compared to non-ADHD. Autism spectrum disorder in males with ADHD lowered the SUD risk.Conclusion: ADHD increased the risk of all SUD outcomes. Individuals with ADHD without comorbidities were also at increased risk, and some comorbid disorders further increased the risk. Females and males with ADHD had comparable risks of SUD, although females had higher risk of some SUDs than males. Females with ADHD may be perceived as less impaired than males, but they are at equally increased risk of SUD. [ABSTRACT FROM AUTHOR]

Objective: Anxiety and depression symptoms are common in individuals with eating disorders. To study these co‐occurrences, we need high‐quality self‐report questionnaires. The 19‐item self‐rated Comprehensive Psychopathological Rating Scale for Affective Syndromes (CPRS‐S‐A) is not validated in patients with eating disorders. We tested its factor structure, invariance, and differences in its latent dimensions. Method: Patients were registered by 45 treatment units in the Swedish nationwide Stepwise quality assurance database for specialised eating disorder care (n = 9509). Patients self‐reported their anxiety and depression symptoms on the CPRS‐S‐A. Analyses included exploratory and confirmatory factor analyses (CFA) in split samples, and testing of invariance and differences in subscales across eating disorder types. Results: Results suggested a four‐factor solution: Depression, Somatic and fear symptoms, Disinterest, and Worry. Multigroup CFA indicated an invariant factor structure. We detected the following differences: Patients with anorexia nervosa binge‐eating/purging subtype scored the highest and patients with unspecified feeding and eating disorders the lowest on all subscales. Patients with anorexia nervosa or purging disorder show more somatic and fear symptoms than individuals with either bulimia nervosa or binge‐eating disorder. Conclusion: Our four‐factor solution of the CPRS‐S‐A is suitable for patients with eating disorders and may help to identify differences in anxiety and depression dimensions amongst patients with eating disorders. [ABSTRACT FROM AUTHOR]

Objective: To examine sex differences in risk factors for anorexia nervosa (AN). Method: This population‐based study involved 44,743 individuals (6,239 AN cases including 5,818 females and 421 males, and 38,504 controls including 18,818 females and 19,686 males) born in Denmark between May 1981 and December 2009. Follow‐up began on the individual's sixth birthday and ended at AN diagnosis, emigration, death, or December 31, 2016, whichever occurred first. Exposures included socioeconomic status (SES), pregnancy, birth, and early childhood factors based on data from Danish registers, and psychiatric and metabolic polygenic risk scores (PRS) based on genetic data. Hazard ratios were estimated using weighted Cox proportional hazards models stratified by sex (assigned at birth), with AN diagnosis as the outcome. Results: The effects of early life exposures and PRS on AN risk were comparable between females and males. Although we observed some differences in the magnitude and direction of effects, there were no significant interactions between sex and SES, pregnancy, birth, or early childhood exposures. The effects of most PRS on AN risk were highly similar between the sexes. We observed significant sex‐specific effects of parental psychiatric history and body mass index PRS, though these effects did not survive corrections for multiple comparisons. Conclusions: Risk factors for AN are comparable between females and males. Collaboration across countries with large registers is needed to further investigate sex‐specific effects of genetic, biological, and environmental exposures on AN risk, including exposures in later childhood and adolescence as well as the additive effects of exposures. Public significance: Sex differences in the prevalence and clinical presentation of AN warrant examination of sex‐specific risk factors. This population‐based study indicates that the effects of polygenic risk and early life exposures on AN risk are comparable between females and males. Collaboration between countries with large registers is needed to further investigate sex‐specific AN risk factors and improve early identification of AN. [ABSTRACT FROM AUTHOR]

Background: Early adversity is a known risk factor for unipolar depression. We examined the impact of 9 types of early adversity on risk for moderate to severe unipolar depression in adolescence or adulthood, and evaluated whether these effects were moderated by gender and adversity timing.Methods: We conducted a prospective, population-based cohort study using Danish national registers. The sample included all individuals born in Denmark between 1980 and 1998 (N=978,647). Exposure to early adversity was assessed from ages 0-15. Types of adversity included parental illness, incarceration, death, disability, and psychiatric diagnosis; family disruption; out-of-home care; and childhood abuse. Individuals were followed from age 15 until first in- or outpatient depression diagnosis (ICD-10 codes F32, F33) in a psychiatric hospital, death, emigration, or December 31st, 2013, whichever came first. Hazard ratios (HRs) were calculated using Cox regressions.Results: All adversities were significantly associated with increased risk for moderate to severe adolescent/adult depression (HR range: 1.30-2.72), although the effects were attenuated after mutual adjustment (adjusted HR range: 1.06-1.70). None of the effects were moderated by gender. The effect of family disruption was strongest between ages 0-4 (HR=1.66, 95% CI=1.61-1.71), while the effect of out-of-home care was strongest between ages 10-14 (HR=2.45, 95% CI=2.28-2.64).Limitations: Untreated and primary-care treated depression were not measured.Conclusions: Our results support past findings that multiple types of early adversity increase risk for moderate to severe unipolar depression in adolescence and adulthood. Certain adversities may be more harmful if they occur during specific developmental time periods. [ABSTRACT FROM AUTHOR]

Background: A subgroup of patients with anorexia nervosa (AN) undergoing involuntary treatment (IT) seems to account for most of the IT events. Little is known about these patients and their treatment including the temporal distribution of IT events and factors associated with subsequent utilization of IT. Hence, this study explores (1) utilization patterns of IT events, and (2) factors associated with subsequent utilization of IT in patients with AN. Methods: In this nationwide Danish register-based retrospective exploratory cohort study patients were identified from their first (index) hospital admission with an AN diagnosis and followed up for 5 years. We explored data on IT events including estimated yearly and total 5-year rates, and factors associated with subsequent increased IT rates and restraint, using regression analyses and descriptive statistics. Results: IT utilization peaked in the initial few years starting at or following the index admission. A small percentage (1.0%) of patients accounted for 67% of all IT events. The most frequent measures reported were mechanical and physical restraint. Factors associated with subsequent increased IT utilization were female sex, lower age, previous admissions with psychiatric disorders before index admission, and IT related to those admissions. Factors associated with subsequent restraint were lower age, previous admissions with psychiatric disorders, and IT related to these. Conclusions: High IT utilization in a small percentage of individuals with AN is concerning and can lead to adverse treatment experiences. Exploring alternative approaches to treatment that reduce the need for IT is an important focus for future research. [ABSTRACT FROM AUTHOR]

Objective: Increasing rates of caesarean sections has led to concerns about long-term effects on the offspring's health, and it has been hypothesised that caesarean section induced differences in the child's microbiota could potentially increase the risk of mental disorders. Methods: Nationwide Danish cohort study of 2,196,687 births was conducted between 1980 and 2015, with 38.5 million observation-years. Exposure was 'Caesarean Section' and outcome was the child's risk of any mental disorder. Absolute and relative risks (RRs) were estimated using inverse probability weighting to adjust for age, calendar time and confounding variables while accounting for the competing risk of death. Results: Caesarean section (n = 364,908, 16.6%), compared to vaginal birth, was associated with a small RR increase of 8% (RR, 1.08; 95% CI, 1.04–1.13; n = 44,352) for the development of any in-patient psychiatric admission at age 36 for the offspring and with a small absolute risk difference of 0.47% (95% CI, 0.23–0.76). When looking at all in-patient, out-patient and emergency room psychiatric contacts among people born after 1995, the effect was diminished (RR, 1.04; 95% CI, 0.99–1.09; n = 15,211). The risk was comparable when comparing prelabour versus intrapartum caesarean section (RR, 0.98; 95% CI, 0.90–1.08) and acute versus planned caesarean section (RR, 1.00; 95% CI, 0.80–1.29). Conclusion: Birth by caesarean section was associated with only a very slightly increased risk of any in-patient psychiatric admission for the offspring and diminished even further when including all psychiatric contacts. The very small associations observed may be explained by unmeasured confounding and is unlikely to be of substantial clinical relevance. [ABSTRACT FROM AUTHOR]

Objective: To determine the association between continued antidepressant use in pregnancy and postpartum psychiatric visits for eating (ED) or mood/anxiety disorders in women with preexisting ED. Method: Using Danish health registry data (1998–2015), we identified 3529 pregnancies in women with ED prepregnancy: (i) 564 with continued antidepressant use before and during pregnancy; (ii) 778 with discontinued antidepressants before pregnancy; (iii) 2137 unexposed. Outpatient and inpatient postpartum visits for an ED or a mood/anxiety disorder constituted the outcome measures. We estimated hazard ratios (HRs) and 95% confidence intervals (CI) using Cox regression with inverse probability of treatment weighting, and performed stratified analyses by antidepressant prescription filling in the first 3 months postpartum. Results: The weighted cumulative incidence for an ED visit at end of follow‐up was 4.5% (continued) and 4.8% (discontinued). We found no association between continued antidepressant and postpartum ED visit, relative to discontinued (HR: 0.89, 95% CI: 0.52–1.52). The HR for postpartum mood/anxiety disorder visit was 1.27 (95% CI: 0.68–2.36) with continued antidepressants versus discontinued but decreased if more than two antidepressant prescriptions were refilled. Continued antidepressant use was associated with a 57% reduced likelihood of a postpartum ED visit versus discontinued use in pregnancies with antidepressant prescription refills in the early postpartum. Conclusion: Among women with preexisting ED, there was no association between continued antidepressant use during pregnancy and the likelihood of postpartum psychiatric visits, relative to discontinued antidepressants before pregnancy. Continuation of treatment into the early postpartum is associated with reduced likelihood of postpartum ED visit. Public Significance: Based on data from the Danish registries, we identified 3529 pregnancies among women with preexisting eating disorders before pregnancy. Women with continued antidepressant treatment both before and during pregnancy did not have a lower probability of having postpartum psychiatric visits for an eating disorder or for mood/anxiety disorders (often coexisting with eating disorders), relative to those who discontinued antidepressants before pregnancy. Further continuation of antidepressant treatment into the early postpartum is associated with improved maternal postpartum outcomes. However, residual confounding by disease severity limits confidence in this conclusion. [ABSTRACT FROM AUTHOR]

Cognitive functions of individuals with psychiatric disorders differ from that of the general population. Such cognitive differences often manifest early in life as differential school performance and have a strong genetic basis. Here we measured genetic predictors of school performance in 30,982 individuals in English, Danish and mathematics via a genome-wide association study (GWAS) and studied their relationship with risk for six major psychiatric disorders. When decomposing the school performance into math and language-specific performances, we observed phenotypically and genetically a strong negative correlation between math performance and risk for most psychiatric disorders. But language performance correlated positively with risk for certain disorders, especially schizophrenia, which we replicate in an independent sample (n = 4547). We also found that the genetic variants relating to increased risk for schizophrenia and better language performance are overrepresented in individuals involved in creative professions (n = 2953) compared to the general population (n = 164,622). The findings together suggest that language ability, creativity and psychopathology might stem from overlapping genetic roots. [ABSTRACT FROM AUTHOR]

Attention deficit hyperactivity disorder (ADHD) is a multifactorial neurodevelopmental disorder, yet the interplay between ADHD polygenic risk scores (PRSs) and other risk factors remains relatively unexplored. The authors investigated associations, confounding, and interactions of ADHD PRS with birth-related, somatic, and psychosocial factors previously associated with ADHD. Participants included a random general population sample (N=21,578) and individuals diagnosed with ADHD (N=13,697) from the genotyped Danish iPSYCH2012 case cohort, born between 1981 and 2005. The authors derived ADHD PRSs and identified 24 factors previously associated with ADHD using national registers. Logistic regression was used to estimate associations of ADHD PRS with each risk factor in the general population. Cox models were used to evaluate confounding of risk factor associations with ADHD diagnosis by ADHD PRS and parental psychiatric history, and interactions between ADHD PRS and each risk factor. ADHD PRS was associated with 12 of 24 risk factors (odds ratio range, 1.03–1.30), namely, small gestational age, infections, traumatic brain injury, and most psychosocial risk factors. Nineteen risk factors were associated with ADHD diagnosis (odds ratio range, 1.20–3.68), and adjusting for ADHD PRS and parental psychiatric history led to only minor attenuations. Only the interaction between ADHD PRS and maternal autoimmune disease survived correction for multiple testing. Higher ADHD PRS in the general population is associated with small increases in risk for certain birth-related and somatic ADHD risk factors, and broadly to psychosocial adversity. Evidence of gene-environment interaction was limited, as was confounding by ADHD PRS and family psychiatric history on ADHD risk factor associations. This suggests that the majority of the investigated ADHD risk factors act largely independently of current ADHD PRS to increase risk of ADHD. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the influence of extensive genetic and psychosocial confounding on the association between early childhood infection and five major psychiatric disorders Methods: A case‐cohort study including participants from the Danish iPSYCH2012 sample, a case‐cohort sample where all cases born between May 1, 1981, and December 31, 2005, diagnosed with attention‐deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar affective disorder (BIP), Major Depressive Disorder (MDD) or schizophrenia (SCZ), were identified and pooled with a representative sample (subcohort) of the Danish population. We used Cox proportional hazards regression customized to the case‐cohort setup to calculate hazard ratios of outcome with 95% confidence intervals (CIs), following exposure to early childhood infection before the age of 5 years for ADHD and ASD, and before the age of 10 years for BIP, MDD, and SCZ. To evaluate psychosocial confounding we included sex, calendar period, sibling infections, urbanicity, parental socio‐economic status, parental mental health information, and polygenic risk scores for all five disorders, as covariates. To estimate how liability for psychiatric disorders measured through the PRS influenced the risk of early childhood infection, we calculated odds ratios (ORs) with 95% CIs, using logistic regression Results: Early childhood infection was associated with ADHD, ASD, MDD, and SCZ with number of childhood infections increasing the hazard. The HR was still significant in the model with full adjustments after 1 infection for ADHD (HR 1.29, 95% CI: 1.19–1.41), ASD (HR 1.28, 95% CI: 1.18–1.40), MDD (HR 1.23, 95% CI: 1.14–1.33), and SCZ (HR 1.21, 95% CI: 1.07–1.36), but not for BIP (HR1.17, 95% CI: 0.96–1.42). Probands exposed to sibling infections, but not own infection had an absolute risk of ADHD, BIP, MDD, and SCZ that closely approached the absolute risk for individuals exposed to own infections. We found evidence of gene–environment correlation with higher PRS of MDD and to some extent SCZ increasing the risk of infections and higher PRS of BIP associated with significantly decreased risk Conclusion: Early childhood infection is significantly associated with ADHD, ASD, MDD, and SCZ and not explained by genetic or psychosocial confounding. Although we found evidence of gene–environment correlation, it had minor impact on the results [ABSTRACT FROM AUTHOR]

Our aim was to characterize the incidence rates and cumulative incidence of anorexia nervosa (AN), bulimia nervosa (BN), and eating disorder not otherwise specified (EDNOS), and examine associations among eating disorder diagnoses, suicide attempts, and mortality. Individuals born in Denmark between 1989 and 2006 were included (N = 966,141, 51.3% male). Eating disorders diagnoses (AN, broad AN, BN, EDNOS) were drawn from the Danish Psychiatric Central Research Register (PCRR) and Danish National Patient Register (NPR). Suicide attempts and deaths were captured in the NPR, the PCRR, and the Danish Civil Registration System (CRS). In females, AN had a peak hazard at approximately age 15 years, BN at 22 years, and EDNOS had an extended peak that spanned 18 years–22 years. Eating disorder diagnoses predicted a significantly higher hazard for death and suicide attempt compared with the referent of individuals with no eating disorders. In males, peak hazard for diagnosis was earlier than in females. The present study represents one of the largest and longest studies of eating disorder incidence and suicide attempts and death in both females and males. Eating disorders are accompanied by increased hazard of suicide attempts and death even in young adults. [ABSTRACT FROM AUTHOR]

Objective: Studies on parental socioeconomic status (SES) and family risk factors for eating disorders (EDs) have yielded inconsistent results; however, several studies have identified high parental educational attainment as a risk factor. The aim was to evaluate associations of parental SES and family composition with anorexia nervosa (AN), bulimia nervosa (BN), and eating disorders not otherwise specified (EDNOS) in the offspring, adjusting for parental age and parental mental health. Methods: The cohort included women born in Denmark between January 1, 1989 and December 31, 2010, derived from Danish national registers. Each person was followed from their sixth birthday until onset of the disorder of interest or to December 31, 2016. Exposure variables were: childhood SES, defined as individually evaluated parental level of income, occupation, and education; sibling status; and family composition. Outcomes were: AN, BN, EDNOS, and major depressive disorder (MDD), included as a psychiatric comparison disorder. Risks were estimated using Cox proportional hazards. Results: High parental SES was associated with increased risk of especially AN, and less so BN and EDNOS, in offspring. In comparison, low SES was associated with a higher risk of MDD. No differences between maternal or paternal socioeconomic risk factors were found. Family composition and sibling status showed limited influence on ED risk. Discussion: SES shows opposite associations with AN than MDD, whereas associations with BN and EDNOS are intermediate. The socioeconomic backdrop of AN differs markedly from that reported in other psychiatric disorders. Whether that is due to genetic and/or environmental factors remains unknown. Public Significance statement: Parental socioeconomic background (SES) may influence eating disorders risk in offspring somewhat differently than other psychiatric disorders. In Denmark, higher parental SES was associated with increased risk of, particularly, anorexia nervosa (AN). Importantly AN does strike across the SES spectrum. We must ensure that individuals of all backgrounds have equal access to care and are equally likely to be detected and treated appropriately for eating disorders. [ABSTRACT FROM AUTHOR]

Background: Many patients with schizophrenia experience psychiatric symptoms long before being diagnosed. We investigated patterns of pre-diagnostic psychopharmacological treatment in individuals diagnosed with first-episode schizophrenia during the last two decades.Design: Using Danish nationwide healthcare registers, we identified all individuals aged ≥10 years registered with their first ICD-10 schizophrenia diagnosis between January 1999 and March 2019. For each calendar year from 1999 to 2019, we calculated the proportion of patients - among those having received their first schizophrenia diagnosis in the respective calendar year - who redeemed prescriptions for various psychotropics in the two years preceding the schizophrenia diagnosis. We calculated proportions of all pre-diagnostic prescriptions since 1995 for a sub-population diagnosed 2011-2019 and for an age- and sex-matched reference group without schizophrenia.Results: Among 33,361 individuals with schizophrenia (58 % males), the schizophrenia incidence rate was stable during the study period but the mean age at diagnosis decreased by >10 years. In the two pre-diagnostic years, 69 % received psychopharmacological treatment (52 % antipsychotics, 40 % antidepressants). This was stable between 1999 and 2019. Among 14,425 individuals diagnosed 2011-2019, psychotropic drug use was observed among 14-20 % between 24 and 10 years before the diagnosis, being four times higher than the reference group. Particularly antipsychotic and antidepressant drug use increased steadily during the ten pre-diagnostic years.Conclusions: Pre-diagnostic psychotropic drug use in schizophrenia was frequent but stable between 1999 and 2019 despite an earlier identification of schizophrenia patients. Our findings emphasize the continued importance of thorough diagnostic interviews, particularly among patients in need of antipsychotic treatment. [ABSTRACT FROM AUTHOR]

• 92 % of those with recorded eating disorder diagnoses in Denmark are female. • However, diagnosed males have especially high rates of subsequent mortality. • Increased mortality following eating disorder is mainly due to suicide or accidents. • Higher risk of anorexia nervosa for genetic variants associated with lower body fat. Eating disorders are a group of severe and potentially enduring psychiatric disorders associated with increased mortality. Compared to other severe mental illnesses, they have received relatively limited research attention. Epidemiological studies often only report relative measures despite these being difficult to interpret having limited practical use. The aims of this study were to evaluate the incidence and prevalence of diagnosed anorexia nervosa (AN), bulimia nervosa, and eating disorder not otherwise specified recorded in Danish hospital registers and estimate both relative and absolute measures of subsequent mortality – both all-cause and cause-specific in a general nationwide population of 1,667,374 individuals. In a smaller, genetically informed case-cohort sample, the prediction of polygenic scores for AN, body fat percentage, and body mass index on AN prevalence and severity was estimated. Despite males being less likely to be diagnosed with an eating disorder, those that do have significantly increased rates of mortality. AN prevalence was highest for individuals with high AN and low body fat percentage/body mass index polygenic scores. [ABSTRACT FROM AUTHOR]

Research on early-life family environment on obsessive-compulsive disorder (OCD) risk is limited, and sex differences have not been sufficiently studied. We investigated early-life family composition and parental socio-economic status (SES) as OCD risk factors while stratifying for sex in a sample of 1,154,067 individuals from the Danish population (7550 of whom had OCD). Data on early-life family composition (birth order, number of siblings, number of parents in household at proband age 6), parental SES at age 6 (parental income, occupation, and education level), history of parental psychiatric illness, and parental age at birth on OCD risk (i.e., an ICD-10 diagnosis of F42.x) were obtained from Danish population registers. Survival analyses using Cox regression were performed with age as the underlying time variable. Analyses were adjusted for calendar time, and differential effect by sex was tested for exposures. We found that birth order and advanced maternal age were risk factors for OCD in males, and being an only child was associated with increased OCD risk in both sexes. Early childhood SES variables including parental education, occupation, and income were associated with OCD risk, and these effects were more pronounced in females. Significant interaction effects for parental education/occupation and the presence of non-OCD psychiatric diagnoses in the proband also emerged. Our results suggest that early-life SES and family composition may be important risk factors for OCD, and heterogeneity in OCD cases in terms of psychiatric comorbidities, as well as sex differences should be carefully examined in relation to risk factors. • Birth order and advanced maternal age risk factors for OCD, especially in males. • Being an only child associated with OCD risk. • Early life parental SES variables increased OCD risk, especially in females. • Interaction between parental education and proband psychiatric comorbidities observed for OCD risk. • Sex differences should be carefully examined in relation to risk factors. [ABSTRACT FROM AUTHOR]

Objective: Previous literature has established an increased risk of eating disorders among individuals with other psychiatric disorders and vice versa. However, often studies have focused on eating disorders as a single diagnostic entity and/or investigated selected psychiatric comorbidities. We conducted a comprehensive study, exploring bidirectional associations between different types of eating disorders and broad groups of all other psychiatric disorders, to identify patterns of comorbidity. Method: We included all people born in Denmark 1963–2010. We collected information on eating disorders and considered the risk of subsequent psychiatric disorders using Cox‐proportional hazards regression. Absolute risks were calculated using competing risks survival analyses. We also considered prior psychiatric disorders and subsequent eating disorders. Results: An increased risk was seen for almost all disorder pairs of diagnoses evaluated. Following an anorexia nervosa (AN) diagnosis, the median hazard ratio for the different subsequent psychiatric disorders was 3.80 (range 2.48–6.15); following an other eating disorder (OED) diagnosis, it was 3.16 (range 2.05–5.14). After different psychiatric disorder diagnoses, the median hazard ratio was 2.66 for later AN (range 1.21–5.31), and 2.51 for later OED (range 1.25–4.10). Absolute risk of eating disorders was also higher among those with other psychiatric disorders than those without. Discussion: In this broad examination, we identified bidirectional increases in risk of comorbidity for those with both eating disorder diagnoses and psychiatric disorder diagnoses. Although our findings indicate different patterns of comorbidity between eating disorders, these variations were generally small. [ABSTRACT FROM AUTHOR]

Abstract: Research on the relationship between social integration and suicide rates has neglected a historical perspective. Analyses are often based on relatively short time periods where there may not be enough variation in integration to affect the national suicide rate, or where overall integration levels are not low enough to buttress a link between a specific index of low integration, such as divorce, and suicide. The present investigation contributes to the literature by testing a hypothesis on domestic integration and suicide over a century, the longest period studied to date, encompassing periods of low and high overall social integration, and emergent risk and protective factors. Data are available for core variables for Denmark, 1906–2006. Annual data include those on suicide, and indicators of integration (divorces, births, marriages), as well as for economic strain (unemployment) and time trends. A log linear Poisson model is estimated, which explores the central divorce–suicide relationship under controls for confounders. Controlling for confounders, a one percent increase in divorce increases male suicides by 0.52% and female suicides by 1.12%. As anticipated, marriages decrease suicide: a one percent increase in marriages reduces suicide by 0.77% for men and by 0.63% for women. The trend in divorce, in particular, offers accurate predictions of suicide throughout the century. The relationship between divorce and suicide over a century is robust. The results offer the strongest support to date in support of a social integration model based on long term historical data on suicide and divorce. [Copyright &y& Elsevier]