White blood cell counts, ratios, and C-reactive protein among individuals with schizophrenia spectrum disorder and associations with long-term outcomes: a population-based study.

BACKGROUND: Immune mechanisms are associated with adverse outcomes in schizophrenia; however, the predictive value of various peripheral immune biomarkers has not been collectively investigated in a large cohort before. OBJECTIVE: To investigate how white blood cell (WBC) counts, ratios, and C-Reactive Protein (CRP) levels influence the long-term outcomes of individuals with schizophrenia spectrum disorder (SSD). METHODS: We identified all adults in the Central Denmark Region during 1994-2013 with a measurement of WBC counts and/or CRP at first diagnosis of SSD. WBC ratios were calculated, and both WBC counts and ratios were quartile-categorized (Q4 upper quartile). We followed these individuals from first diagnosis until outcome of interest (death, treatment resistance and psychiatric readmissions), emigration or December 31, 2016, using Cox regression analysis to estimate adjusted hazard ratios (aHRs). RESULTS: Among 6,845 participants, 375 (5.5 %) died, 477 (6.9 %) exhibited treatment resistance, and 1470 (21.5 %) were readmitted during follow-up. Elevated baseline levels of leukocytes, neutrophils, monocytes, LLR, NLR, MLR, and CRP increased the risk of death, whereas higher levels of lymphocytes, platelets, and PLR were associated with lower risk. ROC analysis identified CRP as the strongest predictor for mortality (AUC=0.84). Moreover, elevated levels of leukocytes, neutrophils, monocytes, LLR, NLR and MLR were associated with treatment resistance. Lastly, higher platelet counts decreased the risk of psychiatric readmissions, while elevated LLR increased this risk. CONCLUSIONS: Elevated levels of WBC counts, ratios, and CRP at the initial diagnosis of SSD are associated with mortality, with CRP demonstrating the highest predictive value. Additionally, certain WBC counts and ratios are associated with treatment resistance and psychiatric readmissions.

Unraveling the metabolomic architecture of autism in a large Danish population-based cohort.

BACKGROUND: The prevalence of autism in Denmark has been increasing, reaching 1.65% among 10-year-old children, and similar trends are seen elsewhere. Although there are several factors associated with autism, including genetic, environmental, and prenatal factors, the molecular etiology of autism is largely unknown. Here, we use untargeted metabolomics to characterize the neonatal metabolome from dried blood spots collected shortly after birth. METHODS: We analyze the metabolomic profiles of a subset of a large Danish population-based cohort (iPSYCH2015) consisting of over 1400 newborns, who later are diagnosed with autism and matching controls and in two Swedish population-based cohorts comprising over 7000 adult participants. Mass spectrometry analysis was performed by a timsTOF Pro operated in QTOF mode, using data-dependent acquisition. By applying an untargeted metabolomics approach, we could reproducibly measure over 800 metabolite features. RESULTS: We detected underlying molecular perturbations across several metabolite classes that precede autism. In particular, the cyclic dipeptide cyclo-leucine-proline (FDR-adjusted p = 0.003) and the carnitine-related 5-aminovaleric acid betaine (5-AVAB) (FDR-adjusted p = 0.03), were associated with an increased probability for autism, independently of known prenatal and genetic risk factors. Analysis of genetic and dietary data in adults revealed that 5-AVAB was associated with increased habitual dietary intake of dairy (FDR-adjusted p < 0.05) and with variants near SLC22A4 and SLC22A5 (p < 5.0e - 8), coding for a transmembrane carnitine transporter protein involved in controlling intracellular carnitine levels. CONCLUSIONS: Cyclo-leucine-proline and 5-AVAB are associated with future diagnosis of autism in Danish neonates, both representing novel early biomarkers for autism. 5-AVAB is potentially modifiable and may influence carnitine homeostasis.

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.

The correlates of neonatal complement component 3 and 4 protein concentrations with a focus on psychiatric and autoimmune disorders.

Complement components have been linked to schizophrenia and autoimmune disorders. We examined the association between neonatal circulating C3 and C4 protein concentrations in 68,768 neonates and the risk of six mental disorders. We completed genome-wide association studies (GWASs) for C3 and C4 and applied the summary statistics in Mendelian randomization and phenome-wide association studies related to mental and autoimmune disorders. The GWASs for C3 and C4 protein concentrations identified 15 and 36 independent loci, respectively. We found no associations between neonatal C3 and C4 concentrations and mental disorders in the total sample (both sexes combined); however, post-hoc analyses found that a higher C3 concentration was associated with a reduced risk of schizophrenia in females. Mendelian randomization based on C4 summary statistics found an altered risk of five types of autoimmune disorders. Our study adds to our understanding of the associations between C3 and C4 concentrations and subsequent mental and autoimmune disorders.

The cost of mental disorders in Denmark: a register-based study.

The aim of the study was to undertake a detailed analysis of healthcare cost, public transfer payments, and income loss associated with a broad range of mental disorders in Denmark. Based on all persons living in Denmark, we identified those with a hospital diagnosis of one of 18 types of mental disorders and 10 age- and sex-matched controls per case. For each mental disorder, the outcomes were nationwide totals, cost per case, and cost per capita, investigated by sex, age strata, and the number of years after diagnosis. We found a substantial annual income loss of 5 billion Euros and excess healthcare cost of 1 billion Euros for persons with any mental disorder. Each mental disorder was associated with an income loss, excess healthcare cost, and excess public transfer payments compared to matched controls. An interactive data visualisation site with summary data is available at https://nbepi.com/cost .

Accumulation of Disadvantages Across Multiple Domains Amongst Subgroups of Children of Parents With Schizophrenia or Bipolar Disorder: Clustering Data from the Danish High Risk and Resilience Study VIA 7.

Objective: Children with familial high-risk of schizophrenia (FHR-SZ) or bipolar disorder (FHR-BP) are frequently affected in a range of domains known to be precursors of severe mental illness. No previous studies have gathered known precursors to examine whether they distribute evenly across familial high risk (FHR) children or if they cluster among a smaller group. Since such examination holds the potential to identify high and low risk of severe mental illness groups, we aimed to cluster FHR and control children affected to various degrees. Method: In The Danish High Risk and Resilience Study VIA 7, a clinical cohort study, 514 7-year-old children with FHR-SZ or FHR-BP and matched controls were assessed in domains of motor function, neurocognition, emotional control, behavior, social cognition, self-perception, language, psychotic experiences, and psychopathology, and grouped using cluster analysis. Associations between clusters and parents' level of education, functioning, caregiver status, child's level of stimulation and support in the home, and polygenic risk scores were examined. Results: A total of four groups including one of broadly affected children were identified. The broadly affected group was represented 4-5-fold (18.1%) amongst FHR-SZ children and 2-3-fold (10.2%) amongst FHR-BP children, compared to controls (4.1%) (P < .001), and the broadly affected group had lower levels of caregiver functioning (P < .001) and stimulation and support at home (P < .001). Conclusion: Precursors of severe mental illness distribute unevenly among FHR children; while approximately half are not affected in any domains, the other half are affected to various degrees. Targeted support towards the affected groups is indicated.