Sedative drug-use in Denmark, 2000 to 2019: a nationwide drug utilization study.

AIM: To describe trends in and characteristics of sedative drug use from 2000 through 2019 in relation to the introduction of central regulations and new drugs. METHODS: In this descriptive study, we used individual prescription data on the entire Danish population from the Danish National Prescription Registry to calculate yearly incidence and prevalence of use of benzodiazepines, benzodiazepine-related drugs (Z-drugs), melatonin, olanzapine, low-dose quetiapine, mianserin/mirtazapine, pregabalin, and promethazine from 2000 through 2019. From the Danish National Patient Registry, we obtained data on drug users' psychiatric and somatic comorbidity. RESULTS: The use of benzodiazepines and Z-drugs declined gradually from 2000 through 2019, whereas the newer alternatives, melatonin, low-dose quetiapine, pregabalin and promethazine, increased in use, while the use of olanzapine and mianserin/mirtazapine was relatively stable. This development was seen in both men and women and across all age groups except for hypnotic benzodiazepines which showed a steep increase in the oldest age group from 2010. For all sedative drugs depression, anxiety, alcohol and misuse disorder, pain and cancer were the most prevalent comorbidities. During our study period, the number of individuals without any of the selected diagnoses increased. CONCLUSION: In Denmark different central regulations have influenced prescription practice toward more restrictive use of Z-drugs and benzodiazepines, except for hypnotic benzodiazepine prescriptions increased after the introduction of special palliative care. An increase in use of newer sedative drugs, however, indicates that the regulations do not remove the need for sedative drugs in the population.

Use of GLP-1 receptor agonists and subsequent risk of alcohol-related events. A nationwide register-based cohort and self-controlled case series study.

Animal studies have related glucagon-like peptide 1 receptor agonists (GLP-1) to lower alcohol intake. We examined whether GLP-1 was associated with risk of alcohol-related events in a nationwide cohort study and a self-controlled case series analysis including all new users of GLP1 (n = 38 454) and dipeptidyl peptidase 4 inhibitors (DPP4) (n = 49 222) in Denmark 2009-2017. They were followed for hospital contacts with alcohol use disorder or purchase of drugs for treatment of alcohol dependence in nationwide registers from 2009 to 2018. Associations were examined using Cox proportional hazard and conditional Poisson regression. During follow-up of median 4.1 years, 649 (0.7%) of participants were registered with an alcohol-related event. Initiation of GLP-1 treatment was associated with lower risk of an alcohol-related event (Hazard ratio = 0.46 (95%CI: 0.24-0.86) compared with initiation of DPP4 during the first 3 months of follow-up. Self-controlled analysis showed the highest risk of alcohol-related events in the 3-month pretreatment period (incidence rate ratio [IRR] = 1.25 (1.00-1.58)), whereas the risk was lowest in the first 3-month treatment period (IRR = 0.74 (0.56-0.97). In conclusion, compared with DPP4 users, individuals who start treatment with GLP-1 had lower incidence of alcohol-related events both in cohort and self-controlled analyses. Thus, there might be a transient preventive effect of GLP1 on alcohol-related events the first months after treatment initiation.

An analysis of the relative and absolute incidence of somatic morbidity in patients with affective disorders-A nationwide cohort study.

BACKGROUND: Patients with affective disorder seem to experience higher risks of several somatic diseases, but no studies have provided estimates of both absolute and relative risks for these diseases in the same population. METHODS: A prospective cohort of all patients age ≥18 years old with a hospital contact with affective disorder between 1997-2014 (n=246,282) and a random sample from the background population (n=167,562) was followed for hospitalizations with cardiovascular disease, diabetes, cancers, chronic obstructive pulmonary disease (COPD), asthma, inflammatory bowel disease, hip fracture, psoriasis, migraine, or dementia. Adjusted absolute and relative risk estimates were calculated using multivariable adjusted Aalen's additive and Cox proportional hazard regression models. RESULTS: After adjustments, the absolute risk difference was 130.6 (95% confidence interval [CI] 125.5-135.7) additional cases per 10,000 person-years among affective disorder patients compared to the reference population. The corresponding hazard ratio for any somatic disease was 1.50 (95% CI 1.48-1.52). The strongest associations were found for dementia, hip fracture, COPD, and stroke on both the relative and absolute scale. The patients did not have higher risk of cancers except for lung cancer and brain tumors. Risk estimates tended to be slightly higher for individuals with depression or other affective disorder compared to bipolar disorder. LIMITATIONS: Limitations include use of register-based data, risk of reverse causation and Berkson's bias. CONCLUSIONS: Patients with affective disorder have both higher absolute and relative risk of most somatic diseases except for cancers. Further identification of the shared mechanisms will facilitate the development of targeted interventions.

Longitudinal association between CRP levels and risk of psychosis: a meta-analysis of population-based cohort studies.

Meta-analyses of cross-sectional studies suggest that patients with psychosis have higher circulating levels of C-reactive protein (CRP) compared with healthy controls; however, cause and effect is unclear. We examined the prospective association between CRP levels and subsequent risk of developing a psychotic disorder by conducting a systematic review and meta-analysis of population-based cohort studies. Databases were searched for prospective studies of CRP and psychosis. We obtained unpublished results, including adjustment for age, sex, body mass index, smoking, alcohol use, and socioeconomic status and suspected infection (CRP > 10 mg/L). Based on random effect meta-analysis of 89,792 participants (494 incident cases of psychosis at follow-up), the pooled odds ratio (OR) for psychosis for participants with high (>3 mg/L), as compared to low (≤3 mg/L) CRP levels at baseline was 1.50 (95% confidence interval [CI], 1.09-2.07). Evidence for this association remained after adjusting for potential confounders (adjusted OR [aOR] = 1.31; 95% CI, 1.03-1.66). After excluding participants with suspected infection, the OR for psychosis was 1.36 (95% CI, 1.06-1.74), but the association attenuated after controlling for confounders (aOR = 1.23; 95% CI, 0.95-1.60). Using CRP as a continuous variable, the pooled OR for psychosis per standard deviation increase in log(CRP) was 1.11 (95% CI, 0.93-1.34), and this association further attenuated after controlling for confounders (aOR = 1.07; 95% CI, 0.90-1.27) and excluding participants with suspected infection (aOR = 1.07; 95% CI, 0.92-1.24). There was no association using CRP as a categorical variable (low, medium or high). While we provide some evidence of a longitudinal association between high CRP (>3 mg/L) and psychosis, larger studies are required to enable definitive conclusions.

Tobacco smoking is causally associated with antipsychotic medication use and schizophrenia, but not with antidepressant medication use or depression.

BACKGROUND: Tobacco smoking is more common among patients with schizophrenia and depression than among healthy individuals. We tested the hypothesis that high tobacco smoking intensity is causally associated with antipsychotic medication use, schizophrenia, antidepressant medication use and/or depression in the general population, and compared results with those for chronic obstructive pulmonary disease. METHODS: We used self-reported smoking intensity in cigarettes/day and a polymorphism in the CHRNA3 gene cluster (rs1051730) associated with smoking intensity, on 63,296 20-100-year-old individuals from the Danish general population; 23,282 were never-smokers and 40,014 ever-smokers. For schizophrenia, we compared our results with those in the Psychiatric Genomics Consortium. RESULTS: In smokers, heterozygotes (CT) and homozygotes (TT) for rs1051730 genotype had higher smoking intensity compared with non-carriers (CC). Furthermore, in ever-smokers homozygotes had increased risk of antipsychotic medication with an odds ratio (OR) of 1.16 [95% confidence interval (CI) 1.02-1.31] compared with non-carriers, whereas in never-smokers the corresponding OR was 1.07 (0.87-1.31) (P-interaction: 0.60). Correspondingly, ORs were 1.60 (0.74-3.47) and 1.02 (0.11-9.10) for schizophrenia (P-interaction: 0.85), 1.02 (0.93-1.13) and 0.99 (0.85-1.15) for antidepressant medication (P-interaction: 0.87), 0.85 (0.66-1.10) and 1.26 (0.87-1.83) for depression (P-interaction: 0.30) and 1.31 (1.16-1.47) and 0.89 (0.58-1.36) for chronic obstructive pulmonary disease (P-interaction: 0.16). Odds ratios per rs1051730 allele for schizophrenia and antipsychotic medication use in ever-smokers in the general population were 1.22 (95% CI: 0.84-1.79) and 1.06 (1.00-1.12). In the Psychiatric Genomics Consortium, the corresponding OR for schizophrenia was 1.06 (1.04-1.08) in ever- and never-smokers combined. CONCLUSION: Our data suggest that tobacco smoking could influence the development of psychotic conditions causally, whereas an influence on depression seems unlikely.

Elevated C-reactive protein, depression, somatic diseases, and all-cause mortality: a mendelian randomization study.

BACKGROUND: Elevated levels of plasma C-reactive protein (CRP) have been associated with many diseases including depression, but it remains unclear whether this association is causal. We tested the hypothesis that CRP is causally associated with depression, and compared these results to those for cancer, ischemic heart disease, chronic obstructive pulmonary disease, and all-cause mortality. METHODS: We performed prospective and instrumental variable analyses using plasma CRP levels and four CRP genotypes on 78,809 randomly selected 20- to 100-year-old men and women from the Danish general population. End points included hospitalization or death with depression and somatic diseases, prescription antidepressant medication use, and all-cause mortality. RESULTS: A doubling in plasma CRP yielded an observed odds ratio (OR) of 1.28 (95% confidence interval [CI]: 1.23-1.33) for hospitalization or death with depression, whereas for genetically elevated CRP, the causal OR was .79 (95% CI: .51-1.22; observed vs. causal estimate, p = .03). For prescription antidepressant medication use, corresponding ORs were 1.12 (1.11-1.15) and .98 (.83-1.15; p = .08). These results were similar to those for risk of cancer (p = .002), ischemic heart disease (p = 4 × 10(-99)), chronic obstructive pulmonary disease (p = 6 × 10(-86)), and all-cause mortality (p = .001) examined in the same individuals. CONCLUSIONS: Elevated CRP was associated with increased risk of depression in individuals in the general population, but genetically elevated CRP was not. This indicates that CRP per se is not a causal risk factor for depression.

Expression of PIK3CA, PTEN mRNA and PIK3CA mutations in primary breast cancer: association with lymph node metastases.

PURPOSE: High activity of the intracellular phosphatidylinositol-3 kinase (PI3K) pathway is common in breast cancer. Here, we explore differences in expression of important PI3K pathway regulators: the activator, phosphatidylinositol-3-kinase catalytic subunit alpha (PIK3CA), and the tumour suppressor, phosphatase and tensin homolog (PTEN), in breast carcinoma tissue and normal breast tissue. Furthermore, we examine whether expression of PIK3CA and PTEN mRNA and occurrence of PIK3CA mutations are associated with lymph node metastases in patients with primary breast cancer. METHODS: Paired tissue samples of breast carcinoma and normal breast tissue were obtained from 175 breast cancer patients at the time of primary surgery, of these 105 patients were lymph node positive. Expression of PIK3CA and PTEN mRNA was quantified with Quantitative Real Time PCR. Somatic mutations in exon 9 and exon 20 of the PIK3CA gene were identified by genotyping. RESULTS: Both PIK3CA and PTEN mRNA expression was significantly increased in breast carcinoma tissue compared to normal breast tissue (p = 2 × 10(-11)) and (p < 0.001), respectively. PIK3CA mutations were present in 68 out of 175 patients (39%), but were not associated with PIK3CA expression (p = 0.59). Expression of PIK3CA and PTEN mRNA, and PIK3CA mutations in breast carcinomas were not associated with presence of lymph node metastases. CONCLUSIONS: The expression of PTEN and PIK3CA mRNA is increased in breast carcinoma tissue compared to normal breast tissue, and PIK3CA mutations are frequent in primary breast carcinoma, however these factors were not associated with lymph node metastases.

Predictors of age at onset of tobacco and cannabis use in Danish adolescents.

INTRODUCTION: Early onset of tobacco and cannabis use predicts later substance abuse and risk behaviour and has large health consequences. OBJECTIVES: The aim of this study was to examine risk factors for the age at onset of smoking and cannabis use among a group of Danish children between 7 years and 18 years of age. METHODS: Four hundred and eighty randomly selected children and their parents participated in a study about the prevalence of asthma. The study included questions about alcohol, tobacco and cannabis use. The children were interviewed face-to-face while the parents answered a questionnaire. RESULTS: The age at onset of daily smoking was significantly associated with the adolescents' tendency to binge drink [hazard ratio 4.78, 95% confidence interval (CI) (1.85-12.34), P = 0.001) and to use hard drugs [hazard ratio 2.81, 95% CI (1.03-7.78), P = 0.047], whereas the age at onset of cannabis use was significantly associated with binge drinking [hazard ratio 3.29, 95% CI (1.51-7.20), P = 0.003] and cigarette smoking [hazard ratio 2.51, 95% CI (1.26-5.00), P = 0.009]. There were no significant effect of the parents' smoking and alcohol habits, their socioeconomic or marital status on the adolescent' age at onset of smoking or cannabis. CONCLUSION: This study shows a close connection between adolescent tobacco and cannabis use and alcohol habits. Knowledge of this is important when planning future prevention strategies.

[Onset of alcohol consumption in 7-18-year-old children and adolescents]. / Alkoholdebutalderen hos 7-18-årige unge.

INTRODUCTION: Early onset of alcohol consumption contributes to increased risk of subsequent heavy alcohol use, alcohol dependence and alcohol-related problems. The objective of this study was to examine the onset of alcohol consumption in a group of Danish children. METHODS: The study was part of an asthma study and was based on face-to-face interviews with 480 randomly chosen children and adolescents between seven and 18 years of age. Questionnaires were sent to their parents. Onset of alcohol was defined as consumption of at least one unit of alcohol. RESULTS: Age at onset of alcohol consumption was 13.4 years for boys and 13.9 years for girls (p = 0.020). There was a significant association between age at onset and smoking of the adolescent (hazard ratio 2.19; 95% confidence interval (CI 1.16-4.12, p = 0.015) and maternal smoking during pregnancy (hazard ratio 2.23; 95% CI 1.31-3.78, p = 0.003). We found no association between early onset of alcohol consumption and parents' smoking, drinking, socioeconomic or marital status. CONCLUSION: Further knowledge is needed to clarify the factors associated with early onset of alcohol consumption among Danish adolescents.