Search

BACKGROUND: Depression is associated with excess mortality, but it is not known how treatment-resistance influences life expectancy. We estimated cause-specific excess mortality and Life Years Lost (LYL) in patients with treatment-resistant depression (TRD).METHODS: The population included all individuals born and living in Denmark who redeemed their first prescription for an antidepressant at age 18-69 years between 2005 and 2012, identified in the Danish National Prescription Registry. TRD was defined as at least two additional and different antidepressant trials within two years. Mortality rate ratios (MRRs) were estimated with Cox regression adjusted for age at first prescription, calendar year and comorbidity. Differences in life expectancy were estimated by the Life Years Lost (LYL) method.RESULTS: The cohort included 154,513 first-time pharmacologically treated patients with depression, of whom 8,294 (5.4%) were identified as having TRD. Patients were followed for 1,032,245 person-years during which 9,795 deaths occurred. Men and women with TRD had significantly higher mortality than non-TRD (aMRR: 1.34, 95% CI 1.18-1.52 and aMRR: 1.39, 95% CI 1.19-1.63, respectively). Life expectancy for men and women with TRD was 1.21 (95% CI 0.36-2.44) and 1.24 (95% CI 0.35-2.34) years shorter than in all patients with depression. Suicide accounted for the majority of excess LYL, with 1.10 (95% CI 0.46-1.61) years in men and 0.82 (95% CI 0.44-1.27) years in women with TRD.LIMITATIONS: Using redeemed prescriptions to define TRD may increase the risk of misclassification.CONCLUSIONS: Patients not responding adequately to several treatment trials are at increased risk for premature death, particularly suicide.

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.

PURPOSE: Prescription drug use during pregnancy has increased during the past decades. However, little is known about prescription drug use for high-risk pregnancies. We aimed to estimate the prevalence of redeemed prescriptions in Danish pregnant women with and without previous psychiatric history.METHODS: A Danish population-based descriptive study of 981 392 pregnancies ending in live-born singletons by 586 988 women aged 15 to 55 years between 1997 and 2012, of which 113 449 (11.6%) pregnancies were by women with a psychiatric history prior to the index pregnancy. All prescription drugs redeemed during pregnancy were identified, and dispensing patterns among the women were reported by therapeutic classes of drugs, calendar year of childbirth, and trimester.RESULTS: Overall, women with psychiatric history prior to pregnancy were more likely to fill a prescription (75.8%; 95% confidence interval [CI], 75.5-76.0%), compared with women with no psychiatric history (64.5%; 95% CI, 64.4-64.6%). The difference was observed even when psychotropic drug use was excluded and in all therapeutic classes except for antineoplastic and immunomodulating drugs. The most commonly prescribed drugs were anti-infectives. Approximately 44.7% (95% CI, 44.5-45.0%) of women with psychiatric history and 31.3% (95% CI, 31.2-31.4%) of women with no psychiatric history redeemed more than one therapeutic class of drugs.CONCLUSIONS: Women with a psychiatric history were more likely to redeem prescriptions during pregnancy across almost all drug classes, especially anti-infectives. Two thirds of all women redeemed at least one prescription drug during pregnancy and one third more than one drug class. Key points We mapped prescription drug use of almost 600 000 women during almost one million pregnancies with focus on women with a history of psychiatric disorder before conception compared with women with no such history. Pregnant women with a previous psychiatric disorder were more likely to redeem prescription drugs compared with pregnant women without a previous psychiatric disorder. The observed overall difference was not due to obvious differences in psychotropic drug use. The difference was evident across calendar years, all trimesters, and almost all drug classes, but to a large extent in anti-infectives, among those mainly antibiotics. Two thirds of pregnant women redeemed prescription drugs during pregnancy, and one third redeemed more than one drug class. Health professionals should be aware of comorbid conditions requiring multiple drug use during pregnancy with the risk of unknown fetal effects.

Childhood infection has been proposed as an important etiologic factor for schizophrenia. However, it is unclear to what extent the association between childhood infection and schizophrenia is confounded by parental socioeconomic status and mental illness, and childhood adversity, and whether the association is explained by familial liability for infections. We used a historical, population-based cohort design, selecting all singletons born in Denmark between 1981 and 1998 (n = 882,813). We identified exposure to infection as having been hospitalized with an infection in the Danish national registers. Data from a range of population-based registers were used to construct a childhood adversity index. The index included the following adversities: family disruption, parental incarceration, parental chronic somatic disease, death of a parent, parent permanently outside of workforce, childhood abuse and placement in out-of-home care. We also assessed parental socioeconomic status and mental illness. Multiple admissions with infections during childhood increased the risk of schizophrenia with an Incidence Rate Ratio (IRR) of 1.28 (95% CI: 1.19–1.38) for 1 infection to an IRR of 1.43 (95% CI: 1.30–1.58) for 2–3 infections and an IRR of 1.95 (95% CI: 1.66–2.29) for ≥4 infections. Parental socioeconomic status and mental illness, and childhood adversities increased the odds of acquiring childhood infections and was associated with schizophrenia, but did not explain the results. Similarly did familial liability for infection increase the risk of schizophrenia, but did not explain the association between infection and schizophrenia. Parental mental health modified the association between childhood infection and schizophrenia (p-value 0.02), and we found no significant effect of childhood infection in those with propensity for psychotic disorders.

There are established associations between advanced paternal age and offspring risk for psychiatric and developmental disorders. These are commonly attributed to genetic mutations, especially de novo single nucleotide variants (dnSNVs), that accumulate with increasing paternal age. However, the actual magnitude of risk from such mutations in the male germline is unknown. Quantifying this risk would clarify the clinical significance of delayed paternity. Using parent-child trio whole-exome-sequencing data, we estimate the relationship between paternal-age-related dnSNVs and risk for five disorders: autism spectrum disorder (ASD), congenital heart disease, neurodevelopmental disorders with epilepsy, intellectual disability and schizophrenia (SCZ). Using Danish registry data, we investigate whether epidemiologic associations between each disorder and older fatherhood are consistent with the estimated role of dnSNVs. We find that paternal-age-related dnSNVs confer a small amount of risk for these disorders. For ASD and SCZ, epidemiologic associations with delayed paternity reflect factors that may not increase with age., Advanced paternal age associates with increased risk for psychiatric and developmental disorders in offspring. Here, Taylor et al. utilize parent-child trio exome sequencing data sets to estimate the contribution of paternal age-related de novo mutations to multiple disorders, including heart disease and schizophrenia.

Context Prenatal infection and traumatizing experiences have both been linked with schizophrenia, but none of these factors seem sufficient to cause the disorder. However, recent evidence suggests that these environmental insults act in synergy to increase schizophrenia risk. Objective To estimate the independent and joint effects of exposure to prenatal infection and peripubertal psychological trauma on the risk of schizophrenia. Design Danish nationwide registers were linked in this prospective cohort study. We used survival analysis to report incidence rate ratios (IRRs) and corresponding 95% confidence intervals (95% CIs). Analyses were adjusted for age and calendar period and stratified by sex. Participants A total of 979701 persons born between 1980 and 1998 were followed up from January 1, 1995 through December 31, 2013, with 9656 having a hospital contact for schizophrenia. Results Females exposed to prenatal infection had a significantly increased risk of schizophrenia (IRR: 1.61, 95% CI: 1.30–2.00), but not males (IRR: 0.99, 95% CI: 0.77–1.28). Peripubertal trauma was associated with increased risk in both sexes. Males, however, had a significantly higher risk of schizophrenia after exposure to both prenatal infection and peripubertal psychological trauma (IRR: 2.85, 95% CI: 2.32–3.51), with significant interaction between infection and peripubertal trauma on the multiplicative scale (P = .007). Conclusions Our study demonstrated for the first time that prenatal infection and psychological trauma in peripubertal life can act in synergy to increase the risk of schizophrenia, with a potentially stronger susceptibility in males.

BACKGROUND: To examine the risk of schizophrenia in a Danish population after exposure to early life stress, and whether this risk is modified by DNA sequence variation, specifically two single nucleotide polymorphisms (SNPs) (rs5479 and rs56303414) from the gene HSD11B2. This gene encodes the enzyme 11-β hydroxysteroid dehydrogenase type 2 which converts active cortisol into inactive cortisone.METHODS: A two-stage analysis involving (1) a population-based cohort study, and (2) a nested case-control study using genotype information. Stage 1 included 1,141,447 people; here, we calculated incidence rate ratios (IRR) for the risk of schizophrenia among children of mothers who experienced loss or serious illness of close relatives before, during, and after pregnancy. In stage 2, we genotyped rs5479 and rs56303414 among 1275 schizophrenia cases and 1367 controls, and investigated interactions between genotypes and early life stress on the risk of schizophrenia.RESULTS: In stage 1, no increased risk of schizophrenia was found in offspring after exposure during pregnancy, but offspring exposed to early life stress at age 0-2 years had a significantly increased risk of schizophrenia (adjusted IRR 1.18, 95% confidence interval 1.07-1.31). For rs5479, the minor allele was nucleotide A, and the major allele was nucleotide C. No interaction was found between rs5479 and exposure during pregnancy. Individuals with the minor A allele of rs5479, however, had a significantly increased risk of schizophrenia after exposure to early life stress at age 3-9 years (adjusted IRR 2.06, 1.04-4.06). No interaction was found between rs56303414 and exposure in any of the time periods.CONCLUSION: No association was found between exposure to early life stress during pregnancy and schizophrenia in the offspring investigated, whereas individuals exposed to early life stress within the first two years of life had an increased risk. No interaction was found between HSD11B2 and exposure during pregnancy, but individuals with the A allele of rs5479 had an increased risk of schizophrenia after exposure at age 3-9 years.

Background: Childhood trauma is a risk factor in the etiology of schizophrenia. Mesolimbic dopamine sensitization has been hypothesized to be a mediating factor of childhood trauma on the risk of schizophrenia. Activity of catechol-O-methyltransferase (COMT) Val158Met increases mesolimbic dopamine signaling, and COMT activity may be further regulated by methylenetetrahydrofolate reductase (MTHFR) C677T. The objective of the present study was to investigate the hypothesized three-way interaction between childhood trauma, COMT and MTHFR.