Lack of fit with the neighbourhood social environment as a risk factor for psychosis - a national cohort study.

BACKGROUND: Many studies report an ethnic density effect whereby psychosis incidence among ethnic minority groups is higher in low co-ethnic density areas. It is unclear whether an equivalent density effect applies with other types of socioeconomic disadvantages. METHODS: We followed a population cohort of 2 million native Danes comprising all those born on 1st January 1965, or later, living in Denmark on their 15th birthday. Socioeconomic disadvantage, based on parents' circumstances at age 15 (low income, manual occupation, single parent and unemployed), was measured alongside neighbourhood prevalence of these indices. RESULTS: Each indicator was associated with a higher incidence of non-affective psychosis which remained the same, or was slightly reduced, if neighbourhood levels of disadvantage were lower. For example, for individuals from a low-income background there was no difference in incidence for those living in areas where a low-income was least common [incidence rate ratio (IRR) 1.01; 95% confidence interval (CI) 0.93-1.10 v. those in the quintile where a low income was most common. Typically, differences associated with area-level disadvantage were the same whether or not cohort members had a disadvantaged background; for instance, for those from a manual occupation background, incidence was lower in the quintile where this was least v. most common (IRR 0.83; 95% CI 0.71-0.97), as it was for those from a non-manual background (IRR 0.77; 95% CI 0.67-0.87). CONCLUSION: We found little evidence for group density effects in contrast to previous ethnic density studies. Further research is needed with equivalent investigations in other countries to see if similar patterns are observed.

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.

Parental income as a marker for socioeconomic position during childhood and later risk of developing a secondary care-diagnosed mental disorder examined across the full diagnostic spectrum: a national cohort study.

BACKGROUND: Links between parental socioeconomic position during childhood and subsequent risks of developing mental disorders have rarely been examined across the diagnostic spectrum. We conducted a comprehensive analysis of parental income level, including income mobility, during childhood and risks for developing mental disorders diagnosed in secondary care in young adulthood. METHODS: National cohort study of persons born in Denmark 1980-2000 (N = 1,051,265). Parental income was measured during birth year and at ages 5, 10 and 15. Follow-up began from 15th birthday until mental disorder diagnosis or 31 December 2016, whichever occurred first. Hazard ratios and cumulative incidence were estimated. RESULTS: A quarter (25.2%; 95% CI 24.8-25.6%) of children born in the lowest income quintile families will have a secondary care-diagnosed mental disorder by age 37, versus 13.5% (13.2-13.9%) of those born in the highest income quintile. Longer time spent living in low-income families was associated with higher risks of developing mental disorders. Associations were strongest for substance misuse and personality disorders and weaker for mood disorders and anxiety/somatoform disorders. An exception was eating disorders, with low parental income being associated with attenuated risk. For all diagnostic categories examined except for eating disorders, downward socioeconomic mobility was linked with higher subsequent risk and upward socioeconomic mobility with lower subsequent risk of developing mental disorders. CONCLUSIONS: Except for eating disorders, low parental income during childhood is associated with subsequent increased risk of mental disorders diagnosed in secondary care across the diagnostic spectrum. Early interventions to mitigate the disadvantages linked with low income, and better opportunities for upward socioeconomic mobility could reduce social and mental health inequalities.

Adolescent residential mobility, genetic liability and risk of schizophrenia, bipolar disorder and major depression.

BACKGROUND: Residential mobility during upbringing, and especially adolescence, is associated with multiple negative mental health outcomes. However, whether associations are confounded by unmeasured familial factors, including genetic liability, is unclear. AIMS: We used a population-based case-cohort study to assess whether polygenic risk scores (PRSs) for schizophrenia, bipolar disorder and major depression were associated with mobility from ages 10-14 years, and whether PRS and parental history of mental disorder together explained associations between mobility and each disorder. METHOD: Information on cases (n = 4207 schizophrenia, n = 1402 bipolar disorder, n = 18 215 major depression) and a random population sample (n = 17 582), born 1981-1997, was linked between Danish civil and psychiatric registries. Genome-wide data were obtained from the Danish Neonatal Screening Biobank and PRSs were calculated based on results of separate, large meta-analyses. RESULTS: PRSs for schizophrenia and major depression were weakly associated with moving once (odds ratio 1.07, 95% CI 1.00-1.16; and odds ratio 1.10, 95% CI 1.04-1.17, respectively), but not twice or three or more times. Mobility was positively associated with each disorder, with more moves associated with greater risk. Adjustment for PRS produced slight reductions in the magnitude of associations. Adjustment for PRS and parental history of mental disorder together reduced estimates by 5-11%. In fully adjusted models mobility was associated with all three disorders; hazard ratios ranged from 1.33 (95% CI 1.08-1.62; one move and bipolar disorder) to 3.05 (95% CI 1.92-4.86; three or more moves and bipolar disorder). CONCLUSIONS: Associations of mobility with schizophrenia, bipolar disorder and depression do not appear to be attributable to genetic liability as measured here. Potential familial confounding of mobility associations may be predominantly environmental in nature.

C-reactive protein levels and treatment resistance in schizophrenia-A Danish population-based cohort study.

OBJECTIVE: Schizophrenia is associated with increased levels of inflammatory markers. However, it remains unclear whether inflammatory markers are associated with treatment-resistant schizophrenia. METHODS: We conducted a population-based follow-up study among individuals with a first-time schizophrenia diagnosis and a baseline C-reactive protein measurement (a commonly available marker of systemic inflammation) from 2000 to 2012. We defined treatment resistance as the earliest observed instance of either clozapine initiation or hospital admission due to schizophrenia after having received at least 2 prior antipsychotic monotherapy trials of adequate duration. We used adjusted Cox regression analysis to calculate hazard ratios. RESULTS: We identified 390 individuals with a C-reactive protein measurement at first-time schizophrenia diagnosis. A nonsignificant higher median C-reactive protein (4.0 vs. 3.1 mg/L, p = .13) was observed among the 52 (13.3%) treatment-resistant individuals. Increased levels of C-reactive protein (above 3 mg/L) at baseline were not associated with treatment resistance (adjusted hazard ratio = 0.99, 95% confidence interval [0.56, 1.73]). CONCLUSIONS: C-reactive protein, as a single inflammatory marker, appears insufficient to detect treatment-resistant schizophrenia.

Trends in the psychopharmacological treatment of bipolar disorder: a nationwide register-based study.

OBJECTIVE: In bipolar disorder, treatment with antidepressants without concomitant use of mood stabilisers (antidepressant monotherapy) is associated with development of mania and rapid cycling and is therefore not recommended. The present study aimed to investigate the psychopharmacological treatment patterns in bipolar disorder over time, with a focus on antidepressant monotherapy. METHODS: Cohort study with annual cross-sectional assessment of the use of psychotropic medications between 1995 and 2012 for all Danish residents aged 10 years or older with a diagnosis of bipolar disorder registered in the Danish Psychiatric Central Research Register. Users of a given psychotropic medication were defined as individuals having filled at least one prescription for that particular medication in the year of interest. RESULTS: We identified 20 618 individuals with bipolar disorder. The proportion of patients with bipolar disorder using antidepressants, atypical antipsychotics and anticonvulsants increased over the study period, while the proportion of patients using lithium, typical antipsychotics and benzodiazepines/sedatives decreased. The proportion of patients treated with antidepressant monotherapy decreased from 20.5% in 1997 to 12.1% in 2012, and among antidepressant users, the proportion in monotherapy decreased from 47.7% to 23.9%, primarily driven by a decrease in the use of tricyclic antidepressants. CONCLUSION: The results show an increase in the proportion of patients with bipolar disorder being treated with antidepressants in the period from 1997 to 2012. However, in accordance with international treatment guidelines, the extent of antidepressant monotherapy decreased during the same period.

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.

Type of preadmission antidiabetic treatment and outcome among patients with ischemic stroke: a nationwide follow-up study.

BACKGROUND: We examined whether the preadmission use of sulfonylureas is associated with improved clinical outcome compared with other antidiabetic treatments after hospitalization with ischemic stroke. METHODS: We conducted a nationwide population-based follow-up study among all Danish patients hospitalized with ischemic stroke between 2003 and 2006 and who were registered in the Danish National Indicator Project. We obtained data on diabetes and type of antidiabetic treatment, patient characteristics, in-hospital quality of care, and mortality and readmissions by linking medical databases. We computed mortality rates and rates of readmission recurrent ischemic stroke or myocardial infarction according to type of treatment and used the Cox proportional hazards regression analysis to compute hazard ratios (HRs). RESULTS: We identified 4817 stroke patients with type 2 diabetes mellitus. We found lower 30-day mortality rates among users of metformin (adjusted HR 0.32; 95% confidence interval [CI] 0.15-0.68), insulin (adjusted HR 0.47; 95% CI 0.27-0.81), and patients without antidiabetic pharmacotherapy (adjusted HR 0.58; 95% CI 0.36-0.93) compared with users of sulfonylureas. Users of any combination had a nonstatistical significant lower 30-day mortality rate (adjusted HR 0.64; 95% CI 0.34-1.21). In contrast, we found no significant differences in 1-year mortality rate. Compared with users of sulfonylureas, users of all other types of treatment had increased risk of readmission; however, it did not reach statistical significance for all treatment groups. CONCLUSIONS: Preadmission use of sulfonylureas appeared not to be associated with an overall improved clinical outcome among type 2 diabetic patients admitted with ischemic stroke.

Antidiabetic treatments and risk of hospitalisation with myocardial infarction: a nationwide case-control study.

PURPOSE: Data on cardiovascular risk associated with different types of antidiabetic treatments are sparse and conflicting. We examined the risk of hospitalisation with myocardial infarction (MI) among patients treated with sulfonylureas, metformin, insulin, any combination and no antidiabetic pharmacotherapy. METHODS: Using nationwide registries, we conducted a population-based nested case-control study among all patients with type 2 diabetes in Denmark and identified all patients hospitalised with a first-time MI and age- and gender-matched non-MI controls in the period 1996-2004. We estimated odds ratios (ORs) of MI according to type of antidiabetic treatment, adjusted for potential confounding factors using patients treated with sulfonylureas as the reference group. RESULTS: A total of 10,616 type 2 diabetic cases hospitalised with MI and 90,697 type 2 diabetic non-MI controls were available for analysis. We found a lower risk of hospitalisation with MI among users of metformin (adjusted OR = 0.86, 95%CI: 0.78-0.95), insulin (adjusted OR = 0.92, 95%CI: 0.86-0.99) and among patients not receiving any antidiabetic pharmacotherapy (adjusted OR = 0.75, 95%CI: 0.71-0.79) compared with users of sulfonylureas. Users of any combination had similar risk as users of sulfonylureas (adjusted OR = 0.99, 95%CI: 0.92-1.06). We found no differences between individual sulfonylureas, and glycaemic control and lipid profile had only minor impact on the risk estimates in subanalyses including HbA(1c) , cholesterol and triglycerides. CONCLUSIONS: Our findings provide some support for the hypothesis that sulfonylureas may be associated with an increased risk of hospitalisation with MI.

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.

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.

Genetic liability to ADHD and substance use disorders in individuals with ADHD.

AIMS: 1) To investigate whether genetic liability to attention-deficit/hyperactivity disorder (ADHD), indexed by polygenic risk scores for ADHD (PRS-ADHD), is associated with substance use disorders (SUD) in individuals with ADHD. 2) To investigate whether other individual- or family-related risk factors for SUD could mediate or confound this association. DESIGN: Population-based cohort study SETTING AND PARTICIPANTS: ADHD cases in the iPSYCH sample (a Danish case-cohort sample of genotyped cases with specific mental disorders), born in Denmark between 1981 and 2003 (N = 13 116). Register-based information on hospital diagnoses of SUD was available until December 31, 2016. MEASUREMENTS: We estimated odds ratios (ORs) with 95% confidence intervals (CIs) for any SUD as well as for different SUD types (alcohol, cannabis, and other illicit drugs) and severities (use, abuse, and addiction), with effect sizes corresponding to a comparison of the highest PRS-ADHD decile to the lowest. FINDINGS: PRS-ADHD were associated with any SUD (OR = 1.30, 95% CI: 1.11-1.51). Estimates were similar across different types and severity levels of SUD. Other risk factors for SUD (male sex, age at ADHD diagnosis, comorbid conduct problems, and parental factors including SUD, mental disorders, and socio-economic status) were independently associated with increased risk of SUD. PRS-ADHD explained a minor proportion of the variance in SUD (0.2% on the liability scale) compared to the other risk factors. The association between PRS-ADHD and any SUD was slightly attenuated (OR = 1.21, 95% CI: 1.03-1.41) after adjusting for the other risk factors for SUD. Furthermore, associations were nominally higher in females than in males (ORfemales  = 1.59, 95% CI: 1.19-2.12, ORmales  = 1.18, 95% CI: 0.98-1.42). CONCLUSIONS: A higher genetic liability to attention-deficit/hyperactivity disorder appears to be associated with higher risks of substance use disorders in individuals with attention-deficit/hyperactivity disorder.

Use of statins and risk of hospitalization with dementia: a Danish population-based case-control study.

Several epidemiologic studies have indicated reduced risk of dementia among users of statins. We assessed the risk of hospitalization with dementia associated with use of statins in a population-based case-control study in 4 Northern Danish counties in the period 1991 to 2005. We identified 11,039 cases with dementia and 110,340 age- matched and sex-matched population controls using data from the National Patient Registry, the Danish Psychiatric Central Register, and the Civil Registration System. Prescriptions for statins filled before the admission for dementia were identified using population-based prescription databases. We used conditional logistic regression analysis to compute relative risk of hospitalization with dementia associated with use of statins using nonusers as reference group. We found an overall reduced risk of hospitalization with dementia among statin users (adjusted odds ratio: 0.67, 95% confidence intervals: 0.60-0.75). The reduced risk associated with statin use remained robust in various subanalyses, however, we found no clear dose-response pattern between the number of filled prescriptions for statin and the risk of hospitalization with dementia. In conclusion, we found a reduced risk of hospitalization with dementia among users of statins, however, whether this association is causal remains to be clarified.

Schizophrenia polygenic risk scores, urbanicity and treatment-resistant schizophrenia.

INTRODUCTION: To investigate the impact of a polygenic risk score for schizophrenia (PRS-SZ) and urbanicity on the risk of treatment-resistant schizophrenia (TRS) in people diagnosed with schizophrenia and to evaluate the association between PRS-SZ and TRS across levels of urbanicity. METHODS: Cohort study of people born after 1981 with a first registered diagnosis of schizophrenia between 1996 and 2012 using Danish population registry data. Through linkage to genome-wide data, we calculated PRS-SZ based on a Psychiatric Genomics Consortium meta-analysis. We assessed urbanicity at birth (capital, provincial and rural areas). TRS was defined using prescription and hospital data. Performing Cox regression analysis, we calculated hazard rate ratios (HRs) and 95% confidence intervals (CI). RESULTS: Among 4475 people with schizophrenia, we identified 593 (13.3%) with TRS during 17,558 person years of follow-up. The adjusted HR for TRS associated with one standard deviation (SD) increase in the PRS-SZ was 1.11 (95% CI: 1.00-1.24). The adjusted HRs for TRS across levels of urbanicity were 1.20 (95% CI: 0.98-1.47) for provincial areas and 1.19 (95% CI 0.96-1.47) for rural areas compared with the capital area. Within strata of urbanicity, the adjusted HR for TRS was 1.39 (95% CI: 1.14-1.70) in the capital area with 1 SD increase in the PRS-SZ, 0.99 (95% CI 0.84-1.17) in provincial areas, and 1.03 (95% CI: 0.86-1.25) in rural areas. CONCLUSION: The effect of genetic liability (i.e. PRS) on risk of TRS varied across urbanicity levels and was highest for people with schizophrenia born in the capital areas.

Association of Childhood Exposure to Nitrogen Dioxide and Polygenic Risk Score for Schizophrenia With the Risk of Developing Schizophrenia.

Importance: Schizophrenia is a highly heritable psychiatric disorder, and recent studies have suggested that exposure to nitrogen dioxide (NO2) during childhood is associated with an elevated risk of subsequently developing schizophrenia. However, it is not known whether the increased risk associated with NO2 exposure is owing to a greater genetic liability among those exposed to highest NO2 levels. Objective: To examine the associations between childhood NO2 exposure and genetic liability for schizophrenia (as measured by a polygenic risk score), and risk of developing schizophrenia. Design, Setting, and Participants: Population-based cohort study including individuals with schizophrenia (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision code F20) and a randomly selected subcohort. Using national registry data, all individuals born in Denmark between May 1, 1981, and December 31, 2002, were followed up from their 10th birthday until the first occurrence of schizophrenia, emigration, death, or December 31, 2012, whichever came first. Statistical analyses were conducted between October 24, 2018, and June 17, 2019. Exposures: Individual exposure to NO2 during childhood estimated as mean daily exposure to NO2 at residential addresses from birth to the 10th birthday. Polygenic risk scores were calculated as the weighted sum of risk alleles at selected single-nucleotide polymorphisms based on genetic material obtained from dried blood spot samples from the Danish Newborn Screening Biobank and on the Psychiatric Genomics Consortium genome-wide association study summary statistics file. Main Outcomes and Measures: The main outcome was schizophrenia. Weighted Cox proportional hazards regression models were fitted to estimate adjusted hazard ratios (AHRs) for schizophrenia with 95% CIs according to the exposures. Results: Of a total of 23 355 individuals, 11 976 (51.3%) were male and all had Danish-born parents. During the period of the study, 3531 were diagnosed with schizophrenia. Higher polygenic risk scores were correlated with higher childhood NO2 exposure (ρ = 0.0782; 95% CI, 0.065-0.091; P < .001). A 10-µg/m3 increase in childhood daily NO2 exposure (AHR, 1.23; 95% CI, 1.15-1.32) and a 1-SD increase in polygenic risk score (AHR, 1.29; 95% CI, 1.23-1.35) were independently associated with increased schizophrenia risk. Conclusions and Relevance: These findings suggest that the apparent association between NO2 exposure and schizophrenia is only slightly confounded by a higher polygenic risk score for schizophrenia among individuals living in areas with greater NO2. The findings demonstrate the utility of including polygenic risk scores in epidemiologic studies.

Association of Secondary Preventive Cardiovascular Treatment After Myocardial Infarction With Mortality Among Patients With Schizophrenia.

Importance: Cardioprotective medication use is an important secondary preventive treatment after cardiovascular events. Patients with schizophrenia have excess cardiovascular morbidity and mortality, but no studies have investigated whether taking recommended cardioprotective medication can reduce this excess mortality. Objective: To assess the association of exposure to secondary cardiovascular treatment with all-cause mortality after myocardial infarction among patients with schizophrenia compared with the general population. Design, Setting, and Participants: This nationwide cohort study included individuals admitted with first-time myocardial infarction in Denmark from January 1, 1995, to December 31, 2015. The cohort was dichotomously divided by a diagnosis of schizophrenia. Data on the prescription of guideline-recommended cardioprotective medication, including antithrombotics, ß-blockers, vitamin K antagonist, angiotensin-converting enzyme inhibitors, and statins, were obtained from the nationwide registries. Exposures: Time exposed to cardioprotective medication. Main Outcomes and Measure: Cox proportional hazards regression was used to calculate hazard ratios (HRs) with 95% CIs for the association between treatment exposure and all-cause mortality after myocardial infarction between patients with and without schizophrenia. Results: The cohort included 105 018 patients with myocardial infarction, including 684 patients with schizophrenia (0.7%; 483 male [70.6%]; mean [SD] age at diagnosis, 57.3 [10.6] years) and 104 334 general population patients (99.3%; 73 454 male [70.4%]; mean [SD] age at diagnosis, 61.0 [10.6] years), with a total follow-up of 796 435 person-years and 28 059 deaths. Patients diagnosed with schizophrenia who did not receive cardioprotective treatment had the highest mortality rate (HR, 8.78; 95% CI, 4.37-17.64) compared with the general population treated, with treated patients diagnosed with schizophrenia having an increased HR of 1.97 (95% CI, 1.25-3.10). The analyses of the associations of different cardiac therapy strategies with mortality rates revealed that patients with schizophrenia who were treated with any combination of triple therapy had mortality rates similar to those observed in the general population (HR, 1.05; 95% CI, 0.43-2.52) in the multivariable analysis. Conclusions and Relevance: Cardioprotective medication after myocardial infarction should be carefully managed to improve prognosis. The study results suggest that some of the increased cardiac mortality among patients with schizophrenia can be reduced if these patients are efficiently administered combinations of secondary preventive treatments after cardiac events.

Validation of an algorithm-based definition of treatment resistance in patients with schizophrenia.

Large-scale pharmacoepidemiological research on treatment resistance relies on accurate identification of people with treatment-resistant schizophrenia (TRS) based on data that are retrievable from administrative registers. This is usually approached by operationalising clinical treatment guidelines by using prescription and hospital admission information. We examined the accuracy of an algorithm-based definition of TRS based on clozapine prescription and/or meeting algorithm-based eligibility criteria for clozapine against a gold standard definition using case notes. We additionally validated a definition entirely based on clozapine prescription. 139 schizophrenia patients aged 18-65years were followed for a mean of 5years after first presentation to psychiatric services in South-London, UK. The diagnostic accuracy of the algorithm-based measure against the gold standard was measured with sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). A total of 45 (32.4%) schizophrenia patients met the criteria for the gold standard definition of TRS; applying the algorithm-based definition to the same cohort led to 44 (31.7%) patients fulfilling criteria for TRS with sensitivity, specificity, PPV and NPV of 62.2%, 83.0%, 63.6% and 82.1%, respectively. The definition based on lifetime clozapine prescription had sensitivity, specificity, PPV and NPV of 40.0%, 94.7%, 78.3% and 76.7%, respectively. Although a perfect definition of TRS cannot be derived from available prescription and hospital registers, these results indicate that researchers can confidently use registries to identify individuals with TRS for research and clinical practices.

Otitis media, antibiotics, and risk of autism spectrum disorder.

Otitis media infections and antibiotic treatment have been linked to the risk of developing autism spectrum disorder. Broad-spectrum antibiotics may alter the composition of the gut flora microbiota, which is hypothesized to be involved in the regulation of the immune system. This study examines the interplay among otitis media, antibiotics, and the subsequent risk of developing autism. Based on the entire Danish population, 780,547 children were followed from birth (January 1, 1997 to December 31, 2008) until December 31, 2012. We calculated adjusted hazard ratios and absolute risks of autism with 95% confidence intervals (CIs) related to previous otitis media diagnoses and antibiotic prescriptions redeemed at Danish pharmacies. The absolute risk of autism before age 10 was increased among children with otitis media (1.2% for females and 3.3% for males) and in children who had redeemed an antibiotic prescription (0.6% and 2.7% for females and males) compared to children without a history of otitis media and antibiotics usage (0.4% for females and 1.9% for males). Similarly, we found an increased hazard ratio of autism associated with otitis media (1.83 95% CI 1.71-1.95) and antibiotics usage (1.29 95% CI 1.17-1.43). A history of both otitis media and antibiotic treatment did not further increase the risk of autism. Although the risk of autism was associated with otitis media and treatment with antibiotics, we found little evidence of a synergistic effect between otitis media infections and treatment with antibiotics. Autism Res 2018, 11: 1432-1440. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: We investigated whether otitis media ear infections and antibiotic treatment were associated with autism spectrum disorder. Autism was more common in children who had had an otitis media infection or who had been treated with antibiotics. Given the observational nature of our data, our study cannot be used to conclude that otitis media or use of antibiotics cause autism, as our findings may be subject to unobserved confounding.

Polygenic Risk Score for Schizophrenia and Treatment-Resistant Schizophrenia.

Treatment-resistant schizophrenia (TRS) affects around one-third of individuals with schizophrenia. Although a number of sociodemographic and clinical predictors of TRS have been identified, data on the genetic risk of TRS are sparse. We aimed to investigate the association between a polygenic risk score for schizophrenia and treatment resistance in patients with schizophrenia. We conducted a nationwide, population-based follow-up study among all Danish individuals born after 1981 and with an incident diagnosis of schizophrenia between 1999 and 2007. Based on genome-wide data polygenic risk scores for schizophrenia were calculated in 862 individuals with schizophrenia. TRS was defined as either clozapine initiation or at least 2 periods of different antipsychotic monotherapies and still being hospitalized. We estimated hazard rate ratios (HRs) for TRS in relation to the polygenic risk score while adjusting for population stratification, age, sex, geographical area at birth, clinical treatment setting, psychiatric comorbidity, and calendar year. Among the 862 individuals with schizophrenia, 181 (21.0%) met criteria for TRS during 4674 person-years of follow-up. We found no significant association between the polygenic risk score and TRS, adjusted HR = 1.13 (95% CI: 0.95-1.35). Based on these results, the use of the polygenic risk score for schizophrenia to identify individuals with TRS is at present inadequate to be of clinical utility at the individual patient level. Future research should include larger genetic samples in combination with non-genetic markers. Moreover, a TRS-specific developed polygenic risk score would be of great interest towards early prediction of TRS.