Greater paternal age is associated with increased risk of schizophrenia, and it has been hypothesized that de novo mutations in paternal germ cells are responsible for this association. An ...alternative hypothesis is that selection into late fatherhood accompanies a predisposition to schizophrenia. However, direct evidence of either hypothesis is lacking. If de novo mutations are responsible, greater paternal age at conception should increase the risk of schizophrenia. Conversely, if selection into late fatherhood is responsible for the association, greater age at which the father had his first child should increase the risk of schizophrenia. The authors aimed to distinguish between these two measures of paternal age.
A total of 2.2 million people born in Denmark between 1955 and 1992 were followed up until first diagnosis with schizophrenia. Incidence rate ratios were estimated in a Cox regression.
Among second- or later-born children, greater paternal age increased the risk of schizophrenia. However, when paternal age at the time of the father's first child was accounted for, the risk of schizophrenia did not depend on paternal age at the birth of later children. In contrast, the risk of schizophrenia increased significantly with increasing paternal age at the time of the father's first child.
Factors related to greater paternal age when the father's first child was born, and not the father's age at conception of later children, are responsible for the association between paternal age and the risk of schizophrenia. These findings do not support the de novo mutation hypothesis.
Abstract Background Many studies have identified urban–rural differences in the occurrence of schizophrenia. Though unknown, the underlying causes responsible for these differences have been ...hypothesized to include urban–rural differences in toxic exposures, diet, infections, stress, or an artifact due to selective migration. Freeman hypothesized that persons with schizophrenia migrate towards larger cities due to development of their disorder or its prodromata. Based on this, the reason for the high frequency of schizophrenia in urban areas is not that those affected have lived in environmentally unfavorable areas, but that people with schizophrenia selectively migrate towards urban areas due to disease onset. No population-based studies accessed the extent and potential impact of this artifact of selective migration. Methods Utilizing a population-based sample of the Danish population, it was investigated if persons with schizophrenia more often migrated towards larger cities due to disease onset. The impact of selective migration on the urban–rural differences was quantified comparing a prospective and a retrospective study. Results Compared to healthy controls, persons with schizophrenia spectrum disorder migrate to a higher degree of urbanization due to disease onset (OR = 1.18 (1.14–1.23)). However, the bias in urban–rural effect sizes due to this artifact of selective migration was limited. Conclusion Persons with schizophrenia drift towards urban areas as a consequence of the disorder or its prodromata, but this drift has only limited impact on the urban–rural differences. Therefore, prospective and retrospective studies are both informative on the unknown underlying factor or factors responsible for the urban–rural differences in schizophrenia risk.
Summary Background No studies have had sufficient size to estimate mortality in children with febrile seizures. We studied mortality after febrile seizures in a large population-based cohort of ...children in Denmark with up to 28 years of follow-up. Methods We identified 1 675 643 children born in Denmark between Jan 1, 1977, and Dec 31, 2004, by linking information from nationwide registers for civil service, health, and cause of death. Children were followed up from 3 months of age, until death, emigration, or Aug 31, 2005. We estimated overall and cause-specific mortality after first febrile seizures with survival analyses. Furthermore, we undertook a case-control study nested within the cohort and retrieved information from medical records about febrile seizure and neurological abnormalities for children who died (N=8172) and individually-matched controls (N=40 860). Findings We identified 8172 children who died, including 232 deaths in 55 215 children with a history of febrile seizures. The mortality rate ratio was 80% higher during the first year (adjusted mortality rate ratio 1·80 95% CI 1·31–2·40) and 90% higher during the second year (1·89 1·27–2·70) after the first febrile seizure; thereafter it was close to that noted for the general population. 132 of 100 000 children (95% CI 102–163) died within 2 years of a febrile seizure compared with 67 (57–76) deaths per 100 000 children without a history of this disorder. In the nested case-control study, children with simple (≤15 min and no recurrence within 24 h) febrile seizure had a mortality rate similar to that of the background population (adjusted mortality rate ratio 1·09 95% CI 0·72–1·64), whereas mortality was increased for those with complex (>15 min or recurrence within 24 h) febrile seizures (1·99 1·24–3·21). This finding was partly explained by pre-existing neurological abnormalities and subsequent epilepsy. Interpretation Long-term mortality is not increased in children with febrile seizures, but there seems to be a small excess mortality during the 2 years after complex febrile seizures. Parents should be reassured that death after febrile seizures is very rare, even in high-risk children. Funding The Danish Research Agency, Lennart Gram Memorial Trust (Denmark), P A Messerschmidt and Wife's Foundation (Denmark), Managing Director Kurt Bønnelycke and Mrs Grethe Bønnelyckes Foundation (Denmark).
Traumatic stress disorders are prevalent in patients with schizophrenia and bipolar disorder. However, there is a lack of prospective longitudinal studies investigating the risk of severe mental ...illness for people diagnosed with traumatic stress disorders. We aimed to assess if patients with acute stress reaction (ASR) or post-traumatic stress disorder (PTSD) are at increased risk of schizophrenia spectrum disorders or bipolar disorder.
We performed a prospective cohort study covering the entire Danish population including information on inpatient and outpatient mental hospitals over 2 decades. Predictors were in- or outpatient diagnoses of ASR or PTSD. We calculated incidence rate ratios (IRR) with 95% CIs of schizophrenia, schizophrenia spectrum disorder, and bipolar disorder.
Persons with a traumatic stress disorder had a significantly increased risk of schizophrenia (IRR 3.80, CI 2.33-5.80), schizophrenia spectrum disorder (IRR 2.34, CI 1.46-3.53), and bipolar disorder (IRR 4.22, CI 2.25-7.13). Risks were highest in the first year after diagnosis of the traumatic stress disorder and remained significantly elevated after more than 5 years. Mental illness in a parent could not explain the association.
Our findings support an association between diagnosed traumatic stress disorders and subsequent schizophrenia spectrum disorder or bipolar disorder. If replicated, this may increase clinical focus on patients with traumatic stress disorders.
There has been recent interest in the findings that the offspring of older fathers have an increased risk of both de novo mutations and neuropsychiatric disorders. However, the offspring of younger ...parents are also at risk for some adverse mental health outcomes.
To determine the association between maternal and paternal age and a comprehensive range of mental health disorders.
A comprehensive, population-based record linkage study using the Danish Psychiatric Central Research Register from January 1, 1995, through December 31, 2011. A total of 2 894 688 persons born in Denmark from January 1, 1955, through December 31, 2006, were followed up during the study period.
Maternal and paternal age at the time of offspring's birth.
We examined a broad range of International Classification of Diseases-defined mental disorders, including substance use; schizophrenia and related disorders; mood disorders; neurotic, stress-related, and somatoform disorders; eating disorders; specific personality disorders; and a range of developmental and childhood disorders. The incidence rate ratios for each mental disorder outcome were estimated by log linear Poisson regression with adjustments for the calendar period, age, sex, and age of the other parent.
The cohort was observed for 42.7 million person-years, during which 218 441 members of the cohort had their first psychiatric contact for any psychiatric disorder. Based on the overall risk of psychiatric disorders, the offspring of younger and older parents were at increased risk compared with those of parents aged 25 to 29 years. When the offspring were examined for particular disorders, the nature of the relationship changed. For example, the offspring of older fathers were at an increased risk of schizophrenia and related disorders, mental retardation, and autism spectrum disorders. In contrast, the offspring of young mothers (and to a lesser extent young fathers) were at an increased risk for substance use disorders, hyperkinetic disorders, and mental retardation.
The offspring of younger mothers and older fathers are at risk for different mental health disorders. These differences can provide clues to the complex risk architecture underpinning the association between parental age and the mental health of offspring.
Manganese (Mn) in drinking water may increase the risk of several neurodevelopmental outcomes, including attention-deficit hyperactivity disorder (ADHD). Earlier epidemiological studies on ...associations between Mn exposure and ADHD-related outcomes had small sample sizes, lacked spatiotemporal exposure assessment, and relied on questionnaire data (not diagnoses)-shortcomings that we address here.
Our objective was to assess the association between exposure to Mn in drinking water during childhood and later development of ADHD.
In a nationwide population-based registry study in Denmark, we followed a cohort of 643,401 children born 1992-2007 for clinical diagnoses of ADHD. In subanalyses, we classified cases into ADHD-Inattentive and ADHD-Combined subtypes based on hierarchical categorization of International Classification of Diseases (ICD)-10 codes. We obtained Mn measurements from 82,574 drinking water samples to estimate longitudinal exposure during the first 5 y of life with high spatiotemporal resolution. We modeled exposure as both peak concentration and time-weighted average. We estimated sex-specific hazard ratios (HRs) in Cox proportional hazards models adjusted for age, birth year, socioeconomic status (SES), and urbanicity.
We found that exposure to increasing levels of Mn in drinking water was associated with an increased risk of ADHD-Inattentive subtype, but not ADHD-Combined subtype. After adjusting for age, birth year, and SES, females exposed to high levels of Mn (i.e.,
) at least once during their first 5 y of life had an HR for ADHD-Inattentive subtype of 1.51 95% confidence interval (CI): 1.18, 1.93 and males of 1.20 (95% CI: 1.01, 1.42) when compared with same-sex individuals exposed to
. When modeling exposure as a time-weighted average, sex differences were no longer present.
Mn in drinking water was associated with ADHD, specifically the ADHD-Inattentive subtype. Our results support earlier studies suggesting a need for a formal health-based drinking water guideline value for Mn. Future Mn-studies should examine ADHD subtype-specific associations and utilize direct subtype measurements rather than relying on ICD-10 codes alone. https://doi.org/10.1289/EHP6391.
Systematic reviews have consistently shown that individuals with mental disorders have an increased risk of premature mortality. Traditionally, this evidence has been based on relative risks or crude ...estimates of reduced life expectancy. The aim of this study was to compile a comprehensive analysis of mortality-related health metrics associated with mental disorders, including sex-specific and age-specific mortality rate ratios (MRRs) and life-years lost (LYLs), a measure that takes into account age of onset of the disorder.
In this population-based cohort study, we included all people younger than 95 years of age who lived in Denmark at some point between Jan 1, 1995, and Dec 31, 2015. Information on mental disorders was obtained from the Danish Psychiatric Central Research Register and the date and cause of death was obtained from the Danish Register of Causes of Death. We classified mental disorders into ten groups and causes of death into 11 groups, which were further categorised into natural causes (deaths from diseases and medical conditions) and external causes (suicide, homicide, and accidents). For each specific mental disorder, we estimated MRRs using Poisson regression models, adjusting for sex, age, and calendar time, and excess LYLs (ie, difference in LYLs between people with a mental disorder and the general population) for all-cause mortality and for each specific cause of death.
7 369 926 people were included in our analysis. We found that mortality rates were higher for people with a diagnosis of a mental disorder than for the general Danish population (28·70 deaths 95% CI 28·57–28·82 vs 12·95 deaths 12·93–12·98 per 1000 person-years). Additionally, all types of disorders were associated with higher mortality rates, with MRRs ranging from 1·92 (95% CI 1·91–1·94) for mood disorders to 3·91 (3·87–3·94) for substance use disorders. All types of mental disorders were associated with shorter life expectancies, with excess LYLs ranging from 5·42 years (95% CI 5·36–5·48) for organic disorders in females to 14·84 years (14·70–14·99) for substance use disorders in males. When we examined specific causes of death, we found that males with any type of mental disorder lost fewer years due to neoplasm-related deaths compared with the general population, although their cancer mortality rates were higher.
Mental disorders are associated with premature mortality. We provide a comprehensive analysis of mortality by different types of disorders, presenting both MRRs and premature mortality based on LYLs, displayed by age, sex, and cause of death. By providing accurate estimates of premature mortality, we reveal previously underappreciated features related to competing risks and specific causes of death.
Danish National Research Foundation.
Onset of mental disorders during childhood or adolescence has been associated with underperformance in school and impairment in social and occupational life in adulthood, which has important ...implications for the affected individuals and society.
To compare the educational achievements at the final examination of compulsory schooling in Denmark between individuals with and those without a mental disorder.
This population-based cohort study was conducted in Denmark and obtained data from the Danish Civil Registration System and other nationwide registers. The 2 cohorts studied were (1) all children who were born in Denmark between January 1, 1988, and July 1, 1999, and were alive at age 17 years (n = 629 622) and (2) all children who took the final examination at the end of ninth grade in both Danish and mathematics subjects between January 1, 2002, and December 31, 2016 (n = 542 500). Data analysis was conducted from March 1, 2018, to March 1, 2019.
Clinical diagnosis by a psychiatrist of any mental disorder or 1 of 29 specific mental disorders before age 16 years.
Taking the final examination at the end of ninth grade and mean examination grades standardized as z scores with differences measured in SDs (standardized mean grade difference).
Of the total study population (n = 629 622; 306 209 female and 323 413 male), 523 312 individuals (83%) took the final examination before 17 years of age and 38 001 (6%) had a mental disorder before that age. Among the 542 500 individuals (274 332 female and 268 168 male), the mean (SD) age was 16.1 (0.33) years for the females and 16.2 (0.34) years for the males. Among the 15 843 female and 22 158 male students with a mental disorder, a lower proportion took the final examination (0.52; 95% CI, 0.52-0.53) compared with individuals without a mental disorder (0.88; 95% CI, 0.88-0.88). Mental disorders affected the grades of male individuals (standardized mean grade difference, -0.30; 95% CI, -0.32 to -0.28) more than the grades of their female peers (standardized mean grade difference, -0.24; 95% CI, -0.25 to -0.22) when compared with same-sex individuals without mental disorders. Most specific mental disorders were associated with statistically significantly lower mean grades, with intellectual disability associated with the lowest grade in female and male students (standardized mean grade difference, -1.07 95% CI, -1.23 to -0.91 and -1.03 95% CI, -1.17 to -0.89; P = .76 for sex differences in the mean grades). Female and male students with anorexia nervosa achieved statistically significantly higher grades on the final examination (standardized mean grade difference, 0.38 95% CI, 0.32-0.44 and 0.31 95% CI, 0.11-0.52; P = .54 for sex differences in the mean grades) compared with their peers without this disorder. For those with anxiety, attachment, attention-deficit/hyperactivity, and other developmental disorders, female individuals attained relatively lower standardized mean grades compared with their male counterparts.
Results of this study suggest that, in Denmark, almost all mental disorders in childhood or adolescence may be associated with a lower likelihood of taking the final examination at the end of ninth grade; those with specific disorders tended to achieve lower mean grades on the examination; and female, compared with male, individuals with certain mental disorders appeared to have relatively more impairment. These findings appear to emphasize the need to provide educational support to young people with mental disorders.
Purpose
Individuals with schizophrenia have been reported to have low employment rates. We examined the associations of schizophrenia with employment, income, and status of cohabitation from a work ...life course perspective.
Methods
Nationwide cohort study including all individuals (
n
= 2,390,127) born in Denmark between 1955 and 1991, who were alive at their 25th birthday. Diagnosis of schizophrenia (yes/no) between ages 15 and 25 was used as an exposure. Employment status, annual wage or self-employment earnings, level of education, and cohabitant status from the age of 25–61 (years 1980–2016) were used as outcomes.
Results
Schizophrenia diagnosis between ages 15 and 25 (
n
= 9448) was associated with higher odds of not being employed (at the age of 30: OR 39.4, 95% CI 36.5–42.6), having no secondary or higher education (7.4, 7.0–7.8), and living alone (7.6, 7.2–8.1). These odds ratios were two-to-three times lower and decreasing over time for those individuals who did not receive treatment in a psychiatric inpatient or outpatient clinic for schizophrenia after the age of 25. Between ages 25–61, individuals with schizophrenia have cumulative earning of $224,000, which is 14% of the amount that the individuals who have not been diagnosed with schizophrenia earn.
Conclusions
Individuals with schizophrenia are at high risk of being outside the labour market and living alone throughout their entire life, resulting in an enormous societal loss in earnings. Individuals with less chronic course of schizophrenia had a gradual but substantial improvement throughout their work life.
Although a family history of schizophrenia is the strongest individual risk factor for schizophrenia, environmental factors related to urbanicity may contribute to a substantial proportion of the ...population occurrence of the disease.
This study replicates previous findings in four mutually exclusive Danish study populations, including out-patient information, ICD-10 diagnoses of schizophrenia, and a broader adjustment for mental illness in family members.
We established a population-based cohort of 2.66 million Danish people using data from the Civil Registration System linked with the Psychiatric Case Register.
Overall, 10 264 persons developed schizophrenia during the 50.7 million person-years of follow-up. The risk of schizophrenia was increased by urbanicity of place of birth and by family history of schizophrenia or other mental disorders.
Urban-rural differences of schizophrenia risk were replicated and could not be associated with the potential sources of bias we assessed. Environmental factors underlying the effect of place of birth are major determinants of schizophrenia occurrence at the population level, although the effect of family history is the strongest at the individual level.
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