Comparison of antipsychotic drug use in children and adolescents in the Netherlands before and during the COVID-19 pandemic.

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.

The relationship between childhood leukaemia and childhood asthma: A pharmacoepidemiological study from the Netherlands.

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.

Chronic Use of Hydrochlorothiazide and Risk of Skin Cancer in Caucasian Adults: A PharmLines Initiative Inception Cohort Study.

Photosensitizing properties of hydrochlorothiazide may increase skin cancer risk. To date, study findings on the association between hydrochlorothiazide use and skin cancer risk are inconsistent, notably regarding confounding and dose-response. The aim of this study was to investigate the association between hydrochlorothiazide use and incidence of skin cancer in a cohort of unselected Caucasian adults, taking dosing into account. As part of the PharmLines Initiative, which links data from the Lifelines Cohort Study and prescription database IADB.nl, patients aged ≥ 40 years were included from Lifelines, a prospective population-based cohort study in the north of the Netherlands. Skin cancer incidence was compared between subjects starting hydrochlorothiazide treatment (n = 608), subjects starting treatment with other antihypertensives (n = 508), and non-antihypertensive long-term medication users (n = 1,710). Cox regression analyses were performed to obtain hazard ratios, adjusted for potential confounders. The risk of any skin cancer, keratinocyte carcinoma, basal cell carcinoma and squamous cell carcinoma was not significantly increased in general hydrochlorothiazide users. A clear association was observed between high cumulative hydrochlorothiazide use (≥ 5,000 defined daily dose; ≥ 125,000 mg) and the risk of any skin cancer (adjusted hazard ratio 5.32, 95% confidence interval (95% CI) 2.40-11.81), keratinocyte carcinoma (adjusted hazard ratio 7.31, 95% CI 3.12-17.13), basal cell carcinoma (adjusted hazard ratio 7.72, 95% CI 3.11-19.16) and squamous cell carcinoma (adjusted hazard ratio 19.63, 95% CI 3.12-123.56). These findings should lead to awareness with high use of hydrochlorothiazide in Caucasian adults.

Exposure to psychotropic drugs before and during pregnancy: what has changed over the last two decades?

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.

Switching pattern and dose adjustment of antidepressants before and during pregnancy.

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.

Risk of neuropsychiatric adverse events associated with varenicline treatment for smoking cessation among Dutch population: A sequence symmetry analysis.

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.

Functional vitamin K status and risk of incident chronic kidney disease and microalbuminuria: a prospective general population-based cohort study.

BACKGROUND: Circulating desphospho-uncarboxylated matrix γ-carboxyglutamate (Gla) protein (dp-ucMGP), a marker of vitamin K status, is associated with renal function and may serve as a potentially modifiable risk factor for incident chronic kidney disease (CKD). We aimed to assess the association between circulating dp-ucMGP and incident CKD. METHODS: We included 3969 participants with a mean age of 52.3 ± 11.6 years, of whom 48.0% were male, enrolled in the general population-based Prevention of REnal and Vascular ENd-stage Disease study. Study outcomes were incident CKD, defined as either development of an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 or microalbuminuria. Associations of dp-ucMGP with these outcomes were quantified using Cox proportional hazards models and were adjusted for potential confounders. RESULTS: Median plasma dp-ucMGP was 363 [interquartile range (IQR) 219-532] pmol/L and mean serum creatinine- and serum cystatin C-based eGFR (eGFRSCr-SCys) was 95.4 ± 21.8 mL/min/1.73 m2. During 7.1 years of follow-up, 205 (5.4%) participants developed incident CKD and 303 (8.4%) developed microalbuminuria. For every doubling of plasma dp-ucMGP, hazard ratios for the development of incident CKD and microalbuminuria were 1.85 [95% confidence interval (CI) 1.59-2.16; P < 0.001] and 1.19 (95% CI 1.07-1.32; P = 0.001), respectively. These associations lost significance after adjustment for baseline eGFRSCr-SCys [0.99 (95% CI 0.88-1.12; P = 0.86)] and baseline age [1.03 (95% CI 0.94-1.14; P = 0.50)], respectively. CONCLUSIONS: The associations of plasma dp-ucMGP with incident CKD and microalbuminuria were driven by the respective baseline effects of renal function and age.

A Prescription Trend Analysis of Methylphenidate: Relation to Study Reports on Efficacy.

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.

Discontinuation and dose adjustment of metoprolol after metoprolol-paroxetine/fluoxetine co-prescription in Dutch elderly.

PURPOSE: Co-prescription of paroxetine/fluoxetine (a strong CYP2D6 inhibitor) in metoprolol (a CYP2D6 substrate) users is common, but data on the clinical consequences of this drug-drug interaction are limited and inconclusive. Therefore, we assessed the effect of paroxetine/fluoxetine initiation on the existing treatment with metoprolol on the discontinuation and dose adjustment of metoprolol among elderly. METHODS: We performed a cohort study using the University of Groningen IADB.nl prescription database (www.IADB.nl). We selected all elderly (≥60 years) who had ever been prescribed metoprolol and had a first co-prescription of paroxetine/fluoxetine, citalopram (weak CYP2D6 inhibitor), or mirtazapine (negative control) from 1994 to 2015. The exposure group was metoprolol and paroxetine/fluoxetine co-prescription, and the other groups acted as controls. The outcomes were early discontinuation and dose adjustment of metoprolol. Logistic regression was applied to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Combinations of metoprolol-paroxetine/fluoxetine, metoprolol-citalopram, and metoprolol-mirtazapine were started in 528, 673, and 625 patients, respectively. Compared with metoprolol-citalopram, metoprolol-paroxetine/fluoxetine was not significantly associated with the early discontinuation and dose adjustment of metoprolol (OR = 1.07, 95% CI:0.77-1.48; OR = 0.87, 95% CI:0.57-1.33, respectively). In comparison with metoprolol-mirtazapine, metoprolol-paroxetine/fluoxetine was associated with a significant 43% relative increase in early discontinuation of metoprolol (OR = 1.43, 95% CI:1.01-2.02) but no difference in the risk of dose adjustment. Stratified analysis by gender showed that women have a significantly high risk of metoprolol early discontinuation (OR = 1.62, 95% CI:1.03-2.53). CONCLUSION: Paroxetine/fluoxetine initiation in metoprolol prescriptions, especially for female older patients, is associated with the risk of early discontinuation of metoprolol.

Antidepressant use during pregnancy and the risk of developing gestational hypertension: a retrospective cohort study.

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.

Economic Consequences and Potentially Preventable Costs Related to Osteoporosis in the Netherlands.

BACKGROUND: Osteoporosis often does not involve symptoms, and so the actual number of patients with osteoporosis is higher than the number of diagnosed individuals. This underdiagnosis results in a treatment gap. OBJECTIVES: To estimate the total health care resource use and costs related to osteoporosis in the Netherlands, explicitly including fractures, and to estimate the proportion of fracture costs that are linked to the treatment gap and might therefore be potentially preventable; to also formulate, on the basis of these findings, strategies to optimize osteoporosis care and treatment and reduce its related costs. METHODS: In this retrospective study, data of the Achmea Health Database representing 4.2 million Dutch inhabitants were used to investigate the economic consequence of osteoporosis in the Netherlands in 2010. Specific cohorts were created to identify osteoporosis-related fractures and their costs. Besides, costs of pharmaceutical treatment regarding osteoporosis were included. Using data from the literature, the treatment gap was estimated. Sensitivity analysis was performed on the base-case results. RESULTS: A total of 108,013 individuals with a history of fractures were included in this study. In this population, 59,193 patients were using anti-osteoporotic medication and 86,776 patients were using preventive supplements. A total number of 3,039 osteoporosis-related fractures occurred. The estimated total costs were €465 million. On the basis of data presented in the literature, the treatment gap in our study population was estimated to vary from 60% to 72%. CONCLUSIONS: The estimated total costs corrected for treatment gap were €1.15 to €1.64 billion. These results indicate room for improvement in the health care policy against osteoporosis.

The burden and management of cytochrome P450 2D6 (CYP2D6)-mediated drug-drug interaction (DDI): co-medication of metoprolol and paroxetine or fluoxetine in the elderly.

PURPOSE: Metoprolol and paroxetine/fluoxetine are inevitably co-prescribed because cardiovascular disorders and depression often coexist in the elderly. This leads to CYP2D6-mediated drug-drug interactions (DDI). Because systematic evaluations are lacking, we assessed the burden of metoprolol-paroxetine/fluoxetine interaction in the elderly and how these interactions are managed in Dutch community pharmacies. METHOD: Dispensing data were collected from the University of Groningen pharmacy database (IADB.nl, 1999-2014) for elderly patients (≥60 years) starting beta-blockers and/or antidepressants. Based on the two main DDI alert systems (G-Standard and Pharmabase), incidences were divided between signalled (metoprolol-fluoxetine/paroxetine) and not-signalled (metoprolol-alternative antidepressants and alternative beta-blockers-paroxetine/fluoxetine) combinations. Incident users were defined as patients starting at least one signalled or a non-signalled combination. G-Standard signalled throughout the study period, whereas Pharmabase stopped after 2005. RESULTS: A total of 1763 patients had 2039 metoprolol-paroxetine/fluoxetine co-prescriptions, despite DDI alert systems, and about 57.3% were signalled. The number of metoprolol-alternative antidepressant combinations (incidences = 3150) was higher than alternative beta-blocker-paroxetine/fluoxetine combinations (incidences = 1872). Metoprolol users are more likely to be co-medicated with an alternative antidepressant (incidences = 2320) than paroxetine/fluoxetine users (incidences = 1232) are. The number of paroxetine/fluoxetine users co-prescribed with alternative beta-blockers was comparable to those co-medicated with metoprolol (about 50%). Less than 5% of patients received a substitute therapy after using metoprolol-paroxetine/fluoxetine. Most of the metoprolol users (90%) received a low dose (mean DDD = 0.47) regardless whether they were prescribed paroxetine/fluoxetine. CONCLUSION: Despite the signalling software, metoprolol-paroxetine/fluoxetine combinations are still observed in the elderly population. The clinical impact of these interactions needs further investigation. Copyright © 2017 John Wiley & Sons, Ltd.

Methylphenidate use and school performance among primary school children: a descriptive study.

BACKGROUND: There is no conclusive evidence that stimulants have beneficial effects on major associated outcome parameters, particularly school performance. We assessed the differences in school performance among children using methylphenidate at the end of primary school in relation to various parameters of methylphenidate use. METHODS: We linked children from a pharmacy prescription database with standardized achievement test results at the end of primary school. We explored differences in test scores between current methylphenidate users versus never users and methylphenidate users who stopped treatment at least 6 months before the test, early versus late starters, different dosage of methylphenidate, and concurrent antipsychotic or asthma treatment. RESULTS: Out of the 7736 children, 377 (4.9%) children were treated with methylphenidate at the time of the test. After adjusting for confounders the methylphenidate users (532.58 ± .48) performed significantly lower on the test than never users (534.72 ± .11). Compared with late starters of methylphenidate treatment (536.94 ± 1.51) we found significantly lower test scores for the early starters (532.33 ± .50). CONCLUSION: Our study indicates that children using methylphenidate still perform less at school compared to their peers. Our study also suggests that earlier start of methylphenidate treatment is associated with a lower school performance compared to children starting later with the treatment. This result could either indicate a limited effect of long term treatment or a more strongly affected group of early starters.

Association between medication prescription for atopic diseases and attention-deficit/hyperactivity disorder.

BACKGROUND: Data on the association between atopic diseases and attention-deficit/hyperactivity disorder (ADHD) have been inconclusive. OBJECTIVE: To assess whether children with drug-treated ADHD are more likely to receive treatment for asthma, allergic rhinitis, or eczema before the start of ADHD medication use compared with controls and to examine the effect of parents receiving medication for ADHD and atopic diseases on ADHD medication use in their offspring. METHODS: We conducted a retrospective nested case-control study among children (6-12 years of age) using the Groningen University prescription database. Cases were defined as children with at least 2 prescriptions of methylphenidate within 12 months. For each case, 4 controls were matched on age, sex, and regional area code. Parental prescription data were linked to cases and controls to assess the influence of parents receiving medication for ADHD and atopic diseases on ADHD medication use in their offspring. RESULTS: We identified 4257 cases and 17,028 matched controls. Drug treatment for asthma, allergic rhinitis, and eczema was more common in cases than controls (adjusted odds ratios [aORs], 1.4 [95% confidence interval (CI), 1.3-1.6], 1.4 [95% CI, 1.1-1.8], and 1.3 [95% CI, 1.1-1.5], respectively). Medication for allergic rhinitis and asthma among parents was associated with ADHD treatment in their children (aORs, 1.3 [95% CI, 1.1-1.5] and 1.2 [95% CI, 1.1-1.3], respectively). CONCLUSION: This study provides further evidence to support the hypothesis that atopic diseases are associated with ADHD. The parental-offspring association suggests a possible genetic and/or environmental component.

Association between statins and infections among patients with diabetes: a cohort and prescription sequence symmetry analysis.

PURPOSE: A previous meta-analysis of randomized trials did not confirm findings from observational studies that suggested that statins reduce the risk of infection. However, animal experiments indicate that statins may be more effective in reducing the risk and/or the severity of infection among patients with diabetes. Hence, we evaluated the effect of statins on antibiotic prescriptions (a proxy for infections) among patients with drug-treated type 2 diabetes using two confounding-reducing observational designs. METHODS: We conducted a prescription sequence symmetry analysis and a cohort study using the IADB.nl pharmacy prescription database. For the prescription sequence symmetry analysis, a sequence ratio was calculated. The matched cohort study, comparing the time to first antibiotic prescription between periods that statins are initiated and non-use periods, was analyzed using stratified Cox regression. RESULTS: Prescription sequence symmetry analysis of 4684 patients with drug-treated type 2 diabetes resulted in an adjusted sequence ratio of 0.86 (95% confidence interval [CI]: 0.81 to 0.91). Corresponding figures for the cohort analysis comparing 9852 statin-initiation with 4928 non-use periods showed similar results (adjusted hazard ratio: 0.88, 95%CI: 0.83 to 0.95). CONCLUSIONS: These findings suggest that statins are associated with a reduced risk of infections among patients with drug-treated type 2 diabetes. © 2016 The Authors. Pharmacoepidemiology and Drug Safety Published by John Wiley & Sons Ltd.

Poor guideline adherence in the initiation of antidepressant treatment in children and adolescents in the Netherlands: choice of antidepressant and dose.

The Dutch guideline for the treatment of depression in young people recommends initiating antidepressant treatment with fluoxetine, as the evidence for its efficacy is strongest and the risk of suicidality may be lower than with other antidepressants. Furthermore, low starting doses are recommended. We aimed to determine whether antidepressant prescriptions are in accord with guidelines. A cohort of young people aged between 6 and 17 at the time of antidepressant initiation was selected from IABD, a Dutch pharmacy prescription database. The percentage of prescriptions for each antidepressant was determined. Starting and maintenance doses were determined and compared with recommendations for citalopram, fluoxetine, fluvoxamine, and sertraline. During the study period, 2942 patients initiated antidepressant treatment. The proportion of these young people who were prescribed fluoxetine increased from 10.1 % in 1994-2003 to 19.7 % in 2010-2014. However, the most commonly prescribed antidepressants were paroxetine in 1994-2003 and citalopram in 2004-2014. The median starting and maintenance doses were ≤0.5 DDD/day for tricyclic antidepressants and 0.5-1 DDD/day for SSRIs and other antidepressants. Starting doses were guideline-concordant 58 % of the time for children, 31 % for preteens, and 16 % for teens. Sixty percent of teens were prescribed an adult starting dose. In conclusion, guideline adherence was poor. Physicians preferred citalopram over fluoxetine, in contrast to the recommendations. Furthermore, although children were prescribed a low starting dose relatively frequently, teens were often prescribed an adult starting dose. These results suggest that dedicated effort may be necessary to improve guideline adherence.

Brief Report: Association Between Statin Use and Cardiovascular Mortality at the Population Level: An Ecologic Study.

BACKGROUND: We assessed the contribution of statin use to the decline in cardiovascular mortality for The Netherlands over the period 1994-2010. METHODS: We combined aggregated mortality data from Statistics Netherlands with dispensing data from a representative drug dispensing database. We estimated mortality as if prevalence of statin use had remained at its observed 1994 levels throughout the period 1994-2010 for acute myocardial infarction, other ischemic heart disease, and cerebrovascular disease using Poisson models adjusted for various confounders. RESULTS: We estimated that keeping prevalence of statin use at observed 1994 levels would have resulted in 6.3 (95% confidence interval [CI] = 4.9, 7.8), 1.6 (95% CI = 0.8, 2.6), and 3.4 (95% CI = 2.2, 4.6) more acute myocardial infarction, ischemic heart disease, and cerebrovascular deaths per 10,000 person-years, respectively. CONCLUSION: The findings indicate that statin therapy was associated with decreasing national cardiovascular mortality rates in the period 1994 to 2010.

Antiepileptic drug prescribing before, during and after pregnancy: a study in seven European regions.

PURPOSE: The aim of this study was to explore antiepileptic drug (AED) prescribing before, during and after pregnancy as recorded in seven population-based electronic healthcare databases. METHODS: Databases in Denmark, Norway, the Netherlands, Italy (Emilia Romagna/Tuscany), Wales and the Clinical Practice Research Datalink, representing the rest of the UK, were accessed for the study. Women with a pregnancy starting and ending between 2004 and 2010, which ended in a delivery, were identified. AED prescriptions issued (UK) or dispensed (non-UK) at any time during pregnancy and the 6 months before and after pregnancy were identified in each of the databases. AED prescribing patterns were analysed, and the choice of AEDs and co-prescribing of folic acid were evaluated. RESULTS: In total, 978 957 women with 1 248 713 deliveries were identified. In all regions, AED prescribing declined during pregnancy and was lowest during the third trimester, before returning to pre-pregnancy levels by 6 months following delivery. For all deliveries, the prevalence of AED prescribing during pregnancy was 51 per 10 000 pregnancies (CI95 49-52%) and was lowest in the Netherlands (43/10 000; CI95 33-54%) and highest in Wales (60/10 000; CI95 54-66%). In Denmark, Norway and the two UK databases lamotrigine was the most commonly prescribed AED; whereas in the Italian and Dutch databases, carbamazepine, valproate and phenobarbital were most frequently prescribed. Few women prescribed with AEDs in the 3 months before pregnancy were co-prescribed with high-dose folic acid: ranging from 1.0% (CI95 0.3-1.8%) in Emilia Romagna to 33.5% (CI95 28.7-38.4%) in Wales. CONCLUSION: The country's differences in prescribing patterns may suggest different use, knowledge or interpretation of the scientific evidence base. The low co-prescribing of folic acid indicates that more needs to be done to better inform clinicians and women of childbearing age taking AEDs about the need to offer and receive complete preconception care.

Drugs associated with teratogenic mechanisms. Part I: dispensing rates among pregnant women in the Netherlands, 1998-2009.

STUDY QUESTION: What are the dispensing rates of drugs suspected to be associated with teratogenic mechanisms among pregnant Dutch women? SUMMARY ANSWER: In a substantial proportion of pregnancies in our study population at least one drug associated with a teratogenic mechanism was dispensed in the first trimester of pregnancy. WHAT IS KNOWN ALREADY: The main teratogenic mechanisms of medical drugs that may affect fetal development in the first trimester of pregnancy have been described previously. However, information on the dispensing rate of such drugs among women at all stages of pregnancy is lacking. STUDY DESIGN, SIZE, DURATION: To determine how often medications suspected to be associated with a teratogenic mechanism are used by pregnant women, we studied 32 016 pregnancies included in the IADB.nl database between 1998 and 2009. PARTICIPANTS/MATERIALS, SETTING, METHODS: We estimated dispensing rates of medical drugs suspected to be associated with teratogenic mechanisms in our study population. The IADB.nl database includes all pharmacy dispensings for an estimated population of 220 000 in 1994-1998 and c.500 000 since 1999. In addition, trends in first trimester dispensing rates over time and patterns of receiving multiple drugs associated with teratogenic mechanisms were evaluated. In addition, we determined the number of pregnancies in which multiple prescription drugs from one or more teratogenic categories were dispensed in the first trimester, and we evaluated the numbers of different medications dispensed that could be grouped within a specific teratogenic mechanism. MAIN RESULTS AND THE ROLE OF CHANCE: In 175 per 1000 pregnancies [95% confidence interval (CI), 171-179] at least one drug associated with a teratogenic mechanism was dispensed in the first trimester. The total dispensing rate was 236 per 1000 pregnancies (95% CI 232-241) in the 3 months before pregnancy and an increasing trend was seen in the second [214 per 1000 (95% CI 209-218)] and third [327 per 1000 (95% CI 322-332)] trimesters. The first trimester dispensing rates increased between 1998 and 2009 for selective serotonin-reuptake inhibitors (P < 0.001) and serotonin receptor agonists/antagonists (P < 0.001). In 71.8% of pregnancies in which drugs associated with teratogenic mechanisms were dispensed in the first trimester, women received drugs related to only one mechanism. Of the pregnancies in which drugs from multiple teratogenic categories were dispensed in the first trimester, 1148 (72.6%) women received drugs from 2 categories, 317 (20.0%) from three categories, 88 (5.6%) from 4 categories, 28 (1.8%) from 5 categories and 1 from 6 categories. Several women received multiple prescription medications grouped within a single teratogenic mechanism in the first trimester, ranging between 13.3% for cyclo-oxygenase inhibitors and 41.8% for serotonin receptor agonists/antagonists. LIMITATIONS, REASONS FOR CAUTION: We used a dispensing database, therefore actual use of the medication prescribed is unknown and non-compliance could have led to overestimation of exposure prevalences. WIDER IMPLICATIONS OF THE FINDINGS: Owing to the uncertainties concerning the safety of medication use during pregnancy, the results of this study stress the need for cautious prescription of medication associated with teratogenic mechanisms to women of reproductive age. This is further supported by our finding that women received multiple prescription medications grouped within a single teratogenic mechanism in the first trimester, which would theoretically increase strongly the risk of birth defects. STUDY FUNDING/COMPETING INTEREST(S): Marleen van Gelder was supported by the Netherlands Organisation for Scientific Research/NWO (grant no. 021.001.008). No competing interests are declared. TRIAL REGISTRATION NUMBER: N/A.