Comparison of antipsychotic drug use among Dutch Youth before and after implementation of the Youth Act (2010-2019).

OBJECTIVE: The Dutch law on youth care (the Youth Act) was implemented from 2015 onwards. One of the government's aims by implementing this new policy was de-medicalization of youths by separating youth mental healthcare from the rest of the healthcare system. A previous study conducted by our research group showed that prevalence rates of antipsychotic drug prescriptions stabilized among Dutch youth in the period 2005-2015, just before the introduction of the Youth Act. In our study, we aimed to describe antipsychotic drug use among Dutch children aged 0-19 years old before and after implementation of the Youth Act (2010-2019). METHODS: We analyzed prescription data of 7405 youths aged 0-19 years using antipsychotic drugs between 2010 and 2019, derived from a large Dutch community pharmacy-based prescription database (IADB.nl). RESULTS: Prevalence rates of antipsychotic drug use per thousand youths decreased significantly in youths aged 7-12 years old in 2019 compared to 2015 (7.9 vs 9.0 p < 0.05). By contrast, prevalence rates increased in adolescent females in 2019 compared to 2015 (11.8 vs 9.5 p < 0.05). Incidence rates increased significantly in adolescent youths in 2019 compared to 2015 (3.9 vs 3.0 p < 0.05), specifically among adolescent girls (4.2 per thousand in 2019 compared to 3.0 per thousand in 2015). Dosages in milligram declined for the most commonly prescribed antipsychotic drugs during the study period. The mean duration of antipsychotic drug use in the study period was 5.7 (95% CI 5.2-6.2) months. CONCLUSION: Despite the aim of the Youth Act to achieve de-medicalization of youths, no clear reduction was observed in prevalence rates of antipsychotic drugs or treatment duration in all subgroups. Prevalence rates even increased in adolescent females.

In utero antidepressant exposure not associated with ADHD in the offspring: A case control sibling design.

Recent studies have reported an association between antidepressant (AD) use during pregnancy and the risk to develop attention-deficit/hyperactivity disorder (ADHD) in the offspring. However, the association might be confounded by risk factors in the pregnant parent. To control for unmeasured factors between pregnancies carried by the same parent, we set up a case-control sibling study using the University of Groningen prescription database IADB.nl. Children receiving medication for ADHD (cases) before the age of 16 years were matched to siblings not receiving such medication (controls). Exposure was defined as at least two prescriptions for any AD during pregnancy, i.e., the period of 39 weeks before the birth date of the offspring. Secondary analyses were performed to assess the effects of the degree of exposure (the amount of Defined Daily Doses) and the type of AD exposed to. Univariate and multivariate logistic regression was used to estimate odds ratios (ORs) with corresponding 95% confidence intervals (CI). In total, 2,833 children (1,304 cases and 1,529 controls) were included in the analysis. Exposure rate to ADs among cases and controls was 2.2% and 2.4%, respectively. After adjusting for the birth date of the child (as a proxy for the date of pregnancy), age of the pregnant parent at birth, use of psychostimulants, opioids, and antiepileptic drugs by the pregnant parent in the 15 months before birth of the child, an adjusted OR of 1.11 (95% CI 0.67-1.83) was found for the risk of ADHD in the offspring when exposed in utero to ADs. This indicates no increased risk of ADHD in offspring following in utero exposure to ADs. The secondary analyses revealed no statistically significant associations either. The present study provides further evidence that an association between in utero AD exposure and ADHD in offspring might not exist. This perceived association may be caused (at least partially) by confounding by indication. The extent to which depression in the pregnant parent could cause mental disorders such as ADHD in offspring, and the mechanisms involved, should be investigated in further studies.

Exploring co-dispensed drug use in patients on sevelamer or polystyrene sulfonate to identify potential novel binding interactions: a cross sectional in silico study : Potential novel binding interactions with resins.

Background Sevelamer and polystyrene sulfonate are used for treating hyperphosphatemia and hyperkalaemia in chronic kidney disease patients. Because of their binding properties, these resins potentially bind other drugs in the gastrointestinal tract, thereby decreasing their bioavailability and clinical effectiveness. Aim The aim of this study was to explore co-dispensed drug use in patients on sevelamer or polystyrene sulfonate to identify potential novel binding interactions. Method In this in silico study, the 100 drugs most frequently co-dispensed with sevelamer/polystyrene sulfonate in the period 2000-2018 were extracted from the University Groningen IADB.nl database. Drugs dispensed to < 5% of patients, drugs not orally administered, drugs administered once daily before bedtime and drugs for which information on binding interactions with sevelamer or polystyrene was already available were excluded. The likelihood of an interaction (yes or no) of the included drugs was assessed based on pKa- and Log P values. For sevelamer, drugs with a pKa (acid) between 1.5 and 7.4 and or a Log P value > 2.0 were identified as potential interacting drug. For polystyrene sulfonate, drugs with a pKa (base) > 1.5 were identified as potential interacting drug. Results Of the top 100 drugs most frequently co-dispensed with sevelamer/polystyrene sulfonate, 22 and 27 potentially clinically relevant new interacting drugs were identified for sevelamer and polystyrene sulfonate respectively. Conclusion Several potentially relevant novel binding interactions for sevelamer and polystyrene sulfonate were identified based on dispensing data and assessment of chemical properties for which further interaction research is warranted.

[Upward trend in the use of psychostimulants by adults]. / Stijgende lijn in het gebruik van psychostimulantia door volwassenen.

OBJECTIVE: To gain insight into the trends in the use of psychostimulants among adults. DESIGN: Retrospective database study. METHODS: We selected data on adults (≥ 18 years) who had had a minimum of 2 prescriptions for a psychostimulant drug within 1 year from IADB.nl, a Netherlands database of filled prescriptions (59 public pharmacies, approximately 600,000 patients). We calculated both the number of new users and the total number of users of psychostimulants per year in the period 2004-2014. We also assessed which agent was the most commonly prescribed psychostimulant drug and who had initiated treatment. RESULTS: The number of adults who were prescribed psychostimulants (methylphenidate, dexamphetamine and amphetamine) increased from 1.5 per 1000 adults in 2004 to 7.8 per 1000 adults in 2014. Users were mainly male (63.0%) and methylphenidate was the most frequently prescribed agent (85.7%). The number of new users of these agents increased from 0.5 to 1.5 per 1000 adults, and the greatest increase was observed among young adults (< 30 years). The increase in new users seems to have stabilized since 2012. Around 40% of new treatments were initiated by the GP. CONCLUSION: The large increase in the number of adults who are prescribed psychostimulants seems mainly to be the result of an increase in the number of new users, especially among young adults. As psychostimulants are only approved for the treatment of ADHD in children from 6 years of age and in adolescents, short- and long-term effects and side effects of these drugs need to be better assessed in the adult population.

International trends in clozapine use: a study in 17 countries.

OBJECTIVE: There is some evidence that clozapine is significantly underutilised. Also, clozapine use is thought to vary by country, but so far no international study has assessed trends in clozapine prescribing. Therefore, this study aimed to assess clozapine use trends on an international scale, using standardised criteria for data analysis. METHOD: A repeated cross-sectional design was applied to data extracts (2005-2014) from 17 countries worldwide. RESULTS: In 2014, overall clozapine use prevalence was greatest in Finland (189.2/100 000 persons) and in New Zealand (116.3/100 000), and lowest in the Japanese cohort (0.6/100 000), and in the privately insured US cohort (14.0/100 000). From 2005 to 2014, clozapine use increased in almost all studied countries (relative increase: 7.8-197.2%). In most countries, clozapine use was highest in 40-59-year-olds (range: 0.6/100 000 (Japan) to 344.8/100 000 (Finland)). In youths (10-19 years), clozapine use was highest in Finland (24.7/100 000) and in the publicly insured US cohort (15.5/100 000). CONCLUSION: While clozapine use has increased in most studied countries over recent years, clozapine is still underutilised in many countries, with clozapine utilisation patterns differing significantly between countries. Future research should address the implementation of interventions designed to facilitate increased clozapine utilisation.

[Antidepressant guidelines poorly adhered to in young people]. / Antidepressivarichtlijnen slecht nageleefd bij jeugd.

OBJECTIVE: To examine if Dutch physicians adhere to the national guidelines on the treatment of depression in children and adolescents. DESIGN: Retrospective database research. METHOD: Data on children and adolescents aged between 6 and 17 years were selected from the IADB, a Dutch database of filled prescriptions. We examined whether children and adolescents were prescribed fluoxetine as recommended by the guideline, and whether the starting dose was in accordance with the guideline. RESULTS: Of 2942 children and adolescents in whom antidepressant treatment was initiated, the proportion prescribed fluoxetine increased from 10.1% in 1994-2003 to 19.7% in 2010-2014. However, paroxetine (1994-2003) and citalopram (2004-2014) were the most frequently prescribed antidepressants. Starting doses were guideline-concordant in 58% of children, 31% of preadolescents and 16% of adolescents. Sixty percent of all adolescents were prescribed an adult starting dose. CONCLUSION: Guideline adherence was poor. In contrast to the guidelines, physicians preferred citalopram to fluoxetine in children and adolescents with depression. Furthermore, adolescents often received an adult starting dose. These results suggest that dedicated effort is necessary to improve guideline adherence.

Cost-Effectiveness Analysis of Screening for and Managing Identified Hypertension for Cardiovascular Disease Prevention in Vietnam.

OBJECTIVE: To inform development of guidelines for hypertension management in Vietnam, we evaluated the cost-effectiveness of different strategies on screening for hypertension in preventing cardiovascular disease (CVD). METHODS: A decision tree was combined with a Markov model to measure incremental cost-effectiveness of different approaches to hypertension screening. Values used as input parameters for the model were taken from different sources. Various screening intervals (one-off, annually, biannually) and starting ages to screen (35, 45 or 55 years) and coverage of treatment were analysed. We ran both a ten-year and a lifetime horizon. Input parameters for the models were extracted from local and regional data. Probabilistic sensitivity analysis was used to evaluate parameter uncertainty. A threshold of three times GDP per capita was applied. RESULTS: Cost per quality adjusted life year (QALY) gained varied in different screening scenarios. In a ten-year horizon, the cost-effectiveness of screening for hypertension ranged from cost saving to Int$ 758,695 per QALY gained. For screening of men starting at 55 years, all screening scenarios gave a high probability of being cost-effective. For screening of females starting at 55 years, the probability of favourable cost-effectiveness was 90% with one-off screening. In a lifetime horizon, cost per QALY gained was lower than the threshold of Int$ 15,883 in all screening scenarios among males. Similar results were found in females when starting screening at 55 years. Starting screening in females at 45 years had a high probability of being cost-effective if screening biannually was combined with increasing coverage of treatment by 20% or even if sole biannual screening was considered. CONCLUSION: From a health economic perspective, integrating screening for hypertension into routine medical examination and related coverage by health insurance could be recommended. Screening for hypertension has a high probability of being cost-effective in preventing CVD. An adequate screening strategy can best be selected based on age, sex and screening interval.

Antibiotic use during pregnancy and asthma in preschool children: the influence of confounding.

BACKGROUND: A recent study suggested that early-life intestinal microbiota may play an important role in the development of childhood asthma, indicating that antibiotics taken during early life or in late pregnancy may be associated with childhood asthma. OBJECTIVE: This study aims to assess the association between prenatal antibiotic use and asthma in preschool children using data from the prescription database IADB.nl. To assess the influence of potential confounding, we conducted both a case-sibling and a case-control study and compared the results. METHODS: We conducted a case-sibling study in which 1228 children with asthma were compared to 1228 siblings without asthma, using data from the prescription database IADB.nl. In addition, a case-control study was conducted. Asthma in preschool children was defined as ≥ 3 prescriptions for anti-asthma medication within a year before the fifth birthday. Conditional logistic regression was used to estimate crude and adjusted odds ratios (aORs). RESULTS: In both the case-sibling and case-control analysis, the use of antibiotics in the third trimester of pregnancy was associated with an increased risk of asthma in preschool children (aOR 1.37; 95% CI 1.02-1.83 and aOR 1.40; 95% CI 1.15-1.47). Time-trend analyses showed that results were not influenced by a time trend in antibiotic exposure. A significant association between exposure to antibiotics in any trimester of pregnancy and the development of asthma in preschool children was observed in the case-control analysis only (aOR 1.46; 95% CI 1.34-1.59). CONCLUSION: Antibiotic use in the third trimester of pregnancy was associated with a small increased risk of asthma in preschool children. This association was robust to time-invariant confounding or exposure time trends, further supporting the important role for early-life intestinal microbiota in the development of childhood asthma.

Prenatal exposure to acid-suppressive drugs and the risk of allergic diseases in the offspring: a cohort study.

BACKGROUND: Recent studies reported increased risks for the development of asthma in children after prenatal exposure to acid-suppressive drugs. As a result of common pathogenesis, associations could also be present for other allergic diseases. METHODS: Using the prescription database IADB.nl, we conducted a cohort study amongst 33 536 children in the Netherlands, with a maximum follow-up of 8 years. Maternal exposure was defined as ≥1 dispensed prescription for proton pump inhibitors (PPIs) and/or Histamine 2-antagonists (H2As) during pregnancy. Children were considered to have a drug-treated allergic disease if they received either ≥2 prescriptions for dermal (atopic dermatitis), inhaled (asthma) or nasal (allergic rhinitis) steroids within a 12-month period. Clustered Cox proportional hazard regression was used to estimate crude and adjusted hazard ratios (aHR) with 95% confidence intervals (95% CI). RESULTS: The aHR for the development of any allergic disease was 1.37 (95% CI: 1.14-1.66) for children exposed to PPIs or H2As. Prenatal exposure to PPIs and/or H2As was associated with atopic dermatitis, asthma and allergic rhinitis with aHRs of 1.32 (95% CI 1.06-1.64), 1.57 (95% CI 1.20-2.05) and 2.40 (95% CI 1.42-4.04), respectively. The aHR for the development of two or more (aHR 2.13 95% CI: 1.43-3.19) and three allergic diseases (aHR 5.18 95% CI: 2.16-12.42) were even more elevated after prenatal exposure to PPIs or H2As. CONCLUSION: Prenatal exposure to PPIs and H2As appeared associated with an increased risk for the development of atopic dermatitis, asthma and allergic rhinitis in the offspring, especially with the development of multiple allergic diseases. Because our study has limitations inherent to observational studies, prospective studies are now warranted to confirm our findings.

Models to Predict the Burden of Cardiovascular Disease Risk in a Rural Mountainous Region of Vietnam.

OBJECTIVE: To compare and identify the most appropriate model to predict cardiovascular disease (CVD) in a rural area in Northern Vietnam, using data on hypertension from the communities. METHODS: A cross-sectional survey was conducted including all residents in selected communities, aged 34 to 65 years, during April to August 2012 in Thai Nguyen province. Data on age, sex, smoking status, blood pressure, and blood tests (glucose, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol) were collected to identify the prevalence of high blood pressure and to use as input variables for the models. We compared three models, Asian, Chinese Multiple-provincial Cohort Study (CMCS), and Framingham, to estimate cardiovascular risk in the coming years in this context and compare these models and outcomes. RESULTS: The prevalence of high blood pressure in these communities was lower than reported nationally (12.3%). CVD risk differed greatly depending on the model applied: approximately 21% of the subjects according to the CMCS and Asian models, but 37% using the Framingham model, had more than 10% risk for CVD. In the group without current CVD, these numbers decreased to 9% using the CMCS and Asian models but increased to 28% according to the Framingham model. There were no significant differences between the Asian and CMCS models, but differences were highly significant when comparing Asian versus Framingham or CMCS versus Framingham model. CONCLUSIONS: The Asian and CMCS models provided similar results in predicting CVD risk in the Vietnamese population in Thai Nguyen. The Framingham model provided vastly different results. The suggestion may be that for the specific Vietnamese setting, the Asian and CMCS models provide most valid and reliable results; however, this has to be investigated in further analyses using real-life data for potential confirmation.

The pharmacists' potential to provide targets for interventions to optimize pharmacotherapy in patients with asthma.

BACKGROUND: Despite of pharmacists' specialized knowledge of medication and his/her regular contact with patients, the expertise of the pharmacist may not be used enough yet. Furthermore, the potential of pharmacy dispensing data is underestimated. OBJECTIVE: To provide targets for tailored interventions in asthma patients and to illustrate the potential value of pharmacists in the identification of these targets using individual pharmacy dispensing data. SETTING: We performed a cross sectional retrospective analysis assessing the quality of asthma patients' pharmacotherapeutic treatment. METHOD: Drug dispensing data from 2008 to 2009 were retrieved from a Dutch pharmacy database. All asthma patients were screened for potential suboptimal pharmacotherapy in 2009. Results were projected to a single community pharmacy to provide an estimate of the number of patients eligible for potential interventions. MAIN OUTCOME MEASURES: (1) frequent use of short-acting ß-agonists without preventive medication, (2) concomitant use of ß-blockers, (3) multiple short courses of oral corticosteroids without using inhaled corticosteroids and 4) use of long-acting ß-agonist without inhaled corticosteroids. RESULTS: A total of 8,504 patients were eligible for analysis of the quality of their asthma treatment. 20.9 % of all asthma patients used >100 DDD short-acting ß-agonists per year, whereas between 21.2 % (≥ 400 DDD) and 31.4 % (100-199 DDD) of these patients did not receive preventive medication. Approximately 5.2 % of the asthma patients are using ß-blockers concomitantly and 21.8 % of them received non-cardioselective ß-blockers. 6.3 % of the asthma patients received two or more oral courses of corticosteroids in 2008 and 17.4 % of these patients did not receive inhaled corticosteroids in 2009. 2.9 % of the patients used a long-acting ß-agonists without inhaled corticosteroids. 8.4 % of the asthma patients using both long-acting ß-agonists and inhaled corticosteroids received these drugs in two separate inhalers. We estimated that about 400 asthma patients could be identified in an average pharmacy population (8,000 patients) and 33 (95 % CI 22-44) of these patients would be eligible for interventions. CONCLUSION: This study shows the potential for pharmacists to use their own pharmacy records to identify suboptimal therapy of asthma patients, who may be targets for tailored interventions.