School performance and genetic propensities for educational attainment and depression in the etiology of self-harm: a Danish population-based study.

BACKGROUND: Poor school performance is linked to higher risks of self-harm. The association might be explained through genetic liabilities for depression or educational attainment. We investigated the association between school performance and self-harm in a population-based sample while assessing the potential influence of polygenic risk scores (PRSs) for depression (PRSMDD) and for educational attainment (PRSEDU). METHOD: We conducted a follow-up study of individuals born 1987-98 and followed from age 18 until 2016. The total sample consisted of a case group (23,779 diagnosed with mental disorders; schizophrenia, bipolar disorder, depression, autism, and attention deficit hyperactivity disorder (ADHD) and a randomly sampled comparison group (n = 10,925). Genome-wide data were obtained from the Neonatal Screening Biobank and information on school performance, family psychiatric history, and socioeconomic status from national administrative registers. RESULTS: Individuals in the top PRSMDD decile were at higher self-harm risk in the case group (IRR: 1.30; 95% CI 1.15-1.46), whereas individuals in the top PRSEDU decile were at lower self-harm risk (IRR: 0.63; 95% CI: 0.55-0.74). Poorer school performance was associated with higher self-harm risk in persons diagnosed with any mental disorder (IRR: 1.69; 95% CI: 1.44-1.99) and among the comparison group (IRR: 7.93; 95% CI: 4.47-15.18). Observed effects of PRSMDD and PRSEDU on self-harm risk were strongest for individuals with poor school performance. CONCLUSION: Associations between PRSMDD and self-harm risk and between PRSEDU and self-harm risk were found. Nevertheless, these polygenic scores seem currently of limited clinical utility for identifying individuals at high self-harm risk.

The association between birth weight, ponderal index, psychotropic medication, and type 2 diabetes in individuals with severe mental illness.

BACKGROUND: Impaired fetal growth may increase vulnerability towards metabolic disturbances associated with some medications. We examined whether birth weight and ponderal index modify the association between psychotropic medication and type 2 diabetes among young adults with severe psychiatric diagnosis. METHODS: A total of 36,957 individuals born in Denmark between 1973 and 1983 with a diagnosis of schizophrenia, bipolar disorder, or depression were followed from first diagnosis until 2018. Cox proportional hazard models were applied to analyse risk of type 2 diabetes with use of psychotropic medications and interactions between psychotropic medication and birth weight and ponderal index, respectively. RESULTS: During follow-up, 1575 (4.2%) individuals received a diagnosis of type 2 diabetes. Use of antipsychotic, mood stabilizing and antidepressant medications were associated with higher hazard ratios (HRs) of type 2 diabetes (HRantipsychotics 1.68 [95%CI 1.49-1.90]; HRmood stabilizing medication 1.41 [95%CI 1.25-1.59]; HRantidepressants 2.00 [95%CI 1.68-2.37]), as were a birth weight below 2500 g (HR 1.13 [95%CI 1.01-1.28]), and high ponderal index (HR 1.26 [95%CI 1.11-1.43]). The highest rates of type 2 diabetes for each psychotropic medication category were found in medication users with low birth weight or high ponderal index. However, neither birth weight nor ponderal index significantly modified the association between psychotropic medication and diabetes risk. CONCLUSION: Psychotropic medication use, birth weight, and ponderal index were risk factors for type 2 diabetes in patients with severe mental illness, but neither birth weight nor ponderal index modified the association between psychotropic medication and type 2 diabetes.

Intergenerational transmission of suicide attempt in a cohort of 4.4 million children.

BACKGROUND: The association between suicide attempts (SAs) in parents and children is unclear, and risk indicators for intergenerational transmission remain undocumented. We aimed to assess this association, considering the child's developmental period at the time of parents' attempted suicide, and the parental relation. METHODS: Using a prospective cohort design, nationwide population data were linked to the Psychiatric Central Register and National Patient Register for all individuals aged 10 years or older living in Denmark between 1980 and 2016. We assessed incidence rate ratios (IRRs) and cumulative hazards for children's first SA. RESULTS: In a cohort of 4 419 651 children, 163 056 (3.7%) had experienced a parental SA. An SA was recorded among 6996 (4.3%) of the exposed children as opposed to 70112 (1.6%) in unexposed individuals. Higher rates were noted when a parental SA occurred during early childhood (0 ⩽ age < 2) [IRR, 4.7; 95% confidence interval (CI) 4.2-5.4] v. late childhood (6 ⩽ age < 13) (IRR, 3.6; 95% CI 3.4-3.8) when compared to those unexposed. Children exposed prior to age 2 had the highest rates of all sub-groups when reaching age 13-17 (IRR, 6.5; 95% CI 6.0-7.1) and 18-25 years (IRR, 6.8; 95% CI 6.2-7.4). Maternal SA (IRR, 3.4; 95% CI 3.2-3.5) was associated with higher rates than paternal (IRR, 2.8; 95% CI 2.7-2.9). CONCLUSION: Parental SA was associated with children's own SA. Exposure during early developmental stages was associated with the highest rates. Early preventive efforts are warranted as is monitoring of suicide risk in the children from age 13.

Lifetime psychiatric hospital diagnoses among 8,412 Danish men registered in an outpatient alcohol clinic.

OBJECTIVE: To describe the prevalence of lifetime psychiatric hospital diagnoses among men registered in an outpatient alcohol clinic and compare the prevalence with matched controls. To assess temporality of alcohol use disorder (AUD) diagnoses and another psychiatric hospital diagnosis and examine the prevalence of lifetime psychiatric hospital diagnoses according to this temporal order. METHODS: The study included 8,412 Danish men registered in an outpatient alcohol clinic, and 8,412 unregistered controls from the Danish Conscription Database matched on birth date, lifespan, intelligence and draft board district. Information on first outpatient AUD treatment was retrieved from the Copenhagen Alcohol Cohort. Information on lifetime psychiatric hospital diagnoses was retrieved from national Danish psychiatric registers and based on the International Classification of Diseases the 8th and 10th Revisions. Prevalence estimates of lifetime psychiatric hospital diagnoses were compared with odds ratios (OR) between men registered in an outpatient alcohol clinic and the control population. RESULTS: Among men registered in an outpatient alcohol clinic, 66.6% had a lifetime psychiatric hospital diagnosis. In total, 8.6% had neuroses and anxiety disorders, while 25.3% had personality disorders. The OR of a lifetime psychiatric hospital diagnosis was 9.77 (95%CI: 8.87-10.75) when comparing men registered in an outpatient alcohol clinic with the control population. Among men with a lifetime psychiatric hospital diagnosis, 42.8% was registered with another psychiatric hospital diagnosis before registration with an AUD diagnosis. CONCLUSION: Among men with a lifetime psychiatric hospital diagnosis, AUD is rarely diagnosed without psychiatric comorbidity at first-time admissions to psychiatric hospital departments.

Young adult predictors of alcohol dependence to age 53: a 44-year prospective cohort study of Danish men.

AIMS: To examine if (1) there is a positive association between drinking volume in young men and life-time risk of alcohol dependence (AD) and (2) there are other associations between young adulthood factors and life-time risk of AD. DESIGN: Prospective cohort study of sons of fathers with alcohol use disorder (AUD) and matched low-risk controls without paternal AUD. Setting and participants A total of 204 men, who were assessed at baseline in 1979 at age 19-20 years, were followed through record linkage with Danish registers and consecutive psychiatric interviews at the ages of 33, 43 and 53 years. MEASUREMENTS: AD diagnoses were interview-based according to the Diagnostic and Statistical Manual of Mental Disorders, 3rd edition, or made by treating clinicians according to the International Classification of Diseases (ICD) revision 8 (ICD-8) until 1993 and revision 10 (ICD-10) from 1994.We estimated odds ratios (ORs) with 95% confidence intervals (CI) for the development of AD after adjustment for confounders including smoking, social status and paternal AUD. FINDINGS: The following variables from the examination at age 19-20 independently predicted life-time AD: alcohol consumption > 21 beverages/week versus 0-21 [odds ratio (OR) = 2.46, 95% confidence interval (CI) = 1.22-4.97], police contact (OR = 2.60, 95% CI = 1.28-5.28) and institutionalization related to the individual (OR = 2.90, 95% CI = 1.39-6.02). Compared with < 1 beverages/week, the risk for AD did not increase significantly for drinking volume categories: 1-7, 8-14 or 15-21 beverages/week. CONCLUSION: Independently of other risk factors in young adulthood, young Danish men's risk for life-time alcohol dependence appears to be predicted by a drinking volume at age 19-20 years exceeding 21 beverages per week.

Association between Mental Disorders and Subsequent Medical Conditions.

BACKGROUND: Persons with mental disorders are at a higher risk than the general population for the subsequent development of certain medical conditions. METHODS: We used a population-based cohort from Danish national registries that included data on more than 5.9 million persons born in Denmark from 1900 through 2015 and followed them from 2000 through 2016, for a total of 83.9 million person-years. We assessed 10 broad types of mental disorders and 9 broad categories of medical conditions (which encompassed 31 specific conditions). We used Cox regression models to calculate overall hazard ratios and time-dependent hazard ratios for pairs of mental disorders and medical conditions, after adjustment for age, sex, calendar time, and previous mental disorders. Absolute risks were estimated with the use of competing-risks survival analyses. RESULTS: A total of 698,874 of 5,940,299 persons (11.8%) were identified as having a mental disorder. The median age of the total population was 32.1 years at entry into the cohort and 48.7 years at the time of the last follow-up. Persons with a mental disorder had a higher risk than those without such disorders with respect to 76 of 90 pairs of mental disorders and medical conditions. The median hazard ratio for an association between a mental disorder and a medical condition was 1.37. The lowest hazard ratio was 0.82 for organic mental disorders and the broad category of cancer (95% confidence interval [CI], 0.80 to 0.84), and the highest was 3.62 for eating disorders and urogenital conditions (95% CI, 3.11 to 4.22). Several specific pairs showed a reduced risk (e.g., schizophrenia and musculoskeletal conditions). Risks varied according to the time since the diagnosis of a mental disorder. The absolute risk of a medical condition within 15 years after a mental disorder was diagnosed varied from 0.6% for a urogenital condition among persons with a developmental disorder to 54.1% for a circulatory disorder among those with an organic mental disorder. CONCLUSIONS: Most mental disorders were associated with an increased risk of a subsequent medical condition; hazard ratios ranged from 0.82 to 3.62 and varied according to the time since the diagnosis of the mental disorder. (Funded by the Danish National Research Foundation and others; COMO-GMC ClinicalTrials.gov number, NCT03847753.).

Family structure and alcohol use disorder: a register-based cohort study among offspring with and without parental alcohol use disorder.

AIMS: To assess whether parental alcohol use disorder (AUD) is associated with higher risks of living in a non-intact family and assess whether non-intact family structure is associated with higher risks of AUD in the offspring. DESIGN: Prospective cohort study. SETTING: Danish nation-wide registries. PARTICIPANTS: A total of 9948 parental AUD offspring and 98 136 reference offspring from the Danish population. MEASUREMENTS: Family structure assessed at birth and at each birthday until age 15 as intact or non-intact (with mother only, father only or neither parent); years lived in an intact family defined as total number of years lived with both parents from birth until the 15th birthday; AUD defined as registration in medical, treatment and cause of death registries. Data were analyzed by Cox regression. FINDINGS: At birth, 30.9% [95% confidence interval (CI) = 29.1-32.6] of parental AUD offspring and 10.7% (95% CI = 10.3-11.0) of reference offspring lived in a non-intact family. At age 15, the numbers were 84.6% (95% CI = 83.9-85.3) and 38.4% (95% CI = 38.1-38.7). Parental AUD was associated with a higher risk of offspring AUD [hazard ratio (HR) = 1.88, 95% CI = 1.74-2.02]. Offspring were at lower risk of AUD if they lived 15 years in an intact family compared with offspring who never lived in an intact family (HR = 0.67, 95% CI = 0.52-0.87 for those with parental AUD, and HR = 0.53, 95% CI = 0.48-0.59 for those whose parents did not have AUD). Findings were inconclusive as to whether or not an association was present between family structure and AUD among offspring with parental AUD and reference offspring. CONCLUSIONS: The prevalence of non-intact family structure appears to be higher in offspring of parents with alcohol use disorder (AUD) than among offspring from the general population. Parental AUD appears to be associated with increased risk of offspring AUD, and non-intact family structure appears to be associated with increased risk of offspring AUD regardless of parental AUD.

Polygenic risk for psychiatric disorder and singleness in patients with severe mental illness and controls.

We aimed to investigate whether the polygenic risk score (PRS) for schizophrenia influences time in couple relationships for patients with severe mental illness and controls. We combined the nationwide Danish registers with genetic information from dried neonatal blood spots. We included 2,599 individuals with schizophrenia, 1,446 with bipolar disorder, 20,315 with depression, and 6,963 controls. PRS for schizophrenia, depression, and bipolar disorder were estimated using data from the Psychiatric Genetics Consortium and analyzed both as a scale-predictor and as highest versus other deciles. The main outcome was number of days in couple relationships. Patients with schizophrenia had markedly fewer days/year in couple relationships: 64 (95% CI; 61-69) than patients with depression: 119 (95% CI; 117-121), bipolar disorder: 103 (95% CI 97-110), and controls: 136 (95% CI 133-139). PRS for schizophrenia was associated with fewer days in couple relationships in patients with schizophrenia (scale-PRS: IRR = 0.95 (0.93-0.97)) or depression (highest decile: IRR = 0.93 (0.87-0.98)). PRS for bipolar disorder (as scale) was also associated with fewer days in couple relationships in patients with depression (IRR = 0.99 (0.99-1.00)) or bipolar disorder (IRR = 0.96 (0.94-0.99)) and controls (IRR = 0.99 (0.97-1.00), and IRR = 0.89 (0.81-0.98) for the highest decile). Due to the number of statistical tests, however, it cannot be concluded definitely that some of these may not be spurious findings. In conclusion, our findings implicate high genetic loading for schizophrenia as a predisposing factor to singleness in patients with schizophrenia or depression, and genetic loading for bipolar disorder a similar predisposing factor in patients with depression, bipolar disorder or controls.

Adult-Life Alcohol Consumption and Age-Related Cognitive Decline from Early Adulthood to Late Midlife.

AIMS: Alcohol consumption is a modifiable and plausible risk factor for age-related cognitive decline but more longitudinal studies investigating the association are needed. Our aims were to estimate associations of adult-life alcohol consumption and consumption patterns with age-related cognitive decline. METHODS: We investigated the associations of self-reported adult-life weekly alcohol consumption and weekly extreme binge drinking (≥10 units on the same occasion) with changes in test scores on an identical validated test of intelligence completed in early adulthood and late midlife in 2498 Danish men from the Lifestyle and Cognition Follow-up study 2015. Analyses were adjusted for year of birth, retest interval, baseline IQ, education and smoking. RESULTS: Men with adult-life alcohol consumption of more than 28 units/week had a larger decline in IQ scores from early adulthood to late midlife than men consuming 1-14 units/week (B29-35units/week = -3.6; P < 0.001). Likewise, a 1-year increase in weekly extreme binge drinking was associated with a 0.12-point decline in IQ scores (P < 0.001). Weekly extreme binge drinking explained more variance in IQ changes than average weekly consumption. In analyses including mutual adjustment of weekly extreme binge drinking and average weekly alcohol consumption, the estimated IQ decline associated with extreme binge drinking was largely unaffected, whereas the association with weekly alcohol consumption became non-significant. CONCLUSIONS: Adult-life heavy alcohol consumption and extreme binge drinking appear to be associated with larger cognitive decline in men. Moreover, extreme binge drinking may be more important than weekly alcohol consumption in relation to cognitive decline.

Association between prior somatic disease and 5-year relapse risk among 11,856 incident patients with schizophrenia.

BACKGROUND: Somatic diseases have been associated with an increased risk for subsequent schizophrenia; however, it is unknown whether prior somatic diseases negatively affect early treatment outcomes after a first-time schizophrenia diagnosis. METHODS: We included all individuals born in Denmark after January 1st, 1977 and first-time diagnosed with schizophrenia between January 1st, 1996 and December 31st, 2015. We identified all life-time somatic hospital contacts and all prescriptions within the year before the first-time schizophrenia diagnosis and followed patients for up to five years regarding risk for schizophrenia (re)-hospitalization (relapse). We performed Cox regression analyses calculating hazard rate ratios (HRR) including 95%-confidence intervals (CI) and adjusted for relevant confounders. RESULTS: We followed a total of 11,856 patients with a first-time schizophrenia diagnosis (58.7% male, mean age 23.1 (SD = 4.7) years) for 39,033 person-years, whereof 5506 (46.4%) had relapse with schizophrenia re-hospitalization during 5-year of follow-up. Somatic hospital contacts ever before (95.4%; HRR = 1.30; 95%-CI = 1.07-1.59), and specifically during the year before schizophrenia diagnosis (42.5%; HRR = 1.36; 95%-CI = 1.11-1.66) were associated with an increased risk of schizophrenia relapse as were a greater number of prior somatic hospital contacts (p < 0.001). Individuals with up to four different prescriptions for somatic medications showed a trend towards a slightly lower risk of relapse. CONCLUSION: Somatic diseases and health seeking patterns might have an impact on the course of schizophrenia, where severe somatic comorbidity, specifically during the year before first-time schizophrenia diagnosis, seem to negatively affect early treatment course, whereas previous somatic medication use may indicate a better compliance and help-seeking behavior.

Associations between education and age-related cognitive changes from early adulthood to late midlife.

The aims of the study were to explore general trends and individual differences in cognitive changes from early adulthood to late midlife and to investigate associations between education and cognitive changes. We used data from the Lifestyle and Cognition Follow-Up Study 2015 on 1,543 Danish men born in 1950-1961. Test scores on the 78-item intelligence test used by the Danish conscription authorities, Børge Priens Prøve (BPP), completed at draft board examination (baseline, mean age = 20 years) and at follow-up (mean age = 61 years) were used to measure cognitive changes. The mean change in BPP scores was -2.94 (SD = 5.57), and a retest correlation of 0.81 between the baseline and follow-up BPP scores was observed. In spite of the substantial retest correlations, the 8.3% of the sample with statistically reliable change had a mean decline in BPP scores of -13.41 (SD = 2.56). In latent change score models adjusted for year of birth and retest interval, more years of education was associated with larger decline in BPP scores, but the association was reversed when further adjusting for baseline BPP scores. Moreover, significant interactions indicated that more years of education was associated with less cognitive decline in men with relatively low or average BPP scores at baseline, whereas no influence of education was found in men with high baseline scores. Hence, more years of education may compensate for low or average intelligence by increasing cognitive reserve in these individuals or by influencing mediating lifestyle and occupational factors. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Exploring Comorbidity Within Mental Disorders Among a Danish National Population.

Importance: Individuals with mental disorders often develop comorbidity over time. Past studies of comorbidity have often restricted analyses to a subset of disorders and few studies have provided absolute risks of later comorbidity. Objectives: To undertake a comprehensive study of comorbidity within mental disorders, by providing temporally ordered age- and sex-specific pairwise estimates between the major groups of mental disorders, and to develop an interactive website to visualize all results and guide future research and clinical practice. Design, Setting, and Participants: This population-based cohort study included all individuals born in Denmark between January 1, 1900, and December 31, 2015, and living in the country between January 1, 2000, and December 31, 2016. The analyses were conducted between June 2017 and May 2018. Main Outcomes and Measures: Danish health registers were used to identify mental disorders, which were examined within the broad 10-level International Statistical Classification of Diseases and Related Health Problems, 10th Revision, subchapter groups (eg, codes F00-F09 and F10-F19). For each temporally ordered pair of disorders, overall and lagged hazard ratios and 95% CIs were calculated using Cox proportional hazards regression models. Absolute risks were estimated using competing risks survival analyses. Estimates for each sex were generated. Results: A total of 5 940 778 persons were included in this study (2 958 293 men and 2 982 485 women; mean [SD] age at beginning of follow-up, 32.1 [25.4] years). They were followed up for 83.9 million person-years. All mental disorders were associated with an increased risk of all other mental disorders when adjusting for sex, age, and calendar time (hazard ratios ranging from 2.0 [95% CI, 1.7-2.4] for prior intellectual disabilities and later eating disorders to 48.6 [95% CI, 46.6-50.7] for prior developmental disorders and later intellectual disabilities). The hazard ratios were temporally patterned, with higher estimates during the first year after the onset of the first disorder, but with persistently elevated rates during the entire observation period. Some disorders were associated with substantial absolute risks of developing specific later disorders (eg, 30.6% [95% CI, 29.3%-32.0%] of men and 38.4% [95% CI, 37.5%-39.4%] of women with a diagnosis of mood disorders before age 20 years developed neurotic disorders within the following 5 years). Conclusions and Relevance: Comorbidity within mental disorders is pervasive, and the risk persists over time. This study provides disorder-, sex-, and age-specific relative and absolute risks of the comorbidity of mental disorders. Web-based interactive data visualization tools are provided for clinical utility.

Polygenic Risk Scores, School Achievement, and Risk for Schizophrenia: A Danish Population-Based Study.

BACKGROUND: Studies have suggested that poor school achievement is associated with increased risk of schizophrenia; however, the possible genetic contribution to this association is unknown. We investigated the possible effect of the polygenic risk score (PRS) for schizophrenia (PRSSCZ) and for educational attainment (PRSEDU) on the association between school performance and later schizophrenia. METHODS: We conducted a case-cohort study on a Danish population-based sample born from 1987 to 1995 comprising 1470 individuals with schizophrenia and 7318 subcohort noncases. Genome-wide data, school performance, and family psychiatric and socioeconomic background information were obtained from national registers and neonatal biobanks. PRSSCZ and PRSEDU were calculated using discovery effect size estimates from a meta-analysis of 34,600 cases and 45,968 controls and 293,723 individuals. RESULTS: Higher PRSSCZ increased the risk (incidence rate ratio [IRR]: 1.28; 95% confidence interval [CI], 1.19-1.36), whereas higher PRSEDU decreased the risk of schizophrenia (IRR, 0.87; 95% CI, 0.82-0.92) per standard deviation. Not completing primary school and receiving low school marks were associated with increased risk of schizophrenia (IRR, 2.92; 95% CI, 2.37-3.60; and IRR, 1.58; 95% CI, 1.27-1.97, respectively), which was not confounded by PRSSCZ or PRSEDU. Adjusting for social factors and parental psychiatric history, effects of not completing primary school and receiving low school marks were attenuated by up to 25% (IRR, 2.19; 95% CI, 1.75-2.73; and IRR, 1.39; 95% CI, 1.11-1.75, respectively). Increasing PRSEDU correlated with better school performance (p < .01; R2 = 7.6%). PRSSCZ and PRSEDU was significantly negatively correlated (r = -.31, p < .01). CONCLUSIONS: The current PRS did not account for the observed association between primary school performance and risk of schizophrenia.

Childhood Infections and Subsequent School Achievement Among 598,553 Danish Children.

BACKGROUND: Hospitalizations for infections have been associated with subsequent decreased cognitive ability, but it is uncertain if childhood infections influence subsequent scholastic achievement (SA). We aimed to estimate the association between infections during childhood and SA. METHODS: Nationwide prospective cohort study including 598,553 children born in Denmark between 1987 and 1997 and their parents. Exposures were hospitalization for infections and treatment with anti-infective agents. Outcomes were completion of ninth grade and ninth grade test scores. Data were analyzed with logistic and linear regression analysis techniques and adjusted for any mental disorder, birthweight, Apgar score, malformations at birth, chronic somatic diseases, first-born child, parental educational level and parental mental disorders. RESULTS: Hospitalization with infections was linked to lower completion of ninth grade with an odds ratio of 0.82 (95% confidence interval: 0.79-0.85) compared with children without prior hospitalizations for infections. Dose-response relationships were observed with respect to number of hospital contacts for infections and a shorter time since last hospitalization (all P < 0.001). Among those who completed the ninth grade test score, we found a dose-response and time-since relationship between number of prior severe infections and subsequent lower grade scores (P < 0.001). Treatment of nonsevere infections with anti-infective agents did not predict lower completion of ninth grade but was associated with lower grade scores (P < 0.001). CONCLUSIONS: Infections, particularly those requiring hospitalizations, were associated with subsequent affected cognitive ability as indicated by lower SA. These findings might also be explained by missed school days or socioeconomic factors associated with the susceptibility of acquiring infections.

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.

A Nationwide Cohort Study of the Association Between Hospitalization With Infection and Risk of Death by Suicide.

IMPORTANCE: Findings suggest that infections might be linked to the development of psychiatric disorders and suicidal behavior. Large-scale studies are needed to investigate the effect of infection on the risk of suicide. OBJECTIVE: To estimate the association between hospitalization with infection and the risk of death by suicide. DESIGN, SETTING, AND PARTICIPANTS: Nationwide, population-based, prospective cohort study with more than 149 million person-years of follow-up. Data were analyzed with survival analysis techniques and were adjusted for sex, age, calendar period, cohabitation status, socioeconomic status, and the Charlson Comorbidity Index. Individual data were drawn from Danish longitudinal registers. A total of 7.22 million individuals 15 years or older living in Denmark between January 1, 1980, and December 31, 2011, were observed during a 32-year follow-up period. MAIN OUTCOMES AND MEASURES: The risk of death by suicide was identified in the Danish Cause of Death Register. Incidence rate ratios (IRRs) and accompanying 95% CIs were used as measures of relative risk. RESULTS: In 7 221 578 individuals (3 601 653 men and 3 619 925 women) observed for a total of 149 061 786 person-years, 32 683 suicides were observed during the follow-up period. Among the suicides, 7892 (24.1%) individuals had previously been diagnosed as having an infection during a hospitalization. Hospitalization with infection was linked to an elevated risk of suicide, with an IRR of 1.42 (95% CI, 1.38-1.46) compared with those without prior infection. Dose-response relationships were observed with respect to the number of hospital contacts for different infections. For example, having 7 or more infections was linked to an IRR of 2.90 (95% CI, 2.14-3.93). The number of days of treatment for infections was associated with an elevated risk of suicide in a dose-response relationship. More than 3 months of hospital treatment was linked to an IRR of 2.38 (95% CI, 2.05-2.76). The population-attributable risk associated with hospitalization with infection accounted for 10.1% of suicides. CONCLUSIONS AND RELEVANCE: An increased risk of death by suicide was found among individuals hospitalized with infection in prospective and dose-response relationships. These findings indicate that infections may have a relevant role in the pathophysiological mechanisms of suicidal behavior.

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.

Predictors and longitudinal course of cognitive functioning in schizophrenia spectrum disorders, 10years after baseline: The OPUS study.

BACKGROUND: Identifying baseline predictors of the long-term course of cognitive functioning in schizophrenia spectrum disorders is important because of associations between cognitive functioning (CF) and functional outcome. Determining whether CF remains stable or change during the course of illness is another matter of interest. METHODS: Participants from The Danish OPUS Trial, aged 18-45years, with a baseline ICD-10 schizophrenia spectrum diagnosis, were assessed on psychopathology, social and vocational functioning at baseline, and cognitive functioning 5 (N=298) and 10years (N=322) after baseline. Uni- and multi-variable regression analyses of potential baseline predictors of 10-year CF were performed. Also, changes in CF and symptomatology between 5 and 10years of follow-up were assessed. FINDINGS: Baseline predictors of impaired CF after 10years included male gender, unemployment, poor premorbid achievement and later age of onset. Having finished high school and receiving early intervention treatment was associated with better CF. Age, growing up with both parents, number of family and friends, primary caregivers education, premorbid social function, negative symptoms, GAF (symptoms, function) and substance abuse, were associated with CF in univariable analyses. Non-participants generally suffered from more severe dysfunction. Longitudinally, amelioration in negative symptoms was associated with improved speed of processing and executive functions. Symptom scores generally improved with time, while scores for all cognitive tests remained stable. CONCLUSION: The current study identifies several robust associations between baseline characteristics and 10-year cognitive outcome. Several other variables were univariably associated with 10-year cognitive outcome. Also, we found evidence for stability of CF over time.

The influence of pre-deployment cognitive ability on post-traumatic stress disorder symptoms and trajectories: The Danish USPER follow-up study of Afghanistan veterans.

OBJECTIVE: New trajectories of PTSD symptoms have recently been identified in war exposed army veterans. The aim of this army veterans study was to examine whether pre-deployment cognitive ability is associated with the risk of developing PTSD symptoms or non-resilient PTSD trajectories. METHOD: Follow up study in 428 Danish soldiers, deployed to Afghanistan in 2009, who were assessed at six occasions from pre-deployment to three years post-deployment. Pre-deployment vulnerabilities, deployment and homecoming stressors were measured. Pre-deployment cognitive test scores on Børge Priens Prøve (based on logical, verbal, numerical and spatial reasoning) were converted to a mean of 100 and with a standard deviation of 15. RESULTS: Higher pre-deployment cognitive ability scores were associated with lower risk of PTSD symptoms as assessed by the Posttraumatic Stress Disorder Checklist-Civilian Version (PCL-C) 2.5 years post-deployment (OR=0.97; 95% CI 0.95-1.00) after adjustment for educational length, baseline PCL-C score and perceived war-zone stress. Compared to a resilient trajectory, a non-resilient relieved-worsening trajectory (high baseline mental symptoms, being symptom free during deployment and a drastic increase in PTSD symptoms at the final assessments of PTSD symptoms) had significantly lower cognitive scores by a mean difference of 14.5 (95% CI 4.7-24.3). This trajectory (n=9) comprised 26.5% of soldiers with moderate-severe PTSD symptoms 2.5 years post-deployment. CONCLUSION: We confirmed an inverse association between pre-deployment cognitive ability and risk of PTSD symptoms, and observed significantly lower mean pre-deployment cognitive scores in one non-resilient PTSD trajectory. If replicated, this might inform relevant prevention efforts for soldiers at pre-deployment.

Predictors of treatment resistance in patients with schizophrenia: a population-based cohort study.

BACKGROUND: Identification of patients at high risk of treatment-resistant schizophrenia at the time of schizophrenia diagnosis would be of great clinical benefit in minimising the delay to clozapine treatment in patients unlikely to respond to non-clozapine antipsychotics. However, little is known about predictors of treatment resistance in this patient population. We used a treatment-based proxy for treatment-resistant schizophrenia to identify candidate predictors of treatment resistance at first hospital contact with a schizophrenia diagnosis. METHODS: In this population-based cohort study, we obtained Danish national registry data for all adult patients (≥18 years) with incident schizophrenia diagnosed between Jan 1, 1996, and Dec 31, 2006, and followed up until Dec 31, 2010. Our main proxy definition of treatment-resistant schizophrenia was the earliest instance of either clozapine initiation or hospital admission for schizophrenia after having had two periods of different antipsychotic monotherapy. We did multivariable Cox proportional hazards regression analysis to estimate the association between baseline candidate predictors and treatment resistance. FINDINGS: 8624 patients fulfilled the criteria for inclusion. In multivariable complete-case analyses, 1703 (21%) of 8044 patients fulfilled the main proxy definition of treatment-resistant schizophrenia during a median follow-up of 9·1 years (IQR 6·3-11·9). Younger age (hazard ratio 0·96 [95% CI 0·95-0·97]), living in a less urban area (provincial 1·38 [1·23-1·56], rural 1·44 [1·25-1·65]), primary education level (0·88 [0·79-0·98]), more than 30 bed-days in psychiatric hospital in the year before first schizophrenia diagnosis (1·54 [1·35-1·75]), inpatient at first schizophrenia diagnosis (2·07 [1·87-2·29]), paranoid subtype (1·24 [1·13-1·37]), comorbid personality disorder (1·24 [1·11-1·39]), psychotropic drug use (antipsychotics 1·51 [1·35-1·69], antidepressants 1·15 [1·03-1·29], and benzodiazepines 1·22 [1·10-1·37]), and previous suicide attempt (1·21 [1·07-1·39]) were all significantly associated with treatment-resistant schizophrenia. INTERPRETATION: Our study identifies several candidate predictors that could potentially be included in future prediction models for treatment-resistant schizophrenia. Notably, established risk factors for schizophrenia did not predict treatment resistance, suggesting that treatment-resistant disease might be a distinct subtype of schizophrenia and not merely a more severe form. FUNDING: European Community's Seventh Framework Programme.