Search

Rahmat Sediq,1 Jurjen van der Schans,1 Aafje Dotinga,2 Rolinde A Alingh,2 Bob Wilffert,1,3 Jens HJ Bos,1 Catharina CM Schuiling-Veninga,1 Eelko Hak1,4 1Department of Pharmaco-Therapy, Epidemiology & Economics, University of Groningen, Groningen Research Institute of Pharmacy, Groningen, the Netherlands; 2Lifelines Cohort Study, Lifelines Databeheer B.V., Groningen, the Netherlands; 3Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, Groningen, the Netherlands; 4Department of Epidemiology, University Medical Center Groningen, Groningen, the Netherlands Background: While self-reported data are commonly used as a source of medication use for pharmaco-epidemiological studies, such information is prone to forms of bias. Several previous studies showed that various factors like age, type of drug and data collection method may influence accuracy. We aimed to assess the concordance of the self-reported medication use that was documented at entry to the Lifelines Cohort Study, a three-generation follow-up study in the Netherlands that started in 2006 and included over 167,000 participants. Materials and methods: As part of the PharmLines Initiative, we collected medication data from the Lifelines participants encoded according to the Anatomical Therapeutic Chemical (ATC) coding scheme and linked the data via Statistics Netherlands to the widely used and representative pharmacy prescription database of the University of Groningen, IADB.nl. Analyses were conducted at second level of ATC coding for all recorded medications as well as a top list of most used medications at drug-specific fifth level. Cohen’s kappa statistics were used to measure the concordance for all participants according to sex and age. Results: The level of concordance between the two data sources largely differed according to the therapeutic class. Medication used for the cardiovascular system and diabetes, thyroid therapy, bisphosphonates and anti-thrombotic drugs showed a very good agreement (κ>0.75). Medication as needed or prone to stigmatization bias showed a moderate agreement (κ=0.41–0.60), whereas medications used for short periods of time showed a fair agreement (κ=0.0–0.4). Concordance was similar for males and females, but younger adults tended to have lower concordance rates than older adults. Conclusion: The self-reported method was valid for capturing prevalent chronic medication use at one moment in time, but invalid for medication used for short periods of time. There is no effect of sex on the agreement, and more studies are needed on the influence of age. Future pharmaco-epidemiological studies should preferably combine the two data sources to achieve the highest accuracy of drug exposure rates. Keywords: self-reported data, prescription data, pharmacy records, agreement, questionnaire, medication, interview, validity

Bianca Mulder,1 Maarten J Bijlsma,1 Catharina CM Schuiling-Veninga,1 Leonard P Morssink,2 Eugene van Puijenbroek,3,4 Jan G Aarnoudse,5 Eelko Hak,1 Tjalling W de Vries6 1Groningen Research Institute of Pharmacy, Unit PharmacoTherapy, Epidemiology & Economics, University of Groningen, Groningen, the Netherlands; 2Department of Obstetrics and Gynaecology, Medical Center Leeuwarden, Leeuwarden, the Netherlands; 3Netherlands Pharmacovigilance Centre Lareb, ´s-Hertogenbosch, the Netherlands; 4Unit of Pharmacotherapy and Pharmaceutical Care, Department of Pharmacy, University of Groningen, Groningen, the Netherlands; 5Department of Obstetrics and Gynaecology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; 6Department of Pediatrics, Medical Center Leeuwarden, Leeuwarden, the Netherlands Background: Understanding perception of risks and benefits is essential for informed patient choices regarding medical care. The primary aim of this study was to evaluate the perception of risks and benefits of 9 drug classes during pregnancy and associations with women’s characteristics.Methods: Questionnaires were distributed to pregnant women who attended a Dutch Obstetric Care facility (first- and second-line care). Mean perceived risk and benefit scores were computed for 9 different drug classes (paracetamol, antacids, antibiotics, antifungal medication, drugs against nausea and vomiting, histamine-2 receptor antagonists/proton pump inhibitors, antidepressants, nonsteroidal anti-inflammatory drugs, and sedatives/anxiolytics). For each participant, we computed weighted risk and benefit sum scores with principal component analysis. In addition, major concerns regarding medication use were evaluated.Results: The questionnaire was completed by 136 women (response rate 77%). Pregnant women were most concerned about having a child with a birth defect (35%), a miscarriage (35%), or their child developing an allergic disease (23%), respectively, as a result of drug use. The majority of studied drug classes were perceived relatively low in risk and high in benefit. Higher risk scores were reported if women were in their first trimesters of pregnancy (p=0.007). Lower benefit scores were reported if women were single (p=0.014), smoking (p=0.028), nulliparous (p=0.006), or did not have a family history of birth defects (p=0.005).Conclusion: Pregnant women’s concerns regarding potential drug adverse effects were not only focused on congenital birth defects but also included a wider range of adverse outcomes. This study showed that most of the studied drug classes were perceived relatively low in risk and high in benefit. Keywords: drugs, perception, risks, benefits, worries, pregnancy

Background There is an economic burden associated with hypertension both worldwide and in Vietnam. In Vietnam, patients with uncontrolled high blood pressure are hospitalized for further diagnosis and initiation of treatment. Because there is no evidence on costs of inpatient care for hypertensive patients available yet to inform policy makers, health insurance and hospitals, this study aims to quantify direct costs of inpatient care for these patients in Vietnam. Methods A retrospective study was conducted in a hospital in Vietnam. Direct costs were analyzed from the health-care provider’s perspective. Hospital-based costing was performed using both bottom-up and micro-costing methods. Patients with sole essential or primary hypertension (ICD-code I10) and those comorbid with sphingolipid metabolism or other lipid storage disorders (ICD-code E75) were selected. Costs were quantified based on financial and other records of the hospital. Total cost per patient resulted from an aggregation of laboratory test costs, drug costs, inpatient-days’ costs and other remaining costs, including appropriate allocation of overheads. Both mean and medians, as well as interquartile ranges (IQRs) were calculated. In addition to a base-case analysis, specific scenarios were analyzed. Results 230 patients were included in the study (147 cases with I10 code only and 83 cases with I10 combined with E75). Median length of hospital stay was 6 days. Median total direct costs per patient were US$65 (IQR: 37 -95). Total costs per patient were higher in the combined hypertensive and lipid population than in the sole hypertensive population at US$78 and US$53, respectively. In all scenarios, hospital inpatient days’ costs were identified as the major cost driver in the total costs. Conclusions Costs of hospitalization of hypertensive patients is relatively high compared to annual medication treatment at a community health station for hypertension as well as to the total health expenditure per capita in Vietnam. Given that untreated/undetected hypertension likely leads to more expensive treatments of complications, these findings may justify investments by the Vietnamese health-care sector to control high blood pressure in order to save downstream health care budgets. [ABSTRACT FROM AUTHOR]

This study aims to describe the patterns and trends in antipsychotic prescription among Dutch youth before and during the corona virus disease 2019 (COVID-19) pandemic (between 2017 and 2022). The study specifically aims to determine whether there has been an increase or decrease in antipsychotic prescription among this population, and whether there are any differences in prescription patterns among different age and sex groups. The study utilized the IADB database, which is a pharmacy prescription database containing dispensing data from approximately 120 community pharmacies in the Netherlands, to analyze the monthly prevalence and incidence rates of antipsychotic prescription among Dutch youth before and during the pandemic. The study also examined the prescribing patterns of the five most commonly used antipsychotics and conducted an autoregressive integrated moving average (ARIMA) analysis using data prior to the pandemic, to predict the expected prevalence rate during the pandemic. The prescription rate of antipsychotics for Dutch youth was slightly affected by the pandemic, with a monthly prevalence of 4.56 [4.50-4.62] per 1000 youths before COVID-19 pandemic and 4.64 [4.59-4.69] during the pandemic. A significant increase in prevalence was observed among adolescent girls aged 13-19 years. The monthly incidence rate remained stable overall, but rose for adolescent girls aged 13-19 years. Aripiprazole, and Quetiapine had higher monthly prevalence rates during the pandemic, while Risperidone and Pipamperon had lower rates. Similarly, the monthly incidence rates of Aripiprazole and Olanzapine went up, while Risperidone went down. Furthermore, the results from the ARIMA analysis revealed that despite the pandemic, the monthly prevalence rate of antipsychotic prescription was within expectation. The findings of this study suggest that there has been a moderate increase in antipsychotic prescription among Dutch youth during the COVID-19 pandemic, particularly in adolescent females aged 13-19 years. However, the study also suggests that factors beyond the pandemic may be contributing to the rise in antipsychotic prescription in Dutch youth., (© 2023. The Author(s).)

Introduction: Antihypertensive drugs are used preventatively to lower the risk of cardiovascular disease events. Comparative effectiveness studies on angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), beta-blockers (BBs), calcium channel blockers (CCBs), and thiazides have yielded inconsistent results and given little consideration to patient adherence. Using a longitudinal cohort and considering time-varying adherence and confounding factors, we aimed to estimate the real-world effectiveness of five major antihypertensive drug monotherapies in the primary prevention of cardiovascular events., Methods: Eligible patients for a retrospective inception cohort study were selected using information obtained from the University of Groningen IADB.nl pharmacy prescription database. Cohort 1 comprised adherent patients with a follow-up time exceeding 1 year, and cohort 2 comprised all patients independent of adherence. The exposures were ACEIs, ARBs, BBs, CCBs, and thiazides. The primary outcome was the time to the first prescription for an acute cardiac drug therapy (CDT) measured using valid drug proxies to identify the first major cardiovascular event. A per-protocol analytical approach was adopted with inverse probability of treatment weighted (IPTW), time-varying Cox regression analysis to obtain the hazard ratios (HRs) and 95% confidence intervals (CIs)., Results: In cohort 1 ( n = 22,441), 1,294 patients (5.8%) were prescribed an acute CDT with an average follow-up time of 4.2 ± 2.8 years. Following IPTW, the hazard measures of ARBs and thiazides were lower than those of BBs (HRs: 0.79 and 0.80, respectively; 95% CIs: 0.64-0.97 and 0.69-0.94, respectively). Among drug-treated diabetic patients, the hazard measures were even lower, with HR point estimates of 0.43 (CI: 0.19-0.98) for ARBs and 0.32 (CI: 0.13-0.82) for thiazides. In cohort 2 ( n = 33,427) and sensitivity analysis, the comparative effectiveness results for thiazides and BBs were similar to those for cohort 1., Conclusion: The findings of this real-world analysis suggest that the incidence of CDT associated with long-term thiazide or ARB monotherapy is lower than the incidence of CDT with BBs, notably among high-risk patients. Incidences of CDT associated with ACEIs and CCBs were comparable relative to those associated with BBs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Li, Bijlsma, de Vos, Bos, Mubarik, Schuiling-Veninga and Hak.)

Conventional therapy is commonly used for the treatment of inflammatory skin conditions, but undesirable effects, such as erythema, dryness, skin thinning, and resistance to treatment, may cause poor patient compliance. Therefore, patients may seek complementary treatment with herbal plant products including essential oils (EOs). This scoping review aims to generate a broad overview of the EOs used to treat inflammatory skin conditions, namely, acne vulgaris, dermatitis and eczema, psoriasis, and rosacea, in a clinical setting. The quality, efficacy, and safety of various EOs, as well as the way in which they are prepared, are reviewed, and the potential, as well as the limitations, of EOs for the treatment of inflammatory skin conditions are discussed. Twenty-nine eligible studies (case studies, uncontrolled clinical studies, and randomized clinical studies) on the applications of EOs for inflammatory skin conditions were retrieved from scientific electronic databases (PubMed, Embase, Scopus, and the Cochrane Library). As an initial result, tea tree ( Melaleuca alternifolia ) oil emerged as the most studied EO. The clinical studies with tea tree oil gel for acne treatment showed an efficacy with fewer adverse reactions compared to conventional treatments. The uncontrolled studies indicated the potential efficacy of ajwain ( Trachyspermum ammi ) oil, eucalyptus ( Eucalyptus globulus ) oil, and cedarwood ( Cedrus libani ) oil in the treatment of acne, but further research is required to reach conclusive evidence. The placebo-controlled studies revealed the positive effects of kānuka ( Kunzea ericoides ) oil and frankincense ( Boswellia spp.) oil in the treatment of psoriasis and eczema. The quality verification of the EO products was inconsistent, with some studies lacking analyses and transparency. The quality limitations of some studies included a small sample size, a short duration, and the absence of a control group. This present review underscores the need for extended, well-designed clinical studies to further assess the efficacy and safety of EOs for treating inflammatory skin conditions with products of assured quality and to further elucidate the mechanisms of action involved.

Background: Alzheimer's disease (AD) is the most common cause of dementia, with a growing number of patients worldwide. The association between AD and treatment with drugs targeting the beta-adrenergic receptor is controversial. The aim of this study is to assess the association between the initiation of AD medication and beta-adrenoceptor antagonists (beta-blockers) in adults., Materials and Methods: We conducted a prescription sequence symmetry analysis using the University of Groningen IADB.nl prescription database. We determined the order of the first prescription for treating AD and the first prescription for beta-blockers, with the dispensing date of the first prescription for AD defined as the index date. Participants were adults over 45 years old starting any AD medication and beta-blockers within two years. We calculated adjusted sequence ratios with corresponding 95% confidence intervals., Results: We identified 510 users of both AD and beta-blockers, and 145 participants were eligible. The results were compatible with either a significant decrease in the incidence of AD after using beta-blockers (adjusted sequence ratio (aSR) = 0.52; 95% CI: 0.35-0.72) or, conversely, an increase in beta-blockers after AD medication (aSR = 1.96; 95% CI: 1.61-2.30)., Conclusions: There is a relationship between the use of beta-blockers and AD medications. Further research is needed with larger populations to determine whether drug therapy for AD increases the risk of hypertension or whether beta-blockers have potential protective properties against AD development.

The purpose of the study is to examine the switching pattern and dose adjustment of antidepressants (ADs) prescribed to women from six months before to six months during pregnancy in the Netherlands. The recorded dispenses or refills were collected from the University of Groningen IADB.nl pregnancy subset for all singleton pregnancies in which the mother received ≥ 1 prescription of an AD dispensed before pregnancy and was present in the database at least six months after conception. The rates of continuation, discontinuation, and switching between 2001 and 2020 were assessed for the ADs studied. The mean number of Defined Daily Doses (DDDs) of the most frequently continued ADs used was calculated both before and during pregnancy, and a paired t-test was used to test for significant changes. The continuation rates for AD users, especially for SSRI and SNRI continued users, increased over time from 27% and 19% (2001-2005) to 65% and 65% (2016-2020). The switching rate between ADs remained consistently low from the start of the study (2001-2005) at 2.0% to the end of the study (2016-2020) at 2.3%. Most women who switched between antidepressants during pregnancy received a different SSRI monotherapy (85%), followed by an SNRI (6%), a TCA (4%), and an "other AD" (4%). In most cases observed, the dose adjustment for the mean DDDs during pregnancy compared to the mean DDDs before pregnancy only changed little (less than 10%). Continued use of SSRIs among singleton pregnancies doubled over the study period. The low rate of AD switching and little changes in the DDD adjustment for most AD continuers indicate that pregnant women prefer to continue their prepregnancy medication rather than switch it. Most observed findings cohere with the Dutch national guidelines for antidepressant use during pregnancy., (© 2023. The Author(s).)

Background: Repurposing registered drugs could reduce coronavirus disease (COVID-19) burden before novel drugs are authorized. Little is known about how the pandemic and imposed restrictions changed their dispensing. We aimed to investigate the impact of COVID-19 pandemic on repurposed drugs dispensing in the Netherlands., Methods: We performed interrupted time-series study using University of Groningen prescription database IADB.nl to evaluate dispensing trends of 24 repurposed drugs before (2017-February 2020) and after (March 2020-2021) the pandemic' start. Primary outcomes were monthly prevalence and incidence rates. An autoregressive integrated moving average model assessed the effect of pandemic and stringency index (measuring strictness of government's restriction policies)., Results: Annual number of IADB.nl population ranged from 919,697 to 952,400. Generally, dispensing of common long-term-used drugs was not significantly affected by pandemic. The prevalence of antibacterials (-4.20 users per 1000 people), antivirals (-0.04), corticosteroids (-1.29), prednisolone (-1.32), calcium channel blocker (-0.41), and diuretics (-1.29) was lower than expected after the pandemic's start, while the prevalence of ivermectin (0.07), sulfonylureas (0.15), sodium-glucose co-transporter-2 (SGLT2) inhibitor (0.17), and anticoagulants (1.95) was higher than expected. The pandemic was associated with statistically significant decreases in the incidence of antibacterials (-1.21), corticosteroids (-0.60), prednisolone (-0.64) and anticoagulants (-0.02), and increases in ivermectin (0.02), aggregated antidiabetic drugs (0.13), and SGLT2 inhibitors (0.06). These trends were positively associated with pandemic and negatively associated with stringency index., Conclusion: Dispensing of most drugs was not significantly associated with pandemic and government's response. Despite some statistically significant disruptions, these were not necessarily clinically relevant due to small absolute differences observed., Competing Interests: All authors declare no competing interests in this work., (© 2023 Zhou et al.)

Objective: To determine the long-term effectiveness of antihypertensive monotherapies in primary prevention of cardiovascular events., Design: Retrospective inception cohort study covering a 25-year study period., Setting: University Groningen IADB.nl pharmacy prescription database with data from 1996 to 2020., Participants: Patients aged 18 years or older, free of any cardiovascular disease (CVD) drug therapies prior to initiation of a preventive antihypertensive monotherapy (ACE inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), beta-blockers (BBs), calcium channel blockers (CCBs) and thiazides)., Outcome Measures: Primary outcome was the time to first prescription of acute cardiac drug therapy (CDT) measured by valid drug proxies to identify a first major CVD event in patients without a history of CVD., Results: Among 33 427 initiators, 5205 (15.6%) patients experienced an acute CDT. The average follow-up time was 7.9±5.5 years. The 25-year incidence rate per 1000 person-years were 25.3, 22.4, 18.2, 24.4 and 22.0 for ACEI, ARB, BB, CCB and thiazide starters, respectively. Inverse probability of treatment-weighted Cox regression showed that thiazide starters had lower hazards than the reference BB starters (HR: 0.88, 95% CI: 0.81 to 0.95). Among patients on diabetes drugs, risks were lower (HR: 0.49, 95% CI: 0.28 to 0.85). CCB starters had higher hazards than reference BB (HR: 1.21, 95% CI: 1.07 to 1.36). The overall estimated number needed to treat for thiazides compared with BBs to prevent one acute CDT in 25 years was 26, and four among patients on diabetes drugs., Conclusions: After adjustments for confounders, patients starting on monotherapy with thiazides had a lower incidence of CDT compared with those starting on BBs, notably among patients on diabetes drugs. Conversely, patients who began CCB monotherapy had a higher incidence of CDT compared with those starting on BBs. Other monotherapies had comparable incidence of cardiovascular disease compared with BBs., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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., (© 2022. The Author(s).)

Purpose: The Global Initiative for Asthma (GINA) suggests a step-wise approach for pharmacological treatment of asthma. Valid study of real-world treatment patterns using dispensing databases includes proper measurement of medication adherence. We aim to explore such patterns by applying a time-varying proportion of days covered (tPDC)-based algorithm., Patients and Methods: We designed a retrospective inception cohort study using the University of Groningen IADB.nl community pharmacy dispensing database. Included were 19,184 young adults who initiated asthma medication anywhere between 1994 and 2021, in the Netherlands. Main treatment steps were defined as: 1 - SABA/ICS-formoterol as needed, 2 - low dose ICS, 3 - low dose ICS + LABA or tiotropium, or intermediate dose ICS, 4 - intermediate to high dose ICS + LABA or tiotropium, triple therapy, or high dose ICS, 5 - treatment prescribed by a specialist. Changes in treatment steps were determined using a time-varying proportion of days covered (tPDC)-based algorithm. Individual drug treatment trajectories were visualized over time using a lasagna plot., Results: At initiation, of the 19,184 included individuals, 52%, 7%, 15%, 16%, and 10% started treatment in steps 1 to 5, respectively. The median (IQR) follow-up time was 3 (1-7) years. Median (IQR) number of switches was 1 (0-3). Comparing starting step to last observed step, 37% never switched between treatment steps, 20% of individuals stepped down and 22% stepped up., Conclusion: The low proportion of treatment switches between steps indicates that tailoring of treatment to patients' needs might be suboptimal. The tPDC-based algorithm functions well in translating dispensing data into continuous drug-utilization data, enabling a more granular assessment of treatment patterns among asthma patients., Competing Interests: Dr Job FM van Boven reports grants and/or personal fees from AstraZeneca, Chiesi, GSK, Novartis, Teva, and Trudell Medical, outside the submitted work. The authors report no other conflicts of interest in this work., (© 2023 Mommers et al.)

Background: It has been suggested that childhood asthma lowers the risk of childhood leukaemia. Studies have found an inverse association between these conditions. However, most studies on this relationship are based on questionnaires and telephone interviews, introducing recall bias. Therefore, we conducted a matched case-control study based on drug prescription data to assess the relationship between both conditions., Methods: In a large database, covering more than one million individuals, we identified cases of children who had been prescribed 6-mercaptopurine (6-MP). This drug is used in the outpatient maintenance therapy of childhood leukaemia. We matched every child with leukaemia on sex and age (±6 months) to children without leukaemia (controls). The variable of having had asthma was defined as receiving at least two prescriptions for an inhaled corticosteroid within 12 months., Results: We identified 59 children aged 2-18 who had been prescribed 6-MP (cases), and they were matched to 21,918 controls. Of the children with childhood leukaemia, three (5%) had childhood asthma, whereas in the control group 4889 (22%) had childhood asthma (odds ratio [OR] 0.19; 95% confidence interval 0.06-0.60)., Conclusion: In this study on the relationship between childhood asthma and childhood leukaemia, we found a strong inverse association., (© 2023 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Trends in prescribing psychotropic drugs before and during pregnancy may have changed over the years, but actual information is lacking. We therefore compared and assessed the exposure and acceptance rates of classes of antipsychotic (+ lithium), anxiolytic, sedative/hypnotic, antidepressant, and psychostimulant before and during pregnancy in the past two decades. All singleton pregnancies with ≥1 prescription of psychotropic drug from six months before pregnancy until child's birthdate were identified in the pregnancy subset of the IADB.nl prescription database. The prescription patterns of psychotropics were distinguished as continuation rate (CR), initiation rate (IR), discontinuation rate (DR), total exposure rate (TER), and acceptance rate. Singleton pregnancies exposed to psychotropic drugs before and during pregnancy increased from 118.4 to 136.5 (per 1000 singleton pregnancies) between decades. Changing trends were observed in decade 2, including a high increase in the TER of antipsychotic class (3.3 to 6.8) and antidepressant class (23.0 to 40.6). A marked increase for individual drugs was seen for sertraline (TER: 0.6 to 6.6 and PAT: 35.3% to 82.5%), citalopram (TER: 2.3 to 10.0 and PAT: 51.1% to 74.6%), and quetiapine (TER: 0.4 to 3.1 and PAT: 57.1% to 66.0%). Although the total exposure rates of five classes of psychotropics in singleton pregnancies increased in decade 2, only antidepressant class had a higher acceptance rate during pregnancy. Certain SSRI antidepressants and atypical antipsychotics were more frequently prescribed in decade 2 than in decade 1, reflecting that treatment options were preferred for safer treatment choices., (© 2023. The Author(s).)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hartwig, Robiyanto, de Vos, Bos, van Puijenbroek, Hak and Schuiling-Veninga.)

Objective: Assess whether propranolol modulates the trigeminovascular system in both men and women., Methods: We investigated the effect of propranolol (80 mg, 90 min after oral administration, corresponding to T max ) on the increase in dermal blood flow of the forehead skin (innervated by the trigeminal nerve) by capsaicin application (0.6 mg/mL) and electrical stimulation (0.2-1.0 mA) before and after placebo (grapefruit juice) or propranolol (oral solution diluted in grapefruit juice) in a randomized, double-blind, placebo-controlled cross-over study, including healthy males (n = 10) and females on contraceptives (n = 11). Additionally, we compared our results with data from the Dutch IADB.nl prescription database by analyzing the change in triptan use after propranolol prescription in a population similar to our dermal blood flow study subjects (males and females, 20-39 years old)., Results: Dermal blood flow responses to capsaicin were significantly attenuated after propranolol, but not after placebo. When stratifying by sex, no significant changes in the capsaicin-induced dermal blood flow were observed in females after propranolol, whereas they remained significant in males. Dermal blood flow responses to electrical stimulation were not modified in any case. In our prescription database study, after propranolol, a more pronounced decrease in triptan use was observed in male patients than in female patients., Interpretation: Propranolol (80 mg) inhibits capsaicin-induced increases in dermal blood flow in a sex-dependent manner. In patients, a more pronounced decrease in triptan use is observed in males when compared with females, suggesting an interaction between propranolol and sex steroids in the modulation of the trigeminovascular system., (© 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

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., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Purpose: Varenicline is an effective treatment for smoking cessation. While clinical trials did not confirm a causal role, case reports suggested a possible link of varenicline with neuropsychiatric adverse drug events (NPAEs). This study aims to investigate the risk of NPAEs associated with varenicline initiation among the general population in a real-world setting., Methods: We conducted a sequence symmetry analysis (SSA) based on the University of Groningen IADB.nl prescription database. We selected incident users of both varenicline and marker drugs for NPAEs, including depression, anxiety and sleep disorder within different time-intervals. Adjusted sequence ratios (aSR) were calculated for each time-interval., Results: Within 365-days' time-interval 1066 patients were incident users of both varenicline and NPAE marker drugs. In total, 505 patients were prescribed varenicline before NPAE marker drugs and 561 vice versa (crude sequence ratio [cSR] 0.90, 95% CI: 0.80-1.02). After adjustments for trends in prescriptions, overall a null association was found (aSR 1.00, 95% CI: 0.89-1.13). Regarding specific NPAEs, no increased risks were found for depression nor anxiety within any time-interval. A small transient increased risk was found for sleep disorders, particularly in earlier time-intervals 3 and 6 months (aSRs 1.52, 95% CI: 1.10-2.11 and 1.45, 95% CI: 1.15-1.83, respectively). Subgroup and sensitivity analyses showed similar findings., Conclusions: Varenicline initiation was unlikely to be associated with an increased risk of taking anti-depressants nor anti-anxiety drugs. Yet a small, but statistically significant, transient association with drugs for sleep disorders was noticed, possibly associated with withdrawal symptoms caused by smoking cessation., (© 2021 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)

Aims: Polypharmacy is common in people with diabetes and is associated with the use of potentially inappropriate medication (PIM). This study aimed to assess trends in the prevalence of polypharmacy and PIM in older and middle-aged people with diabetes., Methods: A repeated cross-sectional study using the University Groningen IADB.nl prescription database was conducted. All people aged 45 years and over who were treated for diabetes registered in the period 2012-2016 were included. Polypharmacy was assessed for three age groups. PIMs were assessed using Beers criteria for people ≥65 years old, and PRescribing Optimally in Middle-aged People's Treatments (PROMPT) criteria for 45-64 years old. Chi-square tests and regression analysis were applied., Results: The prevalence of polypharmacy increased significantly in all age groups in the study period. In 2016, the prevalence of polypharmacy was 36.9% in patients aged 45-54 years, 50.3% in those aged 55-64 years, and 66.2% in those aged ≥65 years. The prevalence of older people with at least one PIM decreased by 3.1%, while in the middle-aged group this prevalence increased by 0.9% from 2012 to 2016. The most common PIMs in both age groups were the use of long-term high-dose proton pump inhibitors, benzodiazepines and strong opioids without laxatives. Of those, only benzodiazepines showed a decreasing trend., Conclusions: Polypharmacy increased in older and middle-aged people with diabetes. While the prevalence of PIM decreased over time in older age, this trend was not observed in middle-aged people with diabetes. Efforts are needed to decrease the use of PIMs in populations already burdened with many drugs, notably at middle age., (© 2020 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Objectives: To evaluate the real-world association between varenicline and neuropsychiatric adverse events (NPAEs) in general and chronic obstructive pulmonary disease (COPD) population with and without psychiatric disorders compared with nicotine replacement therapy (NRT) to strengthen the knowledge of varenicline safety., Design: A retrospective cohort study., Setting: Prescription database IADB.nl, the Netherlands., Participants: New users of varenicline or NRT among general (≥18 years) and COPD (≥40 years) population. Psychiatric subcohort was defined as people prescribed psychotropic medications (≥2) within 6 months before the index date., Outcome Measures: The incidence of NPAEs including depression, anxiety and insomnia, defined by new or naive prescriptions of related medications in IADB.nl within 24 weeks after the first treatment initiation of varenicline or NRT., Results: For the general population in non-psychiatric cohort, the incidence of total NPAEs in varenicline (4480) and NRT (1970) groups was 10.5% and 12.6%, respectively (adjusted OR (aOR) 0.85, 95% CI 0.72 to 1.00). For the general population in psychiatric cohort, the incidence of total NPAEs was much higher, 75.3% and 78.5% for varenicline (1427) and NRT (1200) groups, respectively (aOR 0.82, 95% CI 0.68 to 0.99). For the COPD population (1598), there were no differences in the incidence of NPAEs between comparison groups in both the psychiatric cohort (aOR 0.97, 95% CI 0.66 to 1.44) and non-psychiatric cohort (aOR 0.81, 95% CI 0.54 to 1.20). Results from subgroup or sensitivity analyses also did not reveal increased risks of NPAEs but showed decreased risk of some subgroup NPAEs associated with varenicline., Conclusions: In contrast to the concerns of a possible increased risk of NPAEs among varenicline users, we found a relative decreased risk of total NPAEs in varenicline users of the general population in psychiatric or non-psychiatric cohorts compared with NRT and no difference for NPAEs between varenicline and NRT users in smaller population with COPD., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Although clozapine treatment is often discontinued due to limited efficacy or low tolerability, there is a lack of guidelines and evidence on treatment options after discontinuation of clozapine in patients with schizophrenia. Persistence has proven to be an adequate indicator for treatment effectiveness in patients with schizophrenia. The aim of this study was, therefore, to compare persistence of antipsychotic use between antipsychotic treatment options in patients after stopping clozapine treatment. Registry data from a prescription database representative of the Dutch population (1996-2017) was collected to investigate persistence in patients with schizophrenia who had been using clozapine for ≥ 90 days. Persistence with antipsychotics after clozapine discontinuation was analyzed using Cox-proportional hazard regression models. Our study population consisted of 321 participants, of whom 138 re-initiated clozapine and 183 started some other antipsychotic in the year after clozapine discontinuation (N = 518 antipsychotic use periods, N = 9,178 months). Second-generation antipsychotics (SGAs) as a group were associated with better persistence compared to first-generation antipsychotics (adjusted hazard ratio (aHR), 0.73; 95% confidence interval (CI) 0.57-0.93; P = 0.011). Compared with other antipsychotics, the following oral monotherapy antipsychotics were associated with significantly better persistence: restarting clozapine (aHR 0.48; 95% CI 0.32-0.71; P < 0.001) and switching to risperidone (aHR 0.52; 95% CI 0.32-0.84; P = 0.008) or olanzapine (aHR 0.55; 95% CI 0.35-0.87; P = 0.010). Sensitivity analyses confirmed the results. In conclusion, oral SGAs are associated with better persistence than alternative antipsychotic treatment options in patients discontinuing clozapine for undefined reasons. Especially clozapine (except in those with previous serious adverse reactions to clozapine), olanzapine and risperidone should be considered as oral monotherapy for these patients., (© 2020 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Use of methylphenidate in children has increased substantially, despite conflicting evidence regarding efficacy. In this study, prescription data were analyzed in relation to the publication of new evidence regarding efficacy. Incidence rates and prescribed doses of methylphenidate increased, with a decline during the last few years. Duration of use is still increasing. In half of the cases, starting dosages are higher than recommended in guidelines. There was little evidence that publication of new evidence directly influenced the use of methylphenidate. Recent and critical study findings should receive more attention to contribute to the development and use of treatment guidelines for ADHD and evidence-based methylphenidate use.

Background: The EuroQoL five-dimensional instrument (EQ-5D) is the favoured preference-based instrument to measure health-related quality of life (HRQoL) in several countries. Two versions of the EQ-5D are available: the 3-level version (EQ-5D-3 L) and the 5-level version (EQ-5D-5 L). This study aims to compare specific measurement properties and scoring of the EQ-5D-3 L (3 L) and EQ-5D-5 L (5 L) in Indonesian type 2 diabetes mellitus (T2DM) outpatients., Methods: A survey was conducted in a hospital and two primary healthcare centres on Sulawesi Island. Participants were asked to complete the two versions of the EQ-5D instruments. The 3 L and 5 L were compared in terms of distribution and ceiling, discriminative power and test-retest reliability. To determine the consistency of the participants' answers, we checked the redistribution pattern, i.e., the consistency of a participant's scores in both versions., Results: A total of 198 T2DM outpatients (mean age 59.90 ± 11.06) completed the 3 L and 5 L surveys. A total of 46 health states for 3 L and 90 health states for 5 L were reported. The '11121' health state was reported most often: 17% in the 3 L and 13% in the 5 L. The results suggested a lower ceiling effect for 5 L (11%) than for 3 L (15%). Regarding redistribution, only 6.1% of responses were found to be inconsistent in this study. The 5 L had higher discriminative power than the 3 L version. Reliability as reflected by the index score was 0.64 for 3 L and 0.74 for 5 L. Pain/discomfort was the dimension mostly affected, whereas the self-care dimension was the least affected., Conclusions: This study suggests that the 5 L-version of the EQ-5D instrument performs better than the 3 L-version in T2DM outpatients in Indonesia, regarding measurement and scoring properties. As such, our study supports the use of the 5 L as the preferred health-related quality of life measurement tool. We did not do a trial but this study was approved by the Medical Ethics Committee of Universitas Gadjah Mada Yogyakarta, Indonesia (document number KE/FK/1188/EC, 12 November 2014, amended 16 March 2015).

Introduction: Although bacteria contribute significantly to acute exacerbations of chronic obstructive pulmonary disease (AECOPD), the added value of antibiotics remains controversial, especially in outpatient settings. Age may affect antibiotic effectiveness, but real-world evidence is lacking. We aimed to assess the influence of age on the effectiveness of doxycycline for AECOPD., Methods: A retrospective cohort study among outpatients with the first recorded AECOPD treated with oral corticosteroids was conducted using a large pharmacy dispensing database. The primary outcome was treatment failure within 15-31 days after treatment start. Secondary outcome was time to second exacerbation. All analyses were stratified by age groups., Results: We identified 6300 outpatients with the first AECOPD. 2261 (36%) received doxycycline and 4039 (64%) did not receive any antibiotic (reference group). Overall, there was no difference in treatment failure (adjusted OR: 0.97, 95% CI: 0.84 to 1.12) between two groups. Similarly, no difference in treatment failure was observed in younger groups. However, in patients with advanced age (≥75 years), treatment failure was significantly reduced by doxycycline compared with reference (16% vs 20%, adjusted OR: 0.77, 95% CI: 0.62 to 0.97). Overall, median time to second exacerbation was 169 days (95% CI: 158 to 182 days) in doxycycline group compared with 180 days (95% CI: 169 to 191 days) in reference group (adjusted HR: 1.06, 95% CI: 0.99 to 1.12). Although in older patients there was a trend within 3 months towards longer time of next exacerbation by doxycycline, it did not achieve statistical significance., Conclusions: Our findings showed short-term treatment benefit of doxycycline added to oral corticosteroids for chronic obstructive pulmonary disease patients with advanced age. This value remains unclear for persons aged under 75 years in current primary care. Long-term preventive benefits of doxycycline for the next exacerbation were not observed, irrespective of age., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Background: More than two-thirds of patients diagnosed with type 2 diabetes mellitus (T2DM) in Indonesia encounter medical-related problems connected to routine self-management of medication and the social stigma related to T2DM. The current study aims to explore distress and coping strategies in Indonesian T2DM outpatients in a Primary Healthcare Centre (PHC) in Surabaya, East Java, Indonesia., Methods: We conducted a qualitative study using two different data collection methods: focus group discussions and in-depth interviews. The guideline of interviews and discussions were developed based on seventeen questions derived from the DDS17 Bahasa Indonesia (a Bahasa Indonesia version of the Diabetes Distress Scale questionnaire), which covered physician distress domain, emotional burden domain, regimen distress domain and interpersonal distress domain., Results: The majority of the 43 participants were females and aged 50 or older. Our study discovered two main themes: internal and external diabetes distress and coping strategies. Internal diabetes distress consists of disease burden, fatigue due to T2DM, fatigue not due to T2DM, emotional burden (fear, anxiety, etc.) and lack of knowledge. Internal coping strategies comprised spirituality, positive attitude, acceptance and getting more information about T2DM. External diabetes distress was evoked by distress concerning healthcare services, diet, routine medication, monthly blood sugar checks, interpersonal distress (family) and financial concern. External coping strategies included healthcare support, traditional medicine, vigilance, self-management, social and family support and obtaining information about health insurance., Conclusion: Our study shows that for Indonesian T2DM-patients, spirituality and acceptance are the most common coping mechanisms for reducing DD. Furthermore, our study revealed an overall positive attitude towards dealing with T2DM as well as a need for more information about T2DM and potential coping strategies. Finally, an important finding of ours relates to differences in DD between males and females, potential DD associated with health services provision and the specific challenges faced by housewives with T2DM.

Background and Purpose: Polypharmacy is becoming increasingly common owing to the ageing population, which can pose problems for patients and society. We investigated the trends in polypharmacy and underlying drug groups among adults in the Netherlands from 1999 to 2014 stratified by age, and compared these with findings from the United States (US)., Methods: We conducted a repeated cross-sectional study using the Dutch IADB.nl prescription database. All patients aged 20 years and older in the period 1999 to 2014 were included. Polypharmacy was defined as the dispensing of five or more chronic drugs at the pharmacological subgroup level. Chi-square tests were applied to calculate the p-value for trends. Changes in prevalences were compared between the Netherlands and the US., Results: The prevalence of polypharmacy increased from 3.1% to 8.0% (p-value for trend <0.001) over 15 years, and increased in all age groups. The highest rates were observed in patients aged ≥65 years, but the relative increase over time was higher in the younger age groups. Overall, large increases were observed for angiotensin-II inhibitors, statins and proton-pump inhibitors. The relative increase in polypharmacy was larger in the Netherlands than in the US (ratio of polypharmacy prevalence 2.4 versus 1.8). The Netherlands showed larger relative increases for angiotensin-II inhibitors, statins, proton-pump inhibitors, biguanides and smaller relative increases for antidepressants, benzodiazepines and insulins., Conclusions: Polypharmacy more than doubled from 1999 to 2014, and this increase was not limited to the elderly. The relative increase was larger in the Netherlands compared to the US, which was partly due to larger increases in several guideline-recommended preventive drugs., Competing Interests: The authors have declared that no competing interests exist.

Objective: In the last two decades several new antiepileptic drugs (AEDs) have become available. The aim of our study was to analyse whether and how AED prescribing patterns in Dutch children have changed during the last decade and whether these changes were supported by guidelines and results from recently available trials., Methods: From a large community pharmacy-dispensing database in the Netherlands, we identified children aged 0-19 years who received at least one prescription for an AED between 2006 and 2014. Children who also received prescriptions for migraine or psychiatric disorders were excluded. We calculated year-prevalences and -incidences of AED use with emphasis on old versus new AEDs, and individual AEDs. We evaluated these results, including the course of AED prescribing., Results: During the study period, the prescribing prevalence of old AEDs decreased from 1.61 per 1000 (95% C.I. 1.40-1.82) to 1.39 per 1000 (95% C.I. 1.18-1.60); for new AEDs it increased from 0.58 per 1000 (95% C.I. 0.45-0.71) to 1.35 per 1000 (95% C.I. 1.14-1.56). Valproic acid was the most frequently initiated AED in 2006. From 2010, prescribing of old and new AEDs became equal with levetiracetam as the most often initiated AED since 2012. This drug was recommended for all seizure types in the 2013 Dutch national epilepsy guideline. Only 5.5% of the children used AED combination therapy. Of those on monotherapy, 85.7% remained on the first prescribed AED., Conclusions: In the last 10 years, prescribing of new AEDs increased at the expense of old AEDs. Levetiracetam has replaced valproic acid as the most frequently prescribed first line antiepileptic drug in children since 2012, which is in line with national guidelines., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Aims: To evaluate statin non-persistence and non-adherence as discrete processes in diabetes patients, and identify pharmacy-based predictors of these processes in the first year after statin initiation., Methods: We conducted a retrospective cohort study of statin initiators using a pharmacy database. Persistence and adherence were measured in the first, second and third year. Non-persistence was defined as a gap >180 days. Non-adherence was calculated in persistent patients and defined as a medication possession ratio <80%. Cox regression hazard ratios (HRs) and logistic regression odds ratios (ORs) were assessed for sociodemographic and medication-related factors as possible predictors., Results: Of 12,741 initiators, 20.0% were non-persistent in the first year, while 9.0% and 7.5% were non-persistent in the second and third years. Non-adherence in persistent patients increased from 13.4% in the first to 15.6% and 18.1% in the second and third years. Predictors of non-persistence were female gender (HR: 1.10; 95% CI: 1.01-1.19), older age (HR: 1.52; 95% CI: 1.31-1.75), primary prevention (HR: 1.10; 95% CI: 1.00-1.20), initiating on low dose (HR: 1.44; 95% CI: 1.07-1.94) or standard dose (HR: 1.56; 95% CI: 1.16-2.10), and no cardiovascular co-medication (HR: 1.19; 95% CI: 1.07-1.33), while patients with four or more other medications were more likely to be persistent. Age <50 years (OR: 1.47; 95% CI: 1.22-1.77), low socioeconomic status (OR: 1.27; 95% CI: 1.12-1.45) and primary prevention (OR: 1.21; 95% CI: 1.07-1.38) were predictors of non-adherence, while females were more likely to be adherent (OR: 0.87; 95% CI: 0.77-0.98)., Conclusion: Non-persistence was the foremost problem in the first year after statin initiation, while non-adherence in persistent patients increased in the second and third years. Pharmacy-based predictors of statin non-persistence were different from predictors of non-adherence among persistent patients.

Background: Prior studies reported that exposure to antidepressants during pregnancy may be associated with gestational hypertension. The aim of this study is to assess the association between the use of antidepressants during pregnancy and the risk of developing gestational hypertension., Methods: A retrospective cohort study using the prescription database IADB.nl was conducted among nulliparous women with singleton pregnancies between 1994 and 2015 in the Netherlands. Logistic regression analysis was used to estimate odds ratios (OR), adjusted OR (aOR) and their corresponding 95% confidence intervals (95% CI). Gestational hypertension as main outcome measure was defined as at least one dispensed record of an antihypertensive drug (methyldopa, nifedipine, labetalol, ketanserin, nicardipine) after 20 weeks of gestation until 14 days after delivery. Sub-analyses were conducted for class of antidepressant, duration and amount of use of antidepressant (≤30, ≥30 Defined Daily Doses or DDDs), and maternal age. Sensitivity analyses to assess uncertainties were conducted., Results: Twenty-eight thousand twenty women were included, of which 539 (1.92%) used antidepressants. The risk of gestational hypertension was doubled for women using antidepressant (aOR 2.00 95% CI 1.28-3.13). Significant associations were also found for the subgroup selective serotonin reuptake inhibitors (SSRIs) (aOR 2.07 95% CI 1.25-3.44), ≥30 DDDs (aOR 2.50 95% CI 1.55-3.99) and maternal age of 30-34 years (aOR 2.59 95% CI 1.35-4.98). Varying the theoretical gestational age showed comparable results., Conclusion: Prolonged use of antidepressants during the first 20 weeks of gestation appeared to be associated with an increased risk of developing gestational hypertension. When balancing the benefits and risks of using these drugs during pregnancy, this should be taken into account.

Objectives: The use of antipsychotic drugs by youth is associated with serious side effects, especially when prescribed in higher dosages and for a longer period. Despite this, little is known about recent trends in the dosages and duration of use of antipsychotic drugs in children and adolescents. The aim of this study was to describe trends in prevalence, incidence, dosages, duration of use, and preceding psychotropic medication in Dutch youth who had been prescribed antipsychotic drugs from 2005 to 2015. Methods: We analyzed 84,828 antipsychotic prescriptions of youths aged 0-19 years between 2005 and 2015, derived from a large Dutch community pharmacy-based prescription database (IADB.nl). Results: Since a peak of 9.8 users per 1000 youths in 2009, prevalence rates stabilized. Dosages in milligram per kilogram declined for the most frequently prescribed antipsychotic drugs during the study period. The median duration of use was 6.0 (95% CI 5.4-6.6) months. Boys used antipsychotic drugs significantly longer than girls, with a median of 6.9 (95% CI 6.1-7.7) versus 4.6 (95% CI 3.9-5.3) months ( p  < 0.01). Of the youths prescribed antipsychotics, 12.4% used them for at least 48 months. The majority of youths had used other psychotropic agents in the year before the start of an antipsychotic drug (62.4% in 2005 and 64.7% in 2015). Conclusions: Despite a stabilization of usage rates and decline in dosages and duration of use, one in eight youths still used antipsychotic drugs for 4 years or longer. A substantial share of youths may, therefore, be at high risk for serious side effects.

Over the last decades, an increase in antipsychotic (AP) prescribing and a shift from first-generation antipsychotics (FGA) to second-generation antipsychotics (SGA) among youth have been reported. However, most AP prescriptions for youth are off-label, and there are worrying long-term safety data in youth. The objective of this study was to assess multinational trends in AP use among children and adolescents. A repeated cross-sectional design was applied to cohorts from varied sources from Denmark, Germany, the Netherlands, the United Kingdom (UK) and the United States (US) for calendar years 2005/2006-2012. The annual prevalence of AP use was assessed, stratified by age group, sex and subclass (FGA/SGA). The prevalence of AP use increased from 0.78 to 1.03% in the Netherlands' data, from 0.26 to 0.48% in the Danish cohort, from 0.23 to 0.32% in the German cohort, and from 0.1 to 0.14% in the UK cohort. In the US cohort, AP use decreased from 0.94 to 0.79%. In the US cohort, nearly all ATP dispensings were for SGA, while among the European cohorts the proportion of SGA dispensings grew to nearly 75% of all AP dispensings. With the exception of the Netherlands, AP use prevalence was highest in 15-19 year-olds. So, from 2005/6 to 2012, AP use prevalence increased in all youth cohorts from European countries and decreased in the US cohort. SGA were favoured in all countries' cohorts.

The objective of this study was to assess international trends in antipsychotic use, using a standardised methodology. A repeated cross-sectional design was applied to data extracts from the years 2005 to 2014 from 16 countries worldwide. During the study period, the overall prevalence of antipsychotic use increased in 10 of the 16 studied countries. In 2014, the overall prevalence of antipsychotic use was highest in Taiwan (78.2/1000 persons), and lowest in Colombia (3.2/1000). In children and adolescents (0-19 years), antipsychotic use ranged from 0.5/1000 (Lithuania) to 30.8/1000 (Taiwan). In adults (20-64 years), the range was 2.8/1000 (Colombia) to 78.9/1000 (publicly insured US population), and in older adults (65+ years), antipsychotic use ranged from 19.0/1000 (Colombia) to 149.0/1000 (Taiwan). Atypical antipsychotic use increased in all populations (range of atypical/typical ratio: 0.7 (Taiwan) to 6.1 (New Zealand, Australia)). Quetiapine, risperidone, and olanzapine were most frequently prescribed. Prevalence and patterns of antipsychotic use varied markedly between countries. In the majority of populations, antipsychotic utilisation and especially the use of atypical antipsychotics increased over time. The high rates of antipsychotic prescriptions in older adults and in youths in some countries merit further investigation and systematic pharmacoepidemiologic monitoring., (Copyright © 2017 Elsevier B.V. and ECNP. All rights reserved.)

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., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: M 3 muscarinic receptor antagonism has been associated with glucose intolerance and disturbance of insulin secretion., Objective: Our objective was to examine the risk of type 2 diabetes mellitus (T2DM) in patients using antidepressants with and without M 3 muscarinic receptor antagonism (AD&#95;antaM 3 and AD&#95;nonantaM 3 , respectively)., Methods: We designed a case-control study using a pharmacy prescription database. We selected a cohort of patients who initiated antidepressant use between the ages of 20 and 40 years and who did not receive any anti-diabetic prescriptions at baseline. Cases were defined as those who developed T2DM [i.e., receiving oral anti-diabetic medication, Anatomical Therapeutic Chemical (ATC) code A10B] during the follow-up period (1994-2014), and ten random controls were picked for each case from the cohort of patients who did not develop T2DM., Results: A total of 530 cases with incident T2DM and 5300 controls were included. Compared with no use of antidepressants during the previous 2 years, recent (within the last 6 months) exposure to AD&#95;antaM 3 was associated with a moderately increased risk of T2DM: adjusted odds ratio 1.55 (95% confidence interval 1.18-2.02). In the stratified analyses, this association was dose dependent (>365 defined daily doses) and significant for patients who were in the younger age group (<45 years at the end of follow-up), were female and had no co-morbidity. On the other hand, recent exposure to AD&#95;nonantaM 3 was not associated with a risk for T2DM in any of our analyses., Conclusion: Our results suggest that exposure to AD&#95;antaM 3 was associated with the development of T2DM among antidepressant users.

Over the last two decades, the use of ADHD medication in US youth has markedly increased. However, less is known about ADHD medication use among European children and adolescents. A repeated cross-sectional design was applied to national or regional data extracts from Denmark, Germany, the Netherlands, the United Kingdom (UK) and the United States (US) for calendar years 2005/2006-2012. The prevalence of ADHD medication use was assessed, stratified by age and sex. Furthermore, the most commonly prescribed ADHD medications were assessed. ADHD medication use prevalence increased from 1.8% to 3.9% in the Netherlands cohort (relative increase: +111.9%), from 3.3% to 3.7% in the US cohort (+10.7%), from 1.3% to 2.2% in the German cohort (+62.4%), from 0.4% to 1.5% in the Danish cohort (+302.7%), and from 0.3% to 0.5% in the UK cohort (+56.6%). ADHD medication use was highest in 10-14-year olds, peaking in the Netherlands (7.1%) and the US (8.8%). Methylphenidate use predominated in Europe, whereas in the US amphetamines were nearly as common as methylphenidate. Although there was a substantially greater use of ADHD medications in the US cohort, there was a relatively greater increase in ADHD medication use in youth in the four European countries. ADHD medication use patterns in the US differed markedly from those in western European countries., (Copyright © 2017 Elsevier B.V. and ECNP. All rights reserved.)

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.

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., (Copyright © 2014 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.)