Diagnosed eating disorders in Danish registers - incidence, prevalence, mortality, and polygenic risk.

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.

A comprehensive analysis of age of onset and cumulative incidence of mental disorders: A Danish register study.

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.

Inpatient admissions and mortality of anorexia nervosa patients according to their preceding psychiatric and somatic diagnoses.

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.

Polygenic Risk of Mental Disorders and Subject-Specific School Grades.

BACKGROUND: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: Polygenic risk scores for mental disorders are differentially associated with language and mathematics school grades.

Prenatal antidepressant exposure and the risk of decreased gestational age and lower birthweight: A polygenic score approach to investigate confounding by indication.

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 ß ranges: 1.7-4.5 days, p < 0.001-0.008) and lower mean birthweights (adjusted ß 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.

Identification of women at high risk of postpartum psychiatric episodes: A population-based study quantifying relative and absolute risks following exposure to selected risk factors and genetic liability.

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.

Antidepressant treatment in pregnancy: a Danish registry linkage study in pregnant women with pre-existing obsessive-compulsive disorder.

The association between antidepressant continuation during pregnancy and postpartum mental health in women with obsessive-compulsive disorder (OCD) is uncertain. We identified 1317 women with live-birth singleton pregnancies and having outpatient/inpatient visits for OCD in the 4 years pre-pregnancy from the Danish registries. We defined three groups based on antidepressant prescriptions filled in the 2 years before pregnancy to delivery: (i) unexposed (n = 449); (ii) discontinuers (n = 346), i.e., with pre-pregnancy antidepressant fills only; (iii) continuers (n = 522), i.e., with antidepressant fills before and during pregnancy. We estimated crude and propensity score weighted hazard ratio (HRs) of postpartum visit for OCD and mood/anxiety disorders using Cox proportional hazard models. In weighted analyses, we found no difference in the probability of a postpartum visit for OCD or MADs with antidepressant continuation compared to unexposed and discontinuers. The likelihood of a postpartum OCD visit was higher in pregnancies having only one prescription fill during pregnancy compared to unexposed (HR = 3.44, 95% CI: 1.24, 9.54) or discontinuers (HR = 2.49, 95% CI: 0.91, 6.83). Continuers in pregnancy without antidepressant fill in the first three months postpartum had higher probability for postpartum visit for mood/anxiety disorders compared to discontinuers (HR = 3.84, 95% CI: 1.49, 9.92). Among pregnant women with pre-existing OCD, we found similar probabilities of a postpartum visit for OCD or mood/anxiety disorders in antidepressant continuers compared to unexposed and discontinuers. Continuers with a single prescription fill during pregnancy or no fill postpartum may have higher risks for these outcomes. Our findings highlight the importance of continuity of treatment throughout the perinatal period.

Risk factors for anorexia nervosa: A population-based investigation of sex differences in polygenic risk and early life exposures.

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.

Effect of mode of birth on development of mental disorders in the offspring.

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.

Psychiatric visits during the postpartum year in women with eating disorders who continue or discontinue antidepressant treatment in pregnancy.

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.

Interplay of ADHD Polygenic Liability With Birth-Related, Somatic, and Psychosocial Factors in ADHD: A Nationwide Study.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Postpartum depression: a developed and validated model predicting individual risk in new mothers.

Postpartum depression (PPD) is a serious condition associated with potentially tragic outcomes, and in an ideal world PPDs should be prevented. Risk prediction models have been developed in psychiatry estimating an individual's probability of developing a specific condition, and recently a few models have also emerged within the field of PPD research, although none are implemented in clinical care. For the present study we aimed to develop and validate a prediction model to assess individualized risk of PPD and provide a tentative template for individualized risk calculation offering opportunities for additional external validation of this tool. Danish population registers served as our data sources and PPD was defined as recorded contact to a psychiatric treatment facility (ICD-10 code DF32-33) or redeemed antidepressant prescriptions (ATC code N06A), resulting in a sample of 6,402 PPD cases (development sample) and 2,379 (validation sample). Candidate predictors covered background information including cohabitating status, age, education, and previous psychiatric episodes in index mother (Core model), additional variables related to pregnancy and childbirth (Extended model), and further health information about the mother and her family (Extended+ model). Results indicated our recalibrated Extended model with 14 variables achieved highest performance with satisfying calibration and discrimination. Previous psychiatric history, maternal age, low education, and hyperemesis gravidarum were the most important predictors. Moving forward, external validation of the model represents the next step, while considering who will benefit from preventive PPD interventions, as well as considering potential consequences from false positive and negative test results, defined through different threshold values.

Genetic and psychosocial influence on the association between early childhood infections and later psychiatric disorders.

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.

Associations between parental socioeconomic-, family-, and sibling status and risk of eating disorders in offspring in a Danish national female cohort.

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.

The role of early-life family composition and parental socio-economic status as risk factors for obsessive-compulsive disorder in a Danish national cohort.

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.

Comorbidity between eating disorders and psychiatric disorders.

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.

Cerebrospinal fluid test results and associations with subsequent mental disorders, neurological diseases, and CNS infections: A population-based cohort study.

BACKGROUND: Cerebrospinal fluid (CSF) immune alterations have been associated with mental disorders, neurological disease, and CNS infections; however, comprehensive large-scale longitudinal CSF studies are lacking. METHODS: By using the Clinical Laboratory Information System (LABKA) Research Database in the Central Denmark Region (1994-2012), we included 15,030 individuals tested for CSF WBC, CSF/serum albumin ratio, IgG index, total protein, albumin, or IgG with follow-up for the risk of mental disorders, psychotropic prescriptions, neurological diseases, or CNS infections, estimated by Cox regression. RESULTS: Among individuals receiving a mental disorder diagnosis (N = 1,147) after a CSF test, 30·0% had an abnormal CSF test result, while for those with a neurological disease (N = 3,201), 39·9% had abnormal test results, and among individuals with CNS infections (N = 1,276), 73·0% had abnormal test results. Individuals with abnormal CSF test results had an increased risk of mental disorders (HR = 3·20; 95%CI = 2·86-3·59), neurological diseases (HR = 12·40; 95%CI = 11·65-13·20), and CNS infections (HR = 338·59; 95%CI = 299·06-383·35) compared to individuals not registered with a CSF test. However, the risk of mental disorders was higher (P < 0·001) after CSF test results within the normal range (HR = 4·45; 95%CI = 4·08-4·86), whereas for neurological diseases (HR = 9·72; 95%CI = 9·19-10·29) and CNS infections (HR = 55·17; 95%CI = 47·12-64·60), the risk was highest after abnormal CSF test results (all P < 0·001). The risk of organic mental disorders tended to be highest in individuals with abnormal CSF test results (HR = 19·30; 95%CI = 13·44-27·71) even though not significantly different from the risk in the group of individuals with CSF test results in the normal range (HR = 13·55; 95%CI = 9·36-19·60) (P ≥ 0·05). Abnormal CSF test results were associated with an elevated risk of psychotropic prescriptions (HR = 3·91; 95%CI = 3·66-4·18), as were CSF test results within the normal range (HR = 4·26; 95%CI = 4·03-4·51) (P < 0·05). CONCLUSIONS: Immunological CSF abnormalities are associated with an increased risk of mental disorders, neurological disease, and particularly CNS infections; however, the included CSF parameters were not specific for mental disorders and the relevant CSF biomarkers in psychiatry are yet to be discovered.

Bidirectional associations between treatment-resistant depression and general medical conditions.

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.

Cause-specific life years lost in individuals with treatment-resistant depression: A Danish nationwide register-based cohort study.

BACKGROUND: Depression is associated with excess mortality, but it is not known how treatment-resistance influences life expectancy. We estimated cause-specific excess mortality and Life Years Lost (LYL) in patients with treatment-resistant depression (TRD). METHODS: The population included all individuals born and living in Denmark who redeemed their first prescription for an antidepressant at age 18-69 years between 2005 and 2012, identified in the Danish National Prescription Registry. TRD was defined as at least two additional and different antidepressant trials within two years. Mortality rate ratios (MRRs) were estimated with Cox regression adjusted for age at first prescription, calendar year and comorbidity. Differences in life expectancy were estimated by the Life Years Lost (LYL) method. RESULTS: The cohort included 154,513 first-time pharmacologically treated patients with depression, of whom 8,294 (5.4%) were identified as having TRD. Patients were followed for 1,032,245 person-years during which 9,795 deaths occurred. Men and women with TRD had significantly higher mortality than non-TRD (aMRR: 1.34, 95% CI 1.18-1.52 and aMRR: 1.39, 95% CI 1.19-1.63, respectively). Life expectancy for men and women with TRD was 1.21 (95% CI 0.36-2.44) and 1.24 (95% CI 0.35-2.34) years shorter than in all patients with depression. Suicide accounted for the majority of excess LYL, with 1.10 (95% CI 0.46-1.61) years in men and 0.82 (95% CI 0.44-1.27) years in women with TRD. LIMITATIONS: Using redeemed prescriptions to define TRD may increase the risk of misclassification. CONCLUSIONS: Patients not responding adequately to several treatment trials are at increased risk for premature death, particularly suicide.