New drug candidates for depression - a nationwide population-based study.

OBJECTIVE: To investigate whether continued use of non-aspirin NSAID, low-dose aspirin, high-dose aspirin, statins, allopurinol and angiotensin agents decreases the rate of incident depression using Danish nationwide population-based registers. METHODS: All persons in Denmark who purchased the exposure medications of interest between 1995 and 2015 and a random sample of 30% of the Danish population was included in the study. Two different outcome measures were included, (i) a diagnosis of depressive disorder at a psychiatric hospital as in-patient or out-patient and (ii) a combined measure of a diagnosis of depression or use of antidepressants. RESULTS: A total of 1 576 253 subjects were exposed to one of the six drugs of interest during the exposure period from 2005 to 2015. Continued use of low-dose aspirin, statins, allopurinol and angiotensin agents was associated with a decreased rate of incident depression according to both outcome measures. Continued uses of non-aspirin NSAIDs as well as high-dose aspirin were associated with an increased rate of incident depression. CONCLUSION: The findings support the potential of agents acting on inflammation and the stress response system in depression as well as the potential of population-based registers to systematically identify drugs with repurposing potential.

Patient-controlled hospital admission for patients with severe mental disorders: a nationwide prospective multicentre study.

OBJECTIVE: To assess whether implementing patient-controlled admission (PCA) can reduce coercion and improve other clinical outcomes for psychiatric in-patients. METHODS: During 2013-2016, 422 patients in the PCA group were propensity score matched 1:5 with a control group (n = 2110) that received treatment as usual (TAU). Patients were followed up for at least one year using the intention to treat principle utilising nationwide registers. In a paired design, the outcomes of PCA patients during the year after signing a contract were compared with the year before. RESULTS: No reduction in coercion (risk difference = 0.001; 95% CI: -0.038; 0.040) or self-harming behaviour (risk difference = 0.005; 95% CI: -0.008; 0.018) was observed in the PCA group compared with the TAU group. The PCA group had more in-patient bed days (mean difference = 28.4; 95% CI: 21.3; 35.5) and more medication use (P < 0.0001) than the TAU group. Before and after analyses showed reduction in coercion (P = 0.0001) and in-patient bed days (P = 0.0003). CONCLUSION: Implementing PCA did not reduce coercion, service use or self-harm behaviour when compared with TAU. Beneficial effects of PCA were observed only in the before and after PCA comparisons. Further research should investigate whether PCA affects other outcomes to better establish its clinical value.

Continuation of lithium after a diagnosis of chronic kidney disease.

OBJECTIVE: To investigate whether continued lithium or anticonvulsant treatment after a first diagnosis of chronic kidney disease (CKD) was associated with progression to irreversible end-stage kidney disease. METHODS: Nationwide cohort study including all individuals in Denmark in a period from 1995 to 2012 with a diagnosis of CKD and (i) a history of lithium treatment (N = 754, among whom 238 patients had a diagnosis of bipolar disorder) or (ii) a history of anticonvulsant treatment (N = 5.004, among whom 199 patients had a diagnosis of bipolar disorder). End-stage CKD was defined as chronic dialysis or renal transplantation. RESULTS: Continuing lithium (HR = 0.58 (95% CI: 0.37-0.90) and continuing anticonvulsants (HR = 0.53 (95% CI: 0.44-0.64) were associated with decreased rates of end-stage CKD. In the subcohorts of patients with a diagnosis of bipolar disorder, continuing lithium was associated with decreased end-stage CKD (HR = 0.40 (95% CI: 0.17-0.98), whereas continuing anticonvulsants was not (HR = 0.70 (95% CI: 0.21-2.37). There were no interactions of continuing lithium and anticonvulsants. CONCLUSION: After an initial diagnosis of CKD, patients who are selected by their physicians to continue lithium treatment may not necessarily have an increased risk of developing end-stage CKD. Shifting to an anticonvulsant per se may not be associated with an advantage; however, this requires further investigation.

Evidence for clinical progression of unipolar and bipolar disorders.

OBJECTIVE: It is a widely held belief that affective disorders are progressive of nature; however, some recent reviews have questioned this belief. The objective of the present systematic literature review was to present evidence for associations between number of affective episodes and (i) the risk of recurrence of episodes, (ii) probability of recovery from episodes, (iii) severity of episodes, (iv) the threshold for developing episodes, and (v) progression of cognitive deficits in unipolar and bipolar disorders. METHOD: A systematic review comprising an extensive literature search conducted in Medline, Embase, and PsychInfo up to September 2016 and including cross-references from identified papers and reviews. RESULTS: Most of the five areas are superficially investigated and hampered by methodological challenges. Nevertheless, studies with the longest follow-up periods, using survival analysis methods, taking account of the individual heterogeneity all support a clinical progressive course of illness. Overall, increasing number of affective episodes seems to be associated with (i) increasing risk of recurrence, (ii) increasing duration of episodes, (iii) increasing symptomatic severity of episodes, (iv) decreasing threshold for developing episodes, and (v) increasing risk of developing dementia. CONCLUSION: Although the course of illness is heterogeneous, there is evidence for clinical progression of unipolar and bipolar disorders.

Rates and predictors of remission, recurrence and conversion to bipolar disorder after the first lifetime episode of depression--a prospective 5-year follow-up study.

BACKGROUND: In depression, non-remission, recurrence of depressive episodes after remission and conversion to bipolar disorder are crucial determinants of poor outcome. The present study aimed to determine the cumulative incidences and clinical predictors of these long-term outcomes after the first lifetime episode of depression. METHOD: A total of 301 in- or out-patients aged 18-70 years with a validated diagnosis of a single depressive episode were assessed from 2005 to 2007. At 5 years of follow-up, 262 patients were reassessed by means of the life chart method and diagnostic interviews from 2011 to 2013. Cumulative incidences and the influence of clinical variables on the rates of remission, recurrence and conversion to bipolar disorder, respectively, were estimated by survival analysis techniques. RESULTS: Within 5 years, 83.3% obtained remission, 31.5% experienced recurrence of depression and 8.6% converted to bipolar disorder (6.3% within the first 2 years). Non-remission increased with younger age, co-morbid anxiety and suicidal ideations. Recurrence increased with severity and treatment resistance of the first depression, and conversion to bipolar disorder with treatment resistance, a family history of affective disorder and co-morbid alcohol or drug abuse. CONCLUSIONS: The identified clinical characteristics of the first lifetime episode of depression should guide patients and clinicians for long-term individualized tailored treatment.

Risk factors for miscarriage from a prevention perspective: a nationwide follow-up study.

OBJECTIVE: To identify modifiable risk factors for miscarriage and to estimate the preventable proportion of miscarriages that could be attributed to these. DESIGN: Nationwide observational follow-up study. SETTING: Denmark. POPULATION: Ninety-one thousand four hundred and twenty seven pregnancies included in the Danish National Birth Cohort between 1996 and 2002. METHODS: Information on potentially modifiable risk factors before and during pregnancy was collected by means of computer-assisted telephone interviews and linkage with Danish registers, ensuring almost complete follow-up of pregnancy outcome. Modifiable risk factors for miscarriage were identified by multiple Cox regression analysis, which provided the background for our estimations of population attributable fractions. In all, 88,373 pregnancies had full information on all covariates and were included in this analysis. MAIN OUTCOME MEASURES: Miscarriage before 22 completed weeks of gestation. RESULTS: The potentially modifiable pre-pregnant risk factors associated with increased miscarriage risk were: age of 30 years or more at conception, underweight, and obesity. During pregnancy the modifiable risk factors were: alcohol consumption, lifting of >20 kg daily, and night work. We estimated that 25.2% of the miscarriages might be prevented by reduction of all these risk factors to low risk levels. Modification of risk factors acting before and during pregnancy could lead to prevention of 14.7 and 12.5%, respectively, of the miscarriages. Maternal age at conception and alcohol consumption were the most important risk factors. CONCLUSIONS: Miscarriage risk is increased by multiple potentially modifiable risk factors and a considerable proportion of miscarriages may be preventable.

Decomposition of number of life years lost according to causes of death.

We study the competing risks model and show that the cause j cumulative incidence function integrated from 0 to τ has a natural interpretation as the expected number of life years lost due to cause j before time τ. This is analogous to the τ-restricted mean lifetime, which is the survival function integrated from 0 to τ. It is discussed how the number of years lost may be related to subject-specific explanatory variables in a regression model based on pseudo-observations, and the method is exemplified using data from a bone marrow transplantation study. Finally, inclusion of standard mortality rates is discussed.

Social inequality in breast, lung and colorectal cancers: a sibling approach.

OBJECTIVE: To examine whether family factors shared by siblings explained the association between education and risk of lung, colorectal and breast cancer. DESIGN: We used conventional cohort and intersibling Cox regression analyses to analyse the association between education and risk of cancer. SETTING: Denmark. PARTICIPANTS: We retrieved register data from Statistics Denmark on individuals born in Denmark 1950-1979 with at least one full sibling. The cohorts included between 391 931 and 1 381 369 individuals followed from age 28 for incident lung, colorectal and breast cancer until the end of 2009. RESULTS: In the cohort analysis, low education was associated with an increased risk of colorectal cancer before age 45 and lung cancer, and with a decreased risk of colorectal cancer after age 45 and breast cancer. When compared with the cohort analyses, the intersibling associations were stronger for colorectal cancer after age 45 and weaker for lung cancer. Serious health conditions in childhood/young adulthood did not explain the associations. CONCLUSIONS: Family factors shared by siblings confounded some of the association between education and colorectal cancer after age 45 and lung cancer, but not the associations found for colorectal cancer before age 45 or breast cancer.

Cohabitation patterns among patients with severe psychiatric disorders in the entire Danish population.

BACKGROUND: Assortative mating has been demonstrated in mental disorders but the extent of cohabitation between patients with clinically diagnosed psychiatric disease has been poorly explored. Method We conducted a register-based study of all Danes between 18 and 70 years of age in a 13-year observational period, linking data on individuals' contacts with psychiatric services with data on individuals' cohabitation status. Two different Poisson regression analyses were performed: the first comparing the rates of commencing cohabitation with a psychiatric patient between individuals, depending on whether the individuals themselves had, or did not have, a psychiatric diagnosis; the second comparing the incidence rates of psychiatric diagnoses for individuals cohabitating with psychiatric patients with the similar rates for individuals living with unaffected cohabitants. RESULTS: In total, 159 929 (5.0%) out of 3 204 633 individuals were given a psychiatric diagnosis during the study period. Diagnosed individuals had an overall rate ratio (RR) of commencing cohabitation with a psychiatric patient of 1.95 [95% confidence interval (CI) 1.90-2.00] for women and 1.65 (95% CI 1.61-1.69) for men, when compared with unaffected individuals. The overall RR of receiving a psychiatric diagnosis while cohabitating with a psychiatric patient was 2.40 (95% CI 2.31-2.49) for women and 2.91 (95% CI 2.81-3.01) for men, when compared with those cohabitating with unaffected individuals. Individuals with schizophrenia and men with bipolar disorder had the highest RR of commencing cohabitation with a cohabitant with a similar diagnosis. CONCLUSIONS: Cohabitation among individuals with severe psychiatric disorders is increased. This has implications for research and for the clinical management of patients.

Antidepressant use and risk of out-of-hospital cardiac arrest: a nationwide case-time-control study.

Treatment with some types of antidepressants has been associated with sudden cardiac death. It is unknown whether the increased risk is due to a class effect or related to specific antidepressants within drug classes. All patients in Denmark with an out-of-hospital cardiac arrest (OHCA) were identified (2001-2007). Association between treatment with specific antidepressants and OHCA was examined by conditional logistic regression in case-time-control models. We identified 19,110 patients with an OHCA; 2,913 (15.2%) were receiving antidepressant treatment at the time of OHCA, with citalopram being the most frequently used type of antidepressant (50.8%). Tricyclic antidepressants (TCAs; odds ratio (OR) = 1.69, confidence interval (CI): 1.14-2.50) and selective serotonin reuptake inhibitors (SSRIs; OR = 1.21, CI: 1.00-1.47) were both associated with comparable increases in risk of OHCA, whereas no association was found for serotonin-norepinephrine reuptake inhibitors/noradrenergic and specific serotonergic antidepressants (SNRIs/NaSSAs; OR = 1.06, CI: 0.81-1.39). The increased risks were primarily driven by: citalopram (OR = 1.29, CI: 1.02-1.63) and nortriptyline (OR = 5.14, CI: 2.17-12.2). An association between cardiac arrest and antidepressant use could be documented in both the SSRI and TCA classes of drugs.

Distribution and predictors of exercise habits among pregnant women in the Danish National Birth Cohort.

Physical activity is recommended during pregnancy, although strong evidence on reproductive health is lacking. We present exercise habits and predictors of exercise during pregnancy. From the Danish National Birth Cohort (1996-2002), 88,200 singleton pregnancies were analyzed in logistic regression. About one-third of the women exercised in early/mid pregnancy and slightly less in late pregnancy. Bicycling, swimming, and low-impact activities were most common. Exercising more than three times per week was strongly correlated with older age, being a student or out of work, eating disorders, moderate alcohol consumption, and a healthy diet. Multiparity, a normal or less good self-rated health, smoking, and a less health conscious diet were the strongest predictors of not doing exercise. Women of 25 years or older, with metabolic or psychiatric disorders, or who had received subfecundity treatment were more likely to increase their activity level substantially from early to late pregnancy than comparison groups. In conclusion, exercising during pregnancy correlated with a number of maternal characteristics. The findings may be used to identify pregnant women not likely to exercise, to target activities that may fit their needs, and, for research purposes, to identify adjustment variables or guide sensitivity analyses when data on confounders are lacking.

Influence of female bodyweight on IVF outcome: a longitudinal multicentre cohort study of 487 infertile couples.

This study investigated the impact of women's body mass index (BMI) on the outcome after consecutive IVF/intracytoplasmic sperm injection cycles in 487 patients initiating treatment with 5-year follow-up. The total number of cycles was 1417. In total 103 (21.1%) were overweight (BMI 25-29.9 kg/m²) and 59 (12.1%) were obese (BMI ≥ 30 kg/m²). Number of initiated cycles/woman (P=0.01), number of cancelled cycles/woman (P < 0.01) and the total dose of gonadotrophin used/cycle (P < 0.01) rose with increasing BMI. A negative linear association between BMI and the number of retrieved oocytes (B=-0.243, P < 0.001) and an inverse U-shaped relationship between BMI and the number of developed embryos was seen, with less embryos available among underweight and obese women (P=0.03). The number with positive serum human chorionic gonadotrophin/cycle decreased significantly with increasing BMI (P < 0.01). The ongoing pregnancy rate/cycle among the obese women was lower (20.8% versus 28.3% in normal-weight women; P=0.04). Live-birth rate per cycle was 15.2% versus 21.5%. Multiple logistic regression analysis showed that the only independent predictors of live birth were women's age (P=0.037), women's BMI (P=0.034) and men's age (P=0.040).

Does the association of education with breast cancer replicate within twin pairs? A register-based study on Danish female twins.

BACKGROUND: A positive association between socio-economic position and breast cancer has been widely observed, but not hitherto within twin pairs, where shared familial factors were adjusted for. METHODS: We used data on education and other factors from the Danish Twin Registry, The Danish Cancer Registry, and official registers on a total of 16 310 twins. Unpaired and intrapair Cox regression analyses were compared. RESULTS: In the unpaired analysis, an educational gradient in breast cancer risk was found. Similar results were seen in the intrapair analyses of all twins, although no longer statistically significant. When intrapair analyses were stratified on zygosity, the effect of education was attenuated in the monozygotic twins. CONCLUSION: The main findings support an effect of education beyond shared familial factors.

Familial risk of venous thromboembolism: a nationwide cohort study.

BACKGROUND: Venous thromboembolism has genetic determinants, but population-based data on familial risks are limited. OBJECTIVES: To examine the familial risk of venous thromboembolism. METHODS: We undertook a nationwide study of a cohort of patients with deep venous thrombosis or pulmonary embolism born after 1952. We used the Danish National Registry of Patients covering all Danish hospitals, for the years 1977 through 2009, to identify index cases of venous thromboembolism, and assessed the incidence among their siblings. We compared standardized incidence ratios (SIRs) of the observed and expected number of venous thromboembolism cases among siblings, using population-specific, gender-specific and age-specific incidence rates. RESULTS: We identified 30,179 siblings of 19,599 cases of venous thromboembolism. The incidence among siblings was 2.2 cases per 1000 person-years, representing a relative risk of 3.08 (95% confidence interval [CI] 2.80-3.39) as compared with the general population. The risk was higher for both men (SIR 3.36, 95% CI 2.96-3.82) and women (SIR 2.81, 95% CI 2.45-3.23). The risk was similar among siblings of index cases with venous thrombosis and those of index cases with pulmonary embolism. CONCLUSION: Venous thromboembolism has a strong familial component.

Epidemiological studies of the non-specific effects of vaccines: II--methodological issues in the design and analysis of cohort studies.

We review sources of bias which can affect non-randomized cohort studies of non-specific effects of vaccines on child mortality. Using examples from the literature on non-specific effects, we describe different sources of selection and information bias, and, where possible, outline analysis strategies to mitigate or eliminate such biases.

MTHFR polymorphisms and 5-FU-based adjuvant chemotherapy in colorectal cancer.

BACKGROUND: Methylenetetrahydrofolate reductase is a pivotal enzyme in folate metabolism and 5-fluorouracil (5-FU) cytotoxicity. Two common single-nucleotide polymorphisms (SNPs), MTHFR 677C>T (rs1801133) and 1298A>C (rs1801131), reduce enzyme activity. Initially, these SNPs were claimed to predict clinical efficacy, but further studies have yielded contradictory results. We tested whether these two polymorphisms are determinants of clinical outcome in a large patient group with a long follow-up time. PATIENTS AND METHODS: We included 331 patients who had been treated with adjuvant 5-FU/leucovorin chemotherapy after intended curative resection between 1997 and 2003. Clinical data, including relapse rates, overall survival, and tumor stage, were collected. DNA was extracted from formalin-fixed tumor tissue and analyzed for the MTHFR 677C>T and 1298A>C SNPs with real-time PCR. RESULTS: The MTHFR 677C>T and 1298A>C polymorphisms were not associated with survival or relapse-free survival (P > 0.2). The 677 CC genotype was associated to toxicity (odds ratio = 1.83, P = 0.01). CONCLUSIONS: The MTHFR 677C>T and 1298A>C polymorphisms probably do not predict efficacy of adjuvant 5-FU treatment in colorectal cancer after complete resection; however, the 677C>T polymorphism may be associated with lower toxicity in 5-FU treatment. Implementation of SNP analysis for these polymorphisms for individualized treatment is premature.

Meta-analysis: Nitroglycerin for prevention of post-ERCP pancreatitis.

BACKGROUND: Acute pancreatitis after ERCP is a severe side effect. AIM: To evaluate the preventive effect of nitroglycerin on post-ERCP pancreatitis by a meta-analysis of randomized clinical studies. METHODS: We searched on Pubmed, Embase, Cochrane Library and all abstracts presented at Digestive Disease Week and United European Gastrointestinal Week from 2004 to 2008. We used the MeSH terms 'pancreatitis' together (AND) with the terms: 'glyceryl trinitrate', 'glyceryl dinitrate', 'isosorbide dinitrate' or 'nitroglycerin'. RESULTS: Five clinical studies evaluating the incidence of post-ERCP pancreatitis after administration of nitroglycerin were identified. Meta-analysis including all five studies showed a relative risk (RR) of 0.61 (95% CI; 0.44, 0.86) with the number needed to treat (NNT) of 26 (95% CI: 16, 82). Three studies evaluated nitroglycerin administered by a dermal patch reaching together an RR of 0.66 (95% CI; 0.43, 1.01). The use of nitroglycerin is associated with a significantly increased risk of hypotension (RR 2.25) and headache (RR 3.64). No difference in mortality was observed. CONCLUSIONS: Overall, our meta-analysis supports the use of nitroglycerin in the prevention of post-ERCP pancreatitis, but administration of nitroglycerin by the dermal route, which is the preferred route of administration, did not reach statistical significance.

Leisure time physical exercise during pregnancy and the risk of miscarriage: a study within the Danish National Birth Cohort.

OBJECTIVE: To examine the association between leisure time physical exercise during pregnancy and the risk of miscarriage. DESIGN: Prospective study with elements of retrospective data collection. SETTING: Denmark 1996-2002. POPULATION: A total of 92,671 pregnant women enrolled in the Danish National Birth Cohort and interviewed subsequently. METHODS: Data on exercise during pregnancy and potential confounders were obtained through computer-assisted telephone interviews either during pregnancy or after an early miscarriage. Outcome of pregnancy was identified by register linkage. Using Cox regression analysis, we estimated the hazard ratio (HR) of miscarriage according to weekly amount of exercise and the type of exercise. The HR was estimated for <11, 11-14, 15-18, and 19-22 weeks of gestation, respectively. MAIN OUTCOME MEASURES: Miscarriage, defined as fetal loss before 22 completed weeks of gestation. RESULTS: A stepwise increasing relation was found between amount of exercise and risk of miscarriage, where risk of miscarriage increased by amount of exercise up to HR = 3.7 (95% CI 2.9-4.7) for women who exercised more than 7 hours per week compared with nonexercisers. Particularly 'high-impact exercise' was associated with an increased risk of miscarriage. No association was seen between exercise and risk of miscarriage after 18 weeks of gestation. CONCLUSIONS: This study suggests that exercise early in pregnancy is associated with an increased risk of miscarriage. The results should, however, be interpreted cautiously as potential bias arising from retrospective data collection may explain part of the association.

Depressive disorders and anti-parkinson drug treatment: a case register study.

OBJECTIVE: To estimate the rate of treatment with anti-parkinson drugs (APD) among patients with depression. METHOD: In a nationwide case register linkage study, all persons with a main diagnosis of depression during 5 years were identified. A control group of persons with diagnoses of osteoarthritis was included. The subsequent risk of getting treatment with APD was estimated for the two groups. Statistical analyses involved Poisson's regression and competing risk models. RESULTS: A total of 14 991 persons were included. The rate of getting APD was 2.57 (95% CI: 1.46-4.52) times higher for persons with depression than for persons with osteoarthritis. Overall, the rate was highest for men. However, women with depression had a 3.89 (95% CI: 1.98-7.62) times higher rate of APD treatment as women with osteoarthritis while no significant difference was found among men. CONCLUSION: Provided that prescription of APD reflects the presence of Parkinson's disease, results support a positive statistical association between depressive disorders and Parkinson's disease.