Shared familial risk for type 2 diabetes mellitus and psychiatric disorders: a nationwide multigenerational genetics study.

BACKGROUND: Psychiatric disorders and type 2 diabetes mellitus (T2DM) are heritable, polygenic, and often comorbid conditions, yet knowledge about their potential shared familial risk is lacking. We used family designs and T2DM polygenic risk score (T2DM-PRS) to investigate the genetic associations between psychiatric disorders and T2DM. METHODS: We linked 659 906 individuals born in Denmark 1990-2000 to their parents, grandparents, and aunts/uncles using population-based registers. We compared rates of T2DM in relatives of children with and without a diagnosis of any or one of 11 specific psychiatric disorders, including neuropsychiatric and neurodevelopmental disorders, using Cox regression. In a genotyped sample (iPSYCH2015) of individuals born 1981-2008 (n = 134 403), we used logistic regression to estimate associations between a T2DM-PRS and these psychiatric disorders. RESULTS: Among 5 235 300 relative pairs, relatives of individuals with a psychiatric disorder had an increased risk for T2DM with stronger associations for closer relatives (parents:hazard ratio = 1.38, 95% confidence interval 1.35-1.42; grandparents: 1.14, 1.13-1.15; and aunts/uncles: 1.19, 1.16-1.22). In the genetic sample, one standard deviation increase in T2DM-PRS was associated with an increased risk for any psychiatric disorder (odds ratio = 1.11, 1.08-1.14). Both familial T2DM and T2DM-PRS were significantly associated with seven of 11 psychiatric disorders, most strongly with attention-deficit/hyperactivity disorder and conduct disorder, and inversely with anorexia nervosa. CONCLUSIONS: Our findings of familial co-aggregation and higher T2DM polygenic liability associated with psychiatric disorders point toward shared familial risk. This suggests that part of the comorbidity is explained by shared familial risks. The underlying mechanisms still remain largely unknown and the contributions of genetics and environment need further investigation.

Temporally ordered associations between type 2 diabetes and brain disorders - a Danish register-based cohort study.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is linked with several neurodegenerative and psychiatric disorders, either as a comorbid condition or as a risk factor. We aimed to expand the evidence by examining associations with a broad range of brain disorders (psychiatric and neurological disorders, excluding late-onset neurodegenerative disorders), while also accounting for the temporal order of T2DM and these brain disorders. METHODS: In a population-based cohort-study of 1,883,198 Danish citizens, born 1955-1984 and followed until end of 2016, we estimated associations between T2DM and 16 brain disorders first diagnosed between childhood and mid-adulthood. We calculated odds ratios (OR) and hazard ratios (HR) with 95% confidence intervals (CI) in temporally ordered analyses (brain disorder diagnosis after T2DM and vice versa), adjusted for sex, age, follow-up, birth year, and parental factors. RESULTS: A total of 67,660 (3.6%) of the study population were identified as T2DM cases after age 30 and by a mean age of 45 years (SD of 8 years). T2DM was associated with most psychiatric disorders. Strongest associations were seen with other (i.e. non-anorectic) eating disorders (OR [95% CI]: 2.64 [2.36-2.94]) and schizophrenia spectrum disorder (2.73 [2.63-2.84]). Among neurological disorders especially inflammatory brain diseases (1.73 [1.57-1.91]) and epilepsy (1.67 [1.60-1.75]) were associated with T2DM. Most associations remained in both directions in the temporally ordered analyses. For most psychiatric disorders, associations were strongest in females. CONCLUSIONS: T2DM was associated with several psychiatric and neurological disorders, and most associations were consistently found for both temporal order of disorders. This suggests a shared etiology of T2DM and those brain disorders. This study can form the starting point for studies directed at further elucidating potential causal links between disorders and shared biological mechanisms.

Frequent use of opioids in patients with dementia and nursing home residents: A study of the entire elderly population of Denmark.

BACKGROUND: Pain is believed to be undertreated in patients with dementia; however, no larger studies have been conducted. The aim was to investigate prevalent use of opioids in elderly with and without dementia in the entire elderly population of Denmark. METHOD: A register-based cross-sectional study in the entire elderly (≥65 years) population in 2010 was conducted. Opioid use among elderly with dementia (N = 35,455) was compared with elderly without (N = 870,645), taking age, sex, comorbidity, and living status into account. RESULTS: Nursing home residents (NHRs) used opioids most frequently (41%), followed by home-living patients with dementia (27.5%) and home-living patients without dementia (16.9%). Buprenorphine and fentanyl (primarily patches) were commonly used among NHRs (18.7%) and home-living patients with dementia (10.7%) but less often by home-living patients without dementia (2.4%). CONCLUSIONS: Opioid use in the elderly Danish population was frequent but particularly in patients with dementia and NHR, which may challenge patient safety and needs further investigation.

ADHD medication discontinuation and persistence across the lifespan: a retrospective observational study using population-based databases.

BACKGROUND: Although often intended for long-term treatment, discontinuation of medication for ADHD is common. However, cross-national estimates of discontinuation are missing due to the absence of standardised measures. The aim of this study was to determine the rate of ADHD treatment discontinuation across the lifespan and to describe similarities and differences across countries to guide clinical practice. METHODS: We did a retrospective, observational study using population-based databases from eight countries and one Special Administrative Region (Australia, Denmark, Hong Kong, Iceland, the Netherlands, Norway, Sweden, the UK, and the USA). We used a common analytical protocol approach and extracted prescription data to identify new users of ADHD medication. Eligible individuals were aged 3 years or older who had initiated ADHD medication between 2010 and 2020. We estimated treatment discontinuation and persistence in the 5 years after treatment initiation, stratified by age at initiation (children [age 4-11 years], adolescents [age 12-17 years], young adults [age 18-24 years], and adults [age ≥25 years]) and sex. Ethnicity data were not available. FINDINGS: 1 229 972 individuals (735 503 [60%] males, 494 469 females [40%]; median age 8-21 years) were included in the study. Across countries, treatment discontinuation 1-5 years after initiation was lowest in children, and highest in young adults and adolescents. Within 1 year of initiation, 65% (95% CI 60-70) of children, 47% (43-51) of adolescents, 39% (36-42) of young adults, and 48% (44-52) of adults remained on treatment. The proportion of patients discontinuing was highest between age 18 and 19 years. Treatment persistence for up to 5 years was higher across countries when accounting for reinitiation of medication; at 5 years of follow-up, 50-60% of children and 30-40% of adolescents and adults were covered by treatment in most countries. Patterns were similar across sex. INTERPRETATION: Early medication discontinuation is prevalent in ADHD treatment, particularly among young adults. Although reinitiation of medication is common, treatment persistence in adolescents and young adults is lower than expected based on previous estimates of ADHD symptom persistence in these age groups. This study highlights the scope of medication treatment discontinuation and persistence in ADHD across the lifespan and provides new knowledge about long-term ADHD medication use. FUNDING: European Union Horizon 2020 Research and Innovation Programme.

Experience of Child-Parent Separation and Later Risk of Violent Criminality.

INTRODUCTION: Separation from a parent during childhood has been linked with heightened longer-term violence risk, but it remains unclear how this relationship varies by gender, separation subgroup, and age at separation. This phenomenon was investigated by examining a wide array of child-parent separation scenarios. METHODS: National cohort study including individuals born in Denmark, 1971-1997 (N=1,346,772). Child-parent separation status was ascertained each year from birth to 15th birthday, using residential addresses from the Danish register. Members were followed up from their 15th birthday until the date of first violent offense conviction, or December 31, 2012. Incidence rate ratios were estimated using survival analyses techniques. Analyses were conducted during 2016-2017. RESULTS: Separation from a parent during childhood was associated with elevated risk for subsequent violent offending versus those who lived continuously with both parents. These links were attenuated but persisted after adjustment for parental SES. Associations were stronger for paternal than for maternal separation at least up until mid-childhood and rose with the number of separations. Separation from a father for the first time at a younger age was associated with higher risks than if paternal separation first occurred at an older age, but there was little variation in risk associated with age at first maternal separation. Increasing risks were linked with rising age at first separation from both parents. CONCLUSIONS: Violence prevention should include strategies to tackle a range of correlated familial adversities, with promoting a stable home environment being one salient aspect.

Self-harm risk between adolescence and midlife in people who experienced separation from one or both parents during childhood.

BACKGROUND: Experience of child-parent separation predicts adverse outcomes in later life. We conducted a detailed epidemiological examination of this complex relationship by modelling an array of separation scenarios and trajectories and subsequent risk of self-harm. METHODS: This cohort study examined persons born in Denmark during 1971-1997. We measured child-parent separations each year from birth to 15th birthday via complete residential address records in the Civil Registration System. Self-harm episodes between 15th birthday and early middle age were ascertained through linkage to psychiatric and general hospital registers. Incidence rate ratios (IRRs) from Poisson regression models were estimated against a reference category of individuals not separated from their parents. RESULTS: All exposure models examined indicated an association with raised self-harm risk. For example, large elevations in risk were observed in relation to separation from both parents at 15th birthday (IRR 5.50, 95% CI 5.25-5.77), experiencing five or more changes in child-parent separation status (IRR 5.24, CI 4.88-5.63), and having a shorter duration of familial cohesion during upbringing. There was no significant evidence for varying strength of association according to child's gender. LIMITATIONS: Measuring child-parent separation according to differential residential addresses took no account of the reason for or circumstances of these separations. CONCLUSIONS: These novel findings suggest that self-harm prevention initiatives should be tailored toward exposed persons who remain psychologically distressed into adulthood. These high-risk subgroups include individuals with little experience of familial cohesion during their upbringing, those with the most complicated trajectories who lived through multiple child-parent separation transitions, and those separated from both parents during early adolescence.

Mortality and Self-Harm in Association With Clozapine in Treatment-Resistant Schizophrenia.

OBJECTIVE: This study evaluated rates of all-cause mortality and self-harm in association with clozapine treatment in individuals with treatment-resistant schizophrenia. METHOD: A population-based cohort of 2,370 individuals with treatment-resistant schizophrenia after Jan. 1, 1996, was followed until death, first episode of self-harm, emigration, or June 1, 2013. Time to all-cause death and time to first episode of self-harm were analyzed in Cox regression models with time-varying treatment, adjusted for clinical and sociodemographic covariates. RESULTS: The rate of all-cause mortality was higher for patients not receiving clozapine than for those given clozapine (hazard ratio: 1.88, 95% confidence interval [CI]: 1.16-3.05). This was driven mainly by periods of no antipsychotic treatment (hazard ratio: 2.50, 95% CI: 1.50-4.17), with nonsignificantly higher mortality during treatment with other antipsychotics (hazard ratio: 1.45, 95% CI: 0.86-2.45). Excess mortality was observed in the year after clozapine discontinuation (hazard ratio: 2.65, 95% CI: 1.47-4.78). The rate of self-harm was higher for nonclozapine antipsychotics than for clozapine (hazard ratio: 1.36, 95% CI: 1.04-1.78). CONCLUSIONS: The results demonstrate a nearly twofold higher mortality rate among individuals with treatment-resistant schizophrenia not treated with clozapine compared with clozapine-treated individuals. Furthermore, the results suggest a harmful effect of other antipsychotics regarding self-harm compared with clozapine. It remains to be investigated to what extent the observed excess mortality after clozapine discontinuation is confounded by nonadherence and other unobserved factors and to what extent it is mediated by adverse effects from recent clozapine exposure or deterioration in physical or mental health precipitated by clozapine discontinuation.

Premature Mortality Among Patients Recently Discharged From Their First Inpatient Psychiatric Treatment.

Importance: Nationwide cohorts provide sufficient statistical power for examining premature, cause-specific mortality in patients recently discharged from inpatient psychiatric services. Objective: To investigate premature mortality in a nationwide cohort of patients recently discharged from inpatient psychiatric treatment at ages 15 to 44 years. Design, Setting, and Participants: This single-cohort design included all persons born in Denmark (N = 1 683 385) between January 1, 1967, and December 31, 1996. Exactly 48 599 of these Danish residents were discharged from an inpatient psychiatric unit or ward on or after their 15th birthday, which took place during this study's observation period from January 1, 1982, through December 31, 2011. This group of patients was followed up beginning on their 15th birthday until their death, emigration, or December 31, 2011, whichever came first. Individuals discharged from inpatient psychiatric care at least once before their 15th birthday (n = 5882) were excluded from the study. All data were obtained from the Danish Civil Registration System, Psychiatric Central Research Register, and Register of Causes of Death. Data analysis took place between February 1, 2016, and December 10, 2016. Main Outcomes and Measures: Incidence rates and incidence rate ratios (IRRs) for all-cause mortality and for an array of unnatural and natural causes of death among patients recently discharged from an inpatient psychiatric unit vs persons not admitted to a psychiatric facility. Primary analysis considered risk within the year of first discharge. Results: Of the 48 599 discharged patients who were included in the study, 25 006 (51.4%) were female, 35 660 (73.4%) were aged 15 to 29 years, and 33 995 (70.0%) had a length of stay of 30 days or less. Compared with persons not admitted, patients discharged had an elevated risk for all-cause mortality within 1 year (IRR, 16.2; 95% CI, 14.5-18.0). The relative risk for unnatural death (IRR, 25.0; 95% CI, 22.0-28.4) was much higher than for natural death (IRR, 8.6; 95% CI, 7.0-10.7). The highest IRR found was for suicide at 66.9 (95% CI, 56.4-79.4), followed by alcohol-related death at 42.0 (95% CI, 26.6-66.1). Among the psychiatric diagnostic categories assessed, psychoactive substance abuse conferred the highest risk for all-cause mortality (IRR, 24.8; 95% CI, 21.0-29.4). Across the array of cause-specific outcomes examined, risk of premature death during the first year after discharge was markedly higher than the risk of death beyond the first year of discharge. Conclusions and Relevance: Clinicians may help protect patients after discharge by serving as a liaison between primary and secondary health services to ensure they are receiving holistic care. Early intervention programs for drug and alcohol misuse could substantially decrease the greatly elevated mortality risk among these patients.

Parental Psychiatric Disease and Risks of Attempted Suicide and Violent Criminal Offending in Offspring: A Population-Based Cohort Study.

IMPORTANCE: Self-directed and interpersonal violence share some common risk factors such as a parental history of mental illness. However, relationships between the full spectrum of parental psychiatric disease and these 2 related outcomes are unclear. OBJECTIVE: To examine associations between the full spectrum of parental psychiatric disease and risks of attempted suicide and violent offending among offspring. DESIGN, SETTING, AND PARTICIPANTS: Population-based cohort study of all persons born in Denmark 1967 through 1997, followed up from their 15th birthday until occurrence of adverse outcome or December 31, 2012, whichever came first. EXPOSURES: Array of parental psychiatric disorders and parental suicide attempt, delineated from records of secondary care treatments. MAIN OUTCOMES AND MEASURES: Using survival analyses techniques, incidence rate ratios were estimated for offspring suicide attempt and violent offending. RESULTS: We examined 1 743 525 cohort members (48.7% female; total follow-up, 27.2 million person-years). Risks for offspring suicide attempt and violent offending were elevated across virtually the full spectrum of parental psychiatric disease. Incidence rate ratios were the most elevated for parental diagnoses of antisocial personality disorder (suicide attempt, 3.96; 95% CI, 3.72-4.21; violent offending, 3.62; 95% CI, 3.41-3.84) and cannabis misuse (suicide attempt, 3.57; 95% CI, 3.25-3.92; violent offending, 4.05; 95% CI, 3.72-4.39), and for parental suicide attempt (suicide attempt, 3.42; 95% CI, 3.29-3.55; violent offending, 3.31; 95% CI, 3.19-3.44). Parental mood disorders (and bipolar disorder in particular) conferred more modest risk increases. A history of mental illness or suicide attempt in both parents was associated with double the risks compared with having just 1 affected parent. Associations between parental psychiatric disease and offspring violent offending were stronger for female than for male offspring, whereas little sex difference in risk was found for offspring suicide attempt. CONCLUSIONS AND RELEVANCE: The similarities in risk patterns observed between the 2 outcomes may evidence a shared etiology. Early interventions to tackle parental mental disorders may be beneficial to both parents and children.

Inverse association between urbanicity and treatment resistance in schizophrenia.

BACKGROUND: Living in a larger city is associated with increased risk of schizophrenia; and world-wide, consistent evidence shows that the higher the degree of urbanicity the higher the risk of schizophrenia. However, the association between urbanicity and treatment-resistant schizophrenia (TRS) as a more severe form of schizophrenia or separate entity of schizophrenia has not been fully explored yet. We aimed to investigate the association between urbanicity and incidence of TRS. METHODS: A large Danish population-based cohort of all individuals with a first schizophrenia diagnosis after 1996 was followed until 2013 applying survival analysis techniques. TRS was assessed using a treatment-based proxy, defined as the earliest observed instance of either clozapine initiation or hospital admission due to schizophrenia after having received two prior antipsychotic monotherapy trials of adequate duration. RESULTS: Among the 13,349 schizophrenia patients, 17.3% experienced TRS during follow-up (median follow-up: 7years, inter-quartile range: 3-12years). The 5-year risk of TRS ranged from 10.5% in the capital area to 17.6% in the rural areas. Compared with individuals with schizophrenia residing in the capital area, hazard ratios were 1.44 (1.31-1.59) for provincial areas and 1.60 (1.43-1.79) for rural areas. CONCLUSION: Higher rates of TRS were found in less urbanized areas. The different direction of urban-rural differences regarding TRS and schizophrenia risk may indicate urban-rural systematic differences in treatment practices, or different urban-rural aetiologic types of schizophrenia.

Urbanicity and autism spectrum disorders.

The etiology of autism spectrum disorders (ASD) is for the majority of cases unknown and more studies of risk factors are needed. Geographic variation in ASD occurrence has been observed, and urban residence has been suggested to serve as a proxy for etiologic and identification factors in ASD. We examined the association between urbanicity level and ASD at birth and during childhood. The study used a Danish register-based cohort of more than 800,000 children of which nearly 4,000 children were diagnosed with ASD. We found a dose-response association with greater level of urbanicity and risk of ASD. This association was found for residence at birth as well as residence during childhood. Further, we found an increased risk of ASD in children who moved to a higher level of urbanicity after birth. Also, earlier age of ASD diagnosis in urban areas was observed. While we could not directly examine the specific reasons behind these associations, our results demonstrating particularly strong associations between ASD diagnosis and post-birth migration suggest the influence of identification-related factors such as access to services might have a substantive role on the ASD differentials we observed.