Christiane Gasse

Background: Opioid use is frequent among older people with dementia. Opioid use has been associated with excess mortality in the general population, but whether this also applies to older people with dementia is unknown. Objective: Investigate if new opioid use compared with no use was associated with excess mortality in older people with dementia. Methods: Matched cohort study using Danish nationwide registries including all residents (age 65+) diagnosed with dementia (including Alzheimer's disease) between 2008–2018. Exposure was defined as first opioid prescription after dementia diagnosis (1 year washout before). Persons exposed to opioids were matched with up to two unexposed persons on age and sex. Outcome was all-cause mortality within 180 days after exposure. Cox proportional hazards models compared rates of death and adjusted for potential confounders. Results: Forty-two percent (31,619/75,471) of older people with dementia initiated a prescription for an opioid after dementia diagnosis. 31,619 exposed persons were matched to 63,235 unexposed. Among the exposed, 8540 (27%) died within 180 days after initiating their first opioid prescription compared with 3803 (6.01%) of the unexposed, yielding a 5-fold excess mortality risk (adjusted Hazard ratio: 5.06 (95% CI, 4.86–5.29)). Transdermal fentanyl use was associated with an 8-fold excess mortality risk (8.26 (7.18–9.51)). Conclusions: Opioid use was associated with excess mortality, which may be due to the opioid, the indication or both. This observation calls for further research into the links between opioid use and excess mortality in elderly with dementia as it could have important implications for patient safety.

Introduction: The aim of this study was to compare the multidisciplinary vocational intervention, Morpheus, with standard vocational rehabilitation for young adults with incident schizophrenia undergoing the OPUS specialised early intervention programme. The study evaluated whether the type of vocational intervention was related to attachment to the labour market and educational system, outpatient contacts, hospital admissions and psychotropic drug use.Methods: This retrospective cohort study included patients of the OPUS programme in the period from January 1, 2014, to December 31, 2019. Patients at Aarhus University Hospital Psychiatry (Aarhus) were offered the Morpheus intervention, while patients at Aalborg University Hospital (Aalborg) received standard vocational rehabilitation. The study used register and clinical data. The analyses involved logistic and linear regression presented as crude and adjusted models.Results: Of the 404 OPUS patients from Aarhus and 246 OPUS patients from Aalborg, patients participating in the Morpheus intervention (n = 116) were more likely to be employed or enrolled in education 2 and 4 years after diagnosis compared with patients undergoing standard vocational intervention (n = 130). Specifically, the adjusted odds ratio for employment was 1.14 (0.37; 3.45) and 1.51 (0.70; 3.27) at 2 and 4 years, respectively. Morpheus patients were less likely to attend somatic outpatient contacts, which involve consultations or treatment for physical health conditions, as well as psychiatric outpatient contacts. Furthermore, they were less likely to be admitted to somatic departments or to redeem antipsychotic medication. However, Morpheus patients had a higher likelihood of being admitted to psychiatric departments during the periods 0–2 and 2–4 years after diagnosis.Conclusion: Young adults with incident schizophrenia receiving the Morpheus intervention within the OPUS treatment did not show statistically significant increased odds of employment or education enrolment compared to those in standard vocational rehabilitation.

Objective: To assess the association between cumulative use of anticholinergic bladder drugs and risk of all cause dementia compared with non-use and use of the β3 agonist bladder drug, mirabegron.Design: Danish nationwide active comparator study.Setting: National Danish registries, 1 January 2000 to 31 December 2022.Participants: 1 29 254 individuals with dementia were matched by age and sex to 646 270 controls without dementia, identified from a cohort of 2.26 million individuals aged 60-75 years between 2000 and 2022 with no previous dementia. Two separate nested case-control populations were studied: the general population and an active comparator population of 58 242 new users of bladder drugs (2198 developed dementia and were matched to 10 990 controls). Information on medication use was based on filled prescriptions and defined daily doses.Main outcome measures: Conditional logistic regression provided incidence rate ratios for associations between anticholinergic bladder drugs and dementia compared with non-use and mirabegron use adjusted for educational level, cardiovascular disease, diabetes, hypertension, dyslipidaemia, and Charlson Comorbidity Index.Results: Compared with non-use, ever use of anticholinergic bladder drugs was associated with an increased risk of dementia, with an incidence rate ratio of 1.44 (95% confidence interval (CI) 1.40 to 1.48). The incidence rate ratio increased with increasing cumulative drug use, from 1.31 (95% CI 1.27 to 1.36) for 1-90 defined daily doses to 1.68 (1.59 to 1.76) for >365 defined daily doses. Compared with non-use, all types of anticholinergic bladder drugs were associated with increased incidence rate ratios for dementia: tolterodine 1.43 (95% CI 1.38 to 1.49), solifenacin 1.37 (1.29 to 1.46), trospium 1.52 (1.37 to 1.67), and fesoterodine 1.48 (1.26 to 1.74). The increased risk of dementia with use of anticholinergic bladder drugs was not seen when compared directly with the use of the β3 agonist mirabegron (incidence rate ratio 0.82, 95% CI 0.74 to 0.92), irrespective of the type of anticholinergic drug.Conclusions: In this study, all types of anticholinergic bladder drugs were associated with an increased risk of dementia compared with non-use, but not when applying the active comparator of the β3 agonist bladder drug mirabegron. These findings highlight the relevance of using an active comparator. Future research should evaluate the risk of cognitive impairment and dementia for both types of bladder drugs.

To systematically assess clinical studies involving patients undergoing drug therapy, comparing different genotypes to assess the relationship with changes in QT intervals, with no limitations on study design, setting, population, dosing regimens, or duration. This systematic review followed PRISMA guidelines and a pre-registered protocol. Clinical human studies on PGx markers of diQTP were identified, assessed using standardized tools, and categorized by design. Gene associations were classified as pharmacokinetic or pharmacodynamic. Identified genes underwent pathway enrichment analyses. Drugs were classified by third-level Anatomical Therapeutic Chemical (ATC) codes. Descriptive statistics were computed by study category and drug classes. Of 4,493 reports, 84 studies were included, identifying 213 unique variants across 42 drug classes, of which 10% were replicated. KCNE1-Asp85Asn was the most consistent variant. Most findings (82%) were derived from candidate gene studies, suggesting bias toward known markers. The diQTP-associated genes were mainly linked to "cardiac conduction" and "muscle contraction" pathways (false discovery rate = 4.71 × 10^-14). We also found an overlap between diQTP-associated genes and congenital long QT syndrome genes. Key genes, drugs, and pathways were identified, but few consistent PGx markers emerged. Extensive, unbiased studies with diverse populations are crucial to advancing the field. A protocol was pre-registered at PROSPERO under registration number CRD42022296097. Data sets generated by this review are available at figshare: DOI: 10.6084/m9.figshare.27959616.

Background and Objective: Psychotropic drug use is common in older adults, with off‐label use reported despite limited understanding of the safety outcomes compared to on‐label use. Incomplete recordings of treatment indications in the Danish National Prescription Register (DNPR) raise concerns about potential off‐label medication use, particularly among older adults. We, therefore, investigated the association between psychotropic prescriptions with non‐registered indications in DNPR and the 1‐year all‐cause mortality in older adults, including subgroups with any psychiatric disorders, depression, or dementia.Methods: Register‐based cohort study following all older adults (≥ 65) who redeemed a first‐time (since 1995) prescription of either antidepressants, antipsychotics, or benzodiazepine during 2006–2017. Redemption of a prescription with non‐registered indications in the DNPR was the exposure. The outcome, 1‐year all‐cause mortality was analyzed using Poisson regression, estimating incidence rate ratios with 95% confidence intervals, adjusting for socio‐demographics and clinical factors.Results: 32% of prescriptions filled by 202,067 individuals for antidepressants, 37% of 97,387 for antipsychotics, and 22% of 130,471 for benzodiazepines had non‐registered indications. No significant differences in mortality rates were found for antidepressants and antipsychotics with non‐registered indications, while higher mortality rates were associated with benzodiazepines, mitigated when excluding individuals receiving intravenous administrations representing end‐of‐life treatment. The results remained consistent in subgroup analyses in patients with any psychiatric disorders, depression, or dementia and further stratified analyses by sex and age.Conclusions: We found that while psychotropic prescriptions with non‐registered indications in DNPR were prevalent in older adults, they were not associated with excess mortality.

Background: The clinical impact of the functional CYP2C19 and CYP2D6 gene variants on antidepressant treatment in people with depression is not well studied. Here, we evaluate the utility of pharmacogenetic (PGx) testing in psychiatry by investigating the association between the phenotype status of the cytochrome P450 (CYP) 2C19/2D6 enzymes and the one-year risks of clinical outcomes in patients with depression with incident new-use of (es)citalopram, sertraline, or fluoxetine. Methods: This study is a population-based cohort study of 17,297 individuals who were born between 1981 and 2005 with a depression diagnosis between 1996 and 2012. Using array-based single-nucleotide-polymorphism genotype data, the individuals were categorized according to their metabolizing status of CYP2C19/CYP2D6 as normal (NM, reference group), ultra-rapid- (UM), rapid- (RM), intermediate- (IM), or poor-metabolizer (PM). The outcomes were treatment switching or discontinuation, psychiatric emergency department contacts, and suicide attempt/self-harm. By using Poisson regression analyses, we have estimated the incidence rate ratios (IRR) with 95% confidence intervals (95% CI) that were adjusted for covariates and potential confounders, by age groups (<18 (children and adolescents), 19–25 (young adults), and 26+ years (adults)), comparing the outcomes in individuals with NM status (reference) versus the mutant metabolizer status. For statistically significant outcomes, we have calculated the number needed to treat (NNT) and the number needed to genotype (NNG) in order to prevent one outcome. Results: The children and adolescents who were using (es)citalopram with CYP2C19 PM status had increased risks of switching (IRR = 1.64 [95% CI: 1.10–2.43]) and suicide attempt/self-harm (IRR = 2.67 [95% CI; 1.57–4.52]). The young adults with CYP2C19 PM status who were using sertraline had an increased risk of switching (IRR = 2.06 [95% CI; 1.03–4.11]). The young adults with CYP2D6 PM status who were using fluoxetine had an increased risk of emergency department contacts (IRR = 3.28 [95% CI; 1.11–9.63]). No significant associations were detected in the adults. The NNG for preventing one suicide attempt/suicide in the children who were using (es)citalopram was 463, and the NNT was 11. Conclusion: The CYP2C19 and CYP2D6 PM phenotype statuses were associated with outcomes in children, adolescents, and young adults with depression with incident new-use of (es)citalopram, sertraline, or fluoxetine, therefore indicating the utility of PGx testing, particularly in younger people, for PGx-guided antidepressant treatment.

Objective To describe life-time use of current actionable pharmacogenetic (PGx) somatic and psychotropic drugs according to international PGx consortia in people with and without hospital-diagnosed mental disorders in the Danish population. Methods Population- and register-based observational drug utilization study in 56 065 individuals with mental disorders, i. e. attention-deficit/hyperactivity disorder, autism, bipolar disorder, depression and schizophrenia, and a random, representative sample of 29 975 individuals of the Danish population, born between 1981 and 2005. Individuals were followed from 1995 or birth until 2016 (for a maximum of 22 years). We report prevalence and incidence rates of PGx drug use by age, sex and mental disorders based on redeemed prescriptions between 1995 and 2016. Results Of the 69 PGx drugs, prescriptions of 39 drugs had been redeemed by the study population by 35 years of age. The use of at least 1 PGx drug varied between 23.1% in males without mental disorders and 97.2% in females with schizophrenia. Males with ADHD or autism were the youngest first-time PGx drug users at a mean of 11.6 years. The mean number of different PGx drugs used was 1.2 in males without mental disorders and 5.6 in individuals with schizophrenia. The prevalence of different PGx drugs linked to more than one gene was 25.3% in males without mental disorders to 94.1% in females with schizophrenia. Conclusion PGx drugs are commonly used by younger people, more often by individuals with mental disorders and by females. Panel-based PGx testing could contribute to treatment decisions at a very young age. Received: 19 April 2021 Received: 31 August 2021 Accepted: 08 September 2021 Publication Date: 09 November 2021 (online) © 2019. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/). Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

Pharmacogenetics aims to improve clinical care by studying the relationship between genetic variation and variable drug response. Large population-based datasets could improve our current understanding of pharmacogenetics from selected study populations. We provide real-world pharmacogenetic frequencies of genotypes and (combined) phenotypes of a large Danish population-based case-cohort sample (iPSYCH2012; data of the Integrative Psychiatric Research consortium). The genotyped sample consists of 77,684 individuals, of which 51,464 individuals had diagnoses of severe mental disorders (SMD case-cohort) and 26,220 were individuals randomly selected from the Danish population (population cohort). Array-based genotype data imputed to 8.4 million genetic variants was searched for a selected pharmacogenetic panel of 42 clinically relevant variants and a CYP2D6 gene deletion and duplication. We identified 19 of 42 variants. Minor allele frequencies (MAFs) were consistent with previously reported MAFs, and did not differ between SMD cases and population cohorts. Almost all individuals carried at least one genetic variant (> 99.9%) and 87% carried three or more genetic variants. When genotypes were translated into phenotypes, also > 99.9% of individuals had at least one divergent phenotype (i.e. divergent from the common phenotypes considered normal, e.g. extensive metabolizer). The high number of identified individuals with at least one pharmacogenetic variant or divergent phenotype indicates the importance of pharmacogenetic panel-based genotyping. Combined CYP2C19-CYP2D6 phenotypes revealed that 72.7% of individuals had divergent phenotypes for one or both enzymes. As CYP2D6 and CYP2C19 have an important role in the metabolism of psychotropic drugs, this indicates the relevance of pharmacogenetic testing specifically in individuals using psychotropic drugs.