Changing Neighborhood Income Deprivation Over Time, Moving in Childhood, and Adult Risk of Depression.

Importance: Complex biological, socioeconomic, and psychological variables combine to cause mental illnesses, with mounting evidence that early-life experiences are associated with adulthood mental health. Objective: To evaluate whether changing neighborhood income deprivation and residential moves during childhood are associated with the risk of receiving a diagnosis of depression in adulthood. Design, Setting, and Participants: This cohort study included the whole population of 1 096 916 people born in Denmark from January 1, 1982, to December 31, 2003, who resided in the country during their first 15 years of life. Individuals were followed up from 15 years of age until either death, emigration, depression diagnosis, or December 31, 2018. Longitudinal data on residential location was obtained by linking all individuals to the Danish longitudinal population register. Statistical analysis was performed from June 2022 to January 2024. Exposures: Exposures included a neighborhood income deprivation index at place of residence for each year from birth to 15 years of age and a mean income deprivation index for the entire childhood (aged ≤15 years). Residential moves were considered by defining "stayers" as individuals who lived in the same data zone during their entire childhood and "movers" as those who did not. Main Outcomes and Measures: Multilevel survival analysis determined associations between neighborhood-level income deprivation and depression incidence rates after adjustment for individual factors. Results were reported as incidence rate ratios (IRRs) with 95% credible intervals (95% CrIs). The hypotheses were formulated before data collection. Results: A total of 1 096 916 individuals (563 864 male participants [51.4%]) were followed up from 15 years of age. During follow-up, 35 098 individuals (23 728 female participants [67.6%]) received a diagnosis of depression. People living in deprived areas during childhood had an increased risk of depression (IRR, 1.10 [95% CrI, 1.08-1.12]). After full individual-level adjustment, the risk was attenuated (IRR, 1.02 [95% CrI, 1.01-1.04]), indicating an increase of 2% in depression incidence for each 1-SD increase in income deprivation. Moving during childhood, independent of neighborhood deprivation status, was associated with significantly higher rates of depression in adulthood compared with not moving (IRR, 1.61 [95% CrI, 1.52-1.70] for 2 or more moves after full adjustment). Conclusions and Relevance: This study suggests that, rather than just high or changing neighborhood income deprivation trajectories in childhood being associated with adulthood depression, a settled home environment in childhood may have a protective association against depression. Policies that enable and support settled childhoods should be promoted.

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.

Lifestyle and demographic associations with 47 inflammatory and vascular stress biomarkers in 9876 blood donors.

BACKGROUND: The emerging use of biomarkers in research and tailored care introduces a need for information about the association between biomarkers and basic demographics and lifestyle factors revealing expectable concentrations in healthy individuals while considering general demographic differences. METHODS: A selection of 47 biomarkers, including markers of inflammation and vascular stress, were measured in plasma samples from 9876 Danish Blood Donor Study participants. Using regression models, we examined the association between biomarkers and sex, age, Body Mass Index (BMI), and smoking. RESULTS: Here we show that concentrations of inflammation and vascular stress biomarkers generally increase with higher age, BMI, and smoking. Sex-specific effects are observed for multiple biomarkers. CONCLUSION: This study provides comprehensive information on concentrations of 47 plasma biomarkers in healthy individuals. The study emphasizes that knowledge about biomarker concentrations in healthy individuals is critical for improved understanding of disease pathology and for tailored care and decision support tools.

Blood-based biomarkers are circulating molecules that can help to indicate health or disease. Biomarker levels may vary depending on demographic and lifestyle factors such as age, sex, smoking status, and body mass index. Here, we examine the effects of these demographic and lifestyle factors on levels of biomarkers related to activation of the immune system and cardiovascular stress. Measurements of 47 different proteins were performed on blood samples from nearly 10,000 healthy Danish blood donors. Measurement data were linked with questionnaire data to assess effects of lifestyle. We found that immune activation and vascular stress generally increased with age, BMI, and smoking. As these measurements are from healthy blood donors they can serve as a reference for expectable effects and inflammation levels in healthy individuals. Knowledge about the healthy state is important for understanding disease progression and optimizing care.

Higher depression risks in medium- than in high-density urban form across Denmark.

Urban areas are associated with higher depression risks than rural areas. However, less is known about how different types of urban environments relate to depression risk. Here, we use satellite imagery and machine learning to quantify three-dimensional (3D) urban form (i.e., building density and height) over time. Combining satellite-derived urban form data and individual-level residential addresses, health, and socioeconomic registers, we conduct a case-control study (n = 75,650 cases and 756,500 controls) to examine the association between 3D urban form and depression in the Danish population. We find that living in dense inner-city areas did not carry the highest depression risks. Rather, after adjusting for socioeconomic factors, the highest risk was among sprawling suburbs, and the lowest was among multistory buildings with open space in the vicinity. The finding suggests that spatial land-use planning should prioritize securing access to open space in densely built areas to mitigate depression risks.

Towards more comprehensive nationwide familial aggregation studies in Denmark: The Danish Civil Registration System versus the lite Danish Multi-Generation Register.

AIM: Linking information on family members in the Danish Civil Registration System (CRS) with information in Danish national registers provides unique possibilities for research on familial aggregation of diseases, health patterns, social factors and demography. However, the CRS is limited in the number of generations that it can identify. To allow more complete familial linkages, we introduce the lite Danish Multi-Generation Register (lite MGR) and the future full Danish MGR that is currently being developed. METHODS: We generated the lite MGR by linking the current version of the CRS with historical versions stored by the Danish National Archives in the early 1970s, which contain familial links not saved in the current CRS. We describe and compare the completeness of familial links in the lite MGR and the current version of the CRS. We also describe planned procedures for generating the full MGR by linking the current CRS with scanned archived records from Parish Registers. RESULTS: Among people born in Denmark in 1960 or later, the current CRS contains information on both parents. However, it has limited parental information for people born earlier. Among the 732,232 people born in Denmark during 1950-1959, 444,084 (60.65%) had information on both parents in the CRS. In the lite MGR, it was 560,594 (76.56%). CONCLUSIONS: The lite MGR offers more complete information on familial relationships than the current CRS. The lite and full MGR will offer an infrastructure tying together existing research infrastructures, registers and biobanks, raising their joint research value to an unparalleled level.

Multilevel interactions between family and neighbourhood socioeconomic indices in childhood and later risks of self-harm and violent criminality in Denmark: a national cohort study.

BACKGROUND: A socioeconomically disadvantaged childhood has been associated with elevated self-harm and violent criminality risks during adolescence and young adulthood. However, whether these risks are modified by a neighbourhood's socioeconomic profile is unclear. The aim of our study was to compare risks among disadvantaged young people residing in deprived areas versus risks among similarly disadvantaged individuals residing in affluent areas. METHODS: We did a national cohort study, using Danish interlinked national registers, from which we delineated a longitudinal cohort of people born in Denmark between Jan 1, 1981, and Dec 31, 2001, with two Danish-born parents, who were alive and residing in the country when they were aged 15 years, who were followed up for a hospital-treated self-harm episode or violent crime conviction. A neighbourhood affluence indicator was derived based on nationwide income quartiles, with parental income and educational attainment indicating the socioeconomic position of each cohort member's family. Bayesian multilevel survival analyses were done to examine the moderating influences of neighbourhood affluence on associations between family socioeconomic position and sex-specific risks for the two adverse outcomes. FINDINGS: 1 084 047 cohort members were followed up for 12·8 million person-years in aggregate. Individuals of a low socioeconomic position residing in deprived neighbourhoods had a higher incidence of both self-harm and violent criminality compared with equivalently disadvantaged peers residing in affluent areas. Women from a low-income background residing in affluent areas had, on average, 95 (highest density interval 76-118) fewer self-harm episodes and 25 (15-41) fewer violent crime convictions per 10 000 person-years compared with women of an equally low income residing in deprived areas, whereas men of a low income residing in affluent areas had 61 (39-81) fewer self-harm episodes and 88 (56-191) fewer violent crime convictions per 10 000 person-years than men of a low income residing in deprived areas. INTERPRETATION: Even in a high-income European country with comprehensive social welfare and low levels of poverty and inequality, individuals residing in affluent neighbourhoods have lower risks of self-harm and violent criminality compared with individuals residing in deprived neighbourhoods. More research is needed to explore the potential of neighbourhood policies and interventions to reduce the harmful effects of growing up in socioeconomically deprived circumstances on later risk of self-harm and violent crime convictions. FUNDING: European Research Council, Lundbeck Foundation Initiative for Integrative Psychiatric Research, and BERTHA, the Danish Big Data Centre for Environment and Health funded by the Novo Nordisk Foundation Challenge Programme.

The complexities of suicide: a multilevel survival analysis examining individual, familial and neighbourhood determinants of suicide risk using Danish register-based data.

BACKGROUND: Suicide risk is complex and nuanced, and how place impacts suicide risk when considered alongside detailed individual risk factors remains uncertain. We aimed to examine suicide risk in Denmark with both individual and neighbourhood level risk factors. METHODS: We used Danish register-based data to identify individuals born in Denmark from 1972, with full parental information and psychiatric diagnosis history. We fitted a two-level survival model to estimate individual and neighbourhood determinants on suicide risk. RESULTS: We identified 1723 cases of suicide in Denmark during the follow-up period from 1982 to 2015. Suicide risk was explained mainly by individual determinants. Parental comorbidities, particularly maternal schizophrenia [incidence rate ratio (IRR): 2.29, 95% CI 1.56-3.16] and paternal death (2.29, 95% CI 1.31-3.72) partly explained suicide risk when adjusted for all other determinants. The general contextual effect of suicide risk across neighbourhoods showed a median incidence rate ratio (MRR) of 1.13 (1.01-1.28), which was further reduced with full adjustment. Suicide risk increased in neighbourhoods with a higher proportion of manual workers (IRR: 1.08; 1.03-1.14), and decreased with a higher population density (IRR: 0.89; 0.83-0.96). CONCLUSION: Suicide risk varies mainly between individuals, with parental comorbidities having the largest effect on suicide risk. Suicide risk was less impacted by neighbourhood, though, albeit to a lesser extent than individual determinants, some characteristics were associated with suicide risk. Suicide prevention policies might consider targeting interventions towards individuals more vulnerable due to particular parental comorbidities, whilst taking into account that some neighbourhood characteristics might exacerbate this risk further.

The health care cost of comorbidity in individuals with mental disorders: A Danish register-based study.

AIM: The aim of the study was to estimate the annual health care cost by number of comorbid mental and somatic disorders in persons with a mental disorder. METHODS: All persons living in Denmark between 2004 and 2017 with a hospital diagnosis of a mental disorder were identified. We investigated the cost of different health care services: psychiatric hospitals, somatic hospitals, primary health care (e.g. general practitioners, psychologists and so on) and subsidised prescriptions. Within those with at least one mental disorder, we examined the costs for people with (a) counts of different types of mental disorders (e.g. exactly 1, exactly 2 and so on up to 8 or more) and (b) counts of different types of somatic disorders (e.g. no somatic disorders, exactly 1, exactly 2 and so on up to 15 or more). The estimates are reported in average cost per case and nationwide annual cost in Euro 2017. RESULTS: In total, 447,209 persons (238,659 females and 208,550 males) were diagnosed with at least one mental disorder in the study period. The average annual health care cost per case and nationwide cost was 4471 Euros and 786 million Euro, respectively, for persons with exactly one mental disorder, and 33,273 Euro and 3.6 million Euro for persons with eight or more mental disorders. The annual health care cost was 4613 Euro per case and 386 million Euro for persons without any somatic disorders, while the cost per case was 16,344 Euro and 0.7 million Euro in nationwide cost for persons with 15 or more disorders. The amount and proportion of the different health care costs varied by type of comorbidity and count of disorders. CONCLUSIONS: The annual health care cost per case was higher with increasing number of comorbid mental and somatic disorders, while the nationwide annual health care cost was lower with increasing number of comorbid disorders for persons with a mental disorder in Denmark.

Prenatal exposure to nitrate from drinking water and the risk of preterm birth: A Danish nationwide cohort study.

Evidence is emerging that preterm birth (PTB, birth before 37 completed weeks of gestation), a risk factor for neonatal mortality and future morbidity, may be induced by maternal nitrate ( N O 3 - ) exposure from drinking water. The objective of this study is to assess the association between maternal exposure to nitrate and the risk of PTB in a nationwide study of liveborn singletons. Methods: We estimated maternal nitrate exposure from household tap water for 1,055,584 births in Denmark to Danish-born parents during 1991-2015 by linkage of individual home address(es) with nitrate concentrations from a national monitoring database. Nitrate exposure during pregnancy was modeled using four categories and continuously. Logistic models adjusted for sex, birth year, birth order, urbanicity, and maternal age, smoking, education, income, and employment, with generalized estimating equations were used to account for sibling clusters. Results: A total of 1,009,189 births were included, comprising 51,747 PTB. An increase in the risk of PTB was seen across categories of exposure (P < 0.001) with an odds ratio (OR) in the uppermost category (>25 mg/L nitrate) of 1.05 (95% confidence interval [CI] = 1.00, 1.10). Evidence of an exposure-response relationship was observed in models using continuous nitrate (OR = 1.01 [95% CI = 1.00, 1.03] per 10 mg/L nitrate). In sensitivity analyses, results were robust to the addition of variables for short inter-pregnancy interval (<1 year between births), maternal pre-pregnancy body mass index, paternal socioeconomic status and age, season of birth, and inclusion of post-term births. Results were virtually unchanged when the analysis was restricted to women exposed to less than the current European Union standard of 50 mg/L. Conclusion: We observed an increasing risk of PTB with increases in nitrate in household tap water. These findings add to a growing body of evidence of adverse effects from nitrate in drinking water at levels below current regulatory levels.

The contribution of general medical conditions to the non-fatal burden of mental disorders: register-based cohort study in Denmark.

BACKGROUND: General medical conditions (GMCs) often co-occur with mental and substance use disorders (MSDs). AIMS: To explore the contribution of GMCs to the burden of disease in people with MSDs, and investigate how this varied by age. METHOD: A population-based cohort of 6 988 507 persons living in Denmark during 2000-2015 followed for up to 16 years. Danish health registers were used to identify people with MSDs and GMCs. For each MSD, years lived with disability and health loss proportion (HeLP) were estimated for comorbid MSDs and GMCs, using a multiplicative model for disability weights. RESULTS: Those with any MSD lost the equivalent of 43% of healthy life (HeLP = 0.43, 95% CI 0.40-0.44) after including information on GMCs, which was an increase from 25% before including GMCs (HeLP = 0.25, 95% CI 0.23-0.27). Schizophrenia was associated with the highest burden of disease (HeLP = 0.77, 95% CI 0.68-0.85). However, within each disorder, the relative contribution of MSDs and GMCs varied. For example, in those diagnosed with schizophrenia, MSDs and GMCs accounted for 86% and 14% of the total health loss; in contrast, in those with anxiety disorders, the same proportions were 59% and 41%. In general, HeLP increased with age, and was mainly associated with increasing rates of pulmonary, musculoskeletal and circulatory diseases. CONCLUSIONS: In those with mental disorders, the relative contribution of comorbid GMCs to the non-fatal burden of disease increases with age. GMCs contribute substantially to the non-fatal burden of disease in those with MSDs.

Urban-Rural Differences in Schizophrenia Risk: Multilevel Survival Analyses of Individual- and Neighborhood-Level Indicators, Urbanicity and Population Density in a Danish National Cohort Study.

Background: Urban-rural differences in schizophrenia risk have been widely evidenced across Western countries. However, explanation of these differences is lacking. We aimed to identify contextual risk factors for schizophrenia that explain urban-rural differences in schizophrenia risk. Methods: Utilizing Danish population-based registers, we partitioned Denmark into 1885 geographic "neighborhoods" homogeneously sized in terms of population. Information on the entire Danish population from 1981 to 2016 was used to quantify a spectrum of neighborhood-level domains. We subsequently conducted multilevel survival analyses following persons born in Denmark from 1971 to 1982 for the development of schizophrenia allowing for clustering of people within neighborhoods. We used this method to tease apart the effects of individual, specific, and general contextual risk factors for schizophrenia. Results: A significant general contextual effect in schizophrenia risk across neighborhoods was estimated (Medium Incidence Rate Ratio (MRR):1.41; 95% CI:1.35-1.48). Most of the specific contextual factors examined were associated with schizophrenia risk. For instance, neighborhood-level proportion of lone adult households (Incidence Rate Ratios (IRR):1.53; 95% CI:1.44-1.63) had largest risk estimate. Adjustment for all individual-level and specific contextual constructs reduced the IRR for urbanicity from 1.98 (95% CI:1.77-2.22) to 1.30 (95% CI:1.11-1.51). Conclusions: In the largest prospective multilevel survival analyses of schizophrenia risk conducted to date, multiple neighborhood-level characteristics were associated with raised schizophrenia risk, with these contextual factors explaining most of the elevated risk linked with urbanicity. However, the unexplained heterogeneity that was evident in our multilevel models indicates that our understanding of the role of urbanicity in schizophrenia's etiology remains incomplete.

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 .

A life course approach to understanding associations between natural environments and mental well-being for the Danish blood donor cohort.

Natural environments have been associated with mental health benefits, but globally access to these benefits is threatened by urban development and densification. However, it remains unclear how natural environments relate to mental health and how consistent the association is across populations. Here we use a life-course approach with a population consisting of 66 194 individuals from the Danish Blood Donor Study (DBDS) to investigate the association between green and blue space (e.g. parks and lakes) and self-evaluated mental well-being. Green and blue space was identified from remotely-sensed images from the Landsat program, while mental well-being was based on the mental component score (MCS) calculated using the 12-item short form health survey. We use multivariate linear regression models and logistic regression models to quantify the associations. We adjust for additional environmental (urbanization, and air pollution) and lifestyle factors (smoking, body mass index, socioeconomic status, and physical activity) and specifically evaluate the role of physical activity and air pollution as possible mediating factors. We found a positive association between the MCS and current and childhood green space, and a non-significant association for current and childhood blue space. Adjusting for environmental and the other factors attenuated the effect sizes indicating that a broad range of factors determine mental well-being. Physical activity and air pollution were both associated with the MCS as possible mediators of green space associations. In addition, the odds for successfully completing tasks', seeing others, and feeling less downhearted increased with higher levels of green space, and the odds of feeling calm increased with higher levels of blue space. In conclusion, we found support for an association between green and, to less degree, blue space and mental well-being throughout different life stages. In addition, we found a positive association with individual indicators of mental well-being such as being productive, feeling less downhearted and calmer, and being social. The healthy blood donor effect and the bias towards urban residency may explain why we found smaller effect sizes between green and blue space and mental well-being for this generally healthy and resourceful cohort compared to previous studies.

Register-based metrics of years lived with disability associated with mental and substance use disorders: a register-based cohort study in Denmark.

BACKGROUND: Mental disorders account for a substantial proportion of the years lived with disability (YLDs) globally. These estimates have generally been calculated top down based on summary statistics. The aim for this study was to calculate YLDs and a novel related measure, Health Loss Proportion (HeLP), for 18 mental and substance use disorders, based on person-level register data (bottom up). METHODS: A cohort of 6 989 627 Danish residents (5·9% had a diagnosis of a mental or substance use disorder registered in the Danish Psychiatric Central Research Register) was investigated. YLDs (the duration of disease multiplied by a disability weight) were calculated for the disorder of interest and for comorbid mental and substance use disorders. HeLPs were estimated as YLDs associated with an index disorder and comorbid mental and substance use disorders divided by person-years at risk in persons with the index disorder. All analyses were adjusted for mental and substance use comorbidity using a multiplicative model of disability weights. FINDINGS: Major depressive disorder was the most prevalent disorder, although schizophrenia was the leading cause of YLDs in both sexes combined (YLDs 273·3 [95 % CI 232·3-313·6] per 100 000 person-years). People diagnosed with schizophrenia lost the equivalent of 73% (63-83%) of healthy life per year due to mental and substance use disorders, the largest HeLP of all mental and substance use disorders. Comorbidity of mental and substance use disorders accounted for 69-83% of HeLPs in people with either cannabis use disorders, other drug use disorder and ADHD. By contrast, comorbidity explained 11-23% of the HeLPs in people with autism spectrum disorders, conduct disorder, and schizophrenia. INTERPRETATION: Substantial variation in disability was observed across age, sex, and disorders. The new HeLP metric provides novel details of the contribution of comorbidity to the disability associated with mental and substance use disorders. FUNDING: The Danish National Research Foundation, Queensland Government Department of Health, European Union's Horizon 2020, Lundbeck Foundation, Stanley Medical Research Institute. TRANSLATION: For the Danish translation of the abstract see Supplementary Materials section.

Adverse Childhood Experiences and Risk of Subsequently Engaging in Self-Harm and Violence towards Other People-"Dual Harm".

The etiology of "dual harm" (the co-occurrence of self-harm and externalized violence in the same individual) is under-researched. Risk factors have mostly been investigated for each behavior separately. We aimed to examine adversities experienced between birth and age 15 years among adolescents and young adults with histories of self-harm and violent criminality, with a specific focus on dual harm. Three nested case-control studies were delineated using national interlinked Danish registers; 58,409 cases in total aged 15-35 were identified: 28,956 with a history of violent criminality (but not self-harm), 25,826 with a history of self-harm (but not violent criminality), and 3987 with dual-harm history. Each case was matched by date of birth and gender to 20 controls who had not engaged in either behavior. We estimated exposure prevalence for cases versus controls for each of the three behavior groups, and incidence rate ratios (IRRs). Experiencing five or more childhood adversities was more prevalent among individuals with dual-harm history (19.3%; 95% CI 18.0, 20.8%) versus self-harm (10.9%; 10.5, 11.3%) and violence (11.4%; 11.0%, 11.8%) histories. The highest IRRs for dual harm were linked with parental unemployment (5.15; 95% CI 4.71, 5.64), parental hospitalization following self-harm (4.91; 4.40, 5.48) or assault (5.90; 5.07, 6.86), and parental violent criminality (6.11; 5.57, 6.70). Growing up in environments that are characterized by poverty, violence, and substance misuse, and experiencing multiple adversities in childhood, appear to be especially strongly linked with elevated dual-harm risk. These novel findings indicate potential etiologic pathways to dual harm.

Nature and prevalence of combinations of mental disorders and their association with excess mortality in a population-based cohort study.

The nature and prevalence of combinations of mental disorders and their associations with premature mortality have never been reported in a comprehensive way. We describe the most common combinations of mental disorders and estimate excess mortality associated with these combinations. We designed a population-based cohort study including all 7,505,576 persons living in Denmark at some point between January 1, 1995 and December 31, 2016. Information on mental disorders and mortality was obtained from national registers. A total of 546,090 individuals (10.5%) living in Denmark on January 1, 1995 were diagnosed with at least one mental disorder during the 22-year follow-up period. The overall crude rate of diagnosis of mental disorders was 9.28 (95% CI: 9.26-9.30) per 1,000 person-years. The rate of diagnosis of additional mental disorders was 70.01 (95% CI: 69.80-70.26) per 1,000 person-years for individuals with one disorder already diagnosed. At the end of follow-up, two out of five individuals with mental disorders were diagnosed with two or more disorder types. The most prevalent were neurotic/stress-related/somatoform disorders (ICD-10 F40-F48) and mood disorders (ICD-10 F30-F39), which - alone or in combination with other disorders - were present in 64.8% of individuals diagnosed with any mental disorder. Mortality rates were higher for people with mental disorders compared to those without mental disorders. The highest mortality rate ratio was 5.97 (95% CI: 5.52-6.45) for the combination of schizophrenia (ICD-10 F20-F29), neurotic/stress-related/somatoform disorders and substance use disorders (ICD-10 F10-F19). Any combination of mental disorders was associated with a shorter life expectancy compared to the general Danish population, with differences in remaining life expectancy ranging from 5.06 years (95% CI: 5.01-5.11) to 17.46 years (95% CI: 16.86-18.03). The largest excess mortality was observed for combinations that included substance use disorders. This study reports novel estimates related to the "force of comorbidity" and provides new insights into the contribution of substance use disorders to premature mortality in those with comorbid mental disorders.

Exposure to Manganese in Drinking Water during Childhood and Association with Attention-Deficit Hyperactivity Disorder: A Nationwide Cohort Study.

BACKGROUND: 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. OBJECTIVE: Our objective was to assess the association between exposure to Mn in drinking water during childhood and later development of ADHD. METHODS: 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. RESULTS: 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., >100µg/L) 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 <5µg/L. When modeling exposure as a time-weighted average, sex differences were no longer present. DISCUSSION: 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.

Associations between growing up in natural environments and subsequent psychiatric disorders in Denmark.

Natural environments have been associated with mental health benefits worldwide. However, how different elements and types of natural environments associate with mental health is still largely unknown. In this study, we perform a detailed analysis on a large, nation-wide data set of mental health records (908 553 individuals) for Denmark combined with remotely-sensed land cover and vegetation density data. We explore associations between growing up surrounded by different environments and rates of a spectrum of 18 psychiatric disorders. Childhood land cover exposure for urban, agricultural, near-natural green space, and blue space was determined around the residence of each individual. Vegetation density and air pollution were evaluated as potential pathways. Cox proportional hazards models were used to estimate rates as hazard ratios and then adjusted for potential confounding from other known risk factors. For 12 of 18 disorders, rates were lower for children growing up in environments with more natural elements (near-natural green space, blue space, and agriculture) compared to children growing up in urban environments. High vegetation density was associated with lower rates for most disorders within all the examined environments, whereas mitigation of air pollution by natural environments seemed a less important potential pathway. Rates were not notably changed by adjustment for urbanization, parental and municipal socioeconomic status, family history of mental illness, and parents' age. In conclusion, we found that growing up surrounded by a range of natural environments such as near-natural green space, blue space, and agriculture may lower rates of psychiatric disorders. Our results show the importance of ensuring access to natural environments from as nature-based solutions for improved public health and sustainable, livable cities.

Association Between Childhood Green Space, Genetic Liability, and the Incidence of Schizophrenia.

Childhood exposure to green space has previously been associated with lower risk of developing schizophrenia later in life. It is unclear whether this association is mediated by genetic liability or whether the 2 risk factors work additively. Here, we investigate possible gene-environment associations with the hazard ratio (HR) of schizophrenia by combining (1) an estimate of childhood exposure to residential-level green space based on the normalized difference vegetation index (NDVI) from Landsat satellite images, with (2) genetic liability estimates based on polygenic risk scores for 19 746 genotyped individuals from the Danish iPSYCH sample. We used information from the Danish registers of health, residential address, and socioeconomic status to adjust HR estimates for established confounders, ie, parents' socioeconomic status, and family history of mental illness. The adjusted HRs show that growing up surrounded by the highest compared to the lowest decile of NDVI was associated with a 0.52-fold (95% confidence interval [CI]: 0.40 to 0.66) lower schizophrenia risk, and children with the highest polygenic risk score had a 1.24-fold (95% CI: 1.18 to 1.30) higher schizophrenia risk. We found that NDVI explained 1.45% (95% CI: 1.07 to 1.90) of the variance on the liability scale, while polygenic risk score for schizophrenia explained 1.01% (95% CI: 0.77 to 1.46). Together they explained 2.40% (95% CI: 1.99 to 3.07) with no indication of a gene-environment interaction (P = .29). Our results suggest that risk of schizophrenia is associated additively with green space exposure and genetic liability, and provide no support for an environment-gene interaction between NDVI and schizophrenia.

Association of Mental Disorder in Childhood and Adolescence With Subsequent Educational Achievement.

Importance: 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. Objective: To compare the educational achievements at the final examination of compulsory schooling in Denmark between individuals with and those without a mental disorder. Design, Setting, and Participants: 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. Exposures: Clinical diagnosis by a psychiatrist of any mental disorder or 1 of 29 specific mental disorders before age 16 years. Main Outcomes and Measures: 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). Results: 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. Conclusions and Relevance: 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.