Antipsychotics in Dutch Youth: Prevalence, Dosages, and Duration of Use from 2005 to 2015.

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.

A multi-national comparison of antipsychotic drug use in children and adolescents, 2005-2012.

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.

International trends in antipsychotic use: A study in 16 countries, 2005-2014.

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.

Trends in ADHD medication use in children and adolescents in five western countries, 2005-2012.

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.

Trends and patterns of antidepressant use in children and adolescents from five western countries, 2005-2012.

Following the FDA black box warning in 2004, substantial reductions in antidepressant (ATD) use were observed within 2 years in children and adolescents in several countries. However, whether these reductions were sustained is not known. The objective of this study was to assess more recent trends in ATD use in youth (0-19 years) for the calendar years 2005/6-2012 using data extracted from regional or national databases of Denmark, Germany, the Netherlands, the United Kingdom (UK), and the United States (US). In a repeated cross-sectional design, the annual prevalence of ATD use was calculated and stratified by age, sex, and according to subclass and specific drug. Across the years, the prevalence of ATD use increased from 1.3% to 1.6% in the US data (+26.1%); 0.7% to 1.1% in the UK data (+54.4%); 0.6% to 1.0% in Denmark data (+60.5%); 0.5% to 0.6% in the Netherlands data (+17.6%); and 0.3% to 0.5% in Germany data (+49.2%). The relative growth was greatest for 15-19 year olds in Denmark, Germany and UK cohorts, and for 10-14 year olds in Netherlands and US cohorts. While SSRIs were the most commonly used ATDs, particularly in Denmark (81.8% of all ATDs), Germany and the UK still displayed notable proportions of tricyclic antidepressant use (23.0% and 19.5%, respectively). Despite the sudden decline in ATD use in the wake of government warnings, this trend did not persist, and by contrast, in recent years, ATD use in children and adolescents has increased substantially in youth cohorts from five Western countries.

The EU paediatric regulation: effects on paediatric psychopharmacology in Europe.

Child and adolescent psychiatry is a relatively young field and the recognition, classification, and treatment of disorders in children and adolescents lag behind those in adults. In recent years there is an increasing awareness of the differences between children and adults in psychopathology and pharmacology. Related to this new paediatric regulations have been introduced. This article reviews the regulatory and legislative measures that were adopted in the EU in 2007 and the subsequent impact of these measures on the field of paediatric psychopharmacology. The consequences of the paediatric regulation in the EU are reflected in several domains: regulatory, research aimed at drug development and clinical practices. In the regulatory domain, the consequences include: new paediatric indications, inclusion of special (class) warnings, specification of dose regimens, and information on safety specific to children and adolescents, and development of new medicinal formulations. The paediatric regulation leads to timely development of paediatric friendly formulations and better quality of the clinical evidence. In clinical practices, an increased awareness of the uniqueness of paediatric pharmacology is emerging among medical professionals, and subsequent improvement of medical care (i.e. correct doses, appropriate formulation, monitoring for expected adverse events). In addition, clinical guidelines will have to be revised more frequently in order to integrate the recently acquired knowledge. The new regulations stimulate transparency and discussions between academia, pharmaceutical industry, and regulators. The purpose is to optimize clinical research and obtain evidence for paediatric psychopharmacology, thereby providing adequate support for treatment.

Co-morbidity and patterns of care in stimulant-treated children with ADHD in the Netherlands.

This study aimed at investigating the use of psychosocial interventions and psychotropic co-medication among stimulant-treated children with attention-deficit hyperactivity disorder (ADHD) in relation to the presence of psychiatric co-morbidity. Stimulant users younger than 16 years were identified in 115 pharmacies and a questionnaire was sent to their stimulant prescribing physician. Of 773 questionnaires sent out, 556 were returned and were suitable for analysis (72%). The results are based on 510 questionnaires concerning stimulant-treated children for whom a diagnosis of ADHD was reported. Of the 510 children diagnosed with ADHD, 31% had also received one or more other psychiatric diagnoses, mainly pervasive developmental disorder or oppositional defiant disorder/conduct disorder. We found an association between the presence of co-morbidity and the use of psychosocial interventions for the child (P < 0.001) and the parents (P < 0.001). In the ADHD-only group, 26% did not receive any form of additional interventions, while psychosocial interventions varied from 8 to 18% in children with ADHD and psychiatric co-morbidity. The presence of diagnostic co-morbidity was also associated with the use of psychotropic co-medication (overall, P = 0.012) and antipsychotics (P < 0.001). Stimulant-treated youths with ADHD and psychiatric co-morbidity received more psychosocial interventions and psychotropic co-medication than children with ADHD-only. The type of psychosocial interventions and psychotropic co-medication received by the children and their parents, depended on the specific co-morbid psychiatric disorder being present.

Large increase of the use of psycho-stimulants among youth in the Netherlands between 1996 and 2006.

AIM: To describe the use of psycho-stimulants in the Netherlands between 1996 and 2006 in children and adolescents, and in relation to age and sex. METHODS: With the pharmacy prescription database the IADB.nl, yearly prevalences of psycho-stimulants per 1000 children were calculated, as was the length of psycho-stimulant use with Kaplan-Meier method in SPSS 12.0. RESULTS: Psycho-stimulant use increased in boys (0-19) from 4.5 per thousand in 1996 to 31.1 per thousand in 2006 and for girls from 0.7 to 8.1 per thousand, respectively. The largest increase was among boys aged 10-19 years. There is a trend towards prescribing the sustained release preparation of methylphenidate (Concerta). CONCLUSIONS: In the Netherlands a large increase in psycho-stimulants use is observed. However, in the Netherlands the prevalence ratio male/female declined from 6.4 in 1996 to 3.8 in 2006.

InforMatrix for attention deficit hyperactivity disorder.

The purpose of this review is to facilitate discussion on drug selection for the treatment of ADHD by using only clinically relevant selection criteria and providing an up-to-date overview. The InforMatrix method was used to select drugs to treat attention deficit hyperactivity disorder (ADHD). The following selection criteria were applied: clinical efficacy, safety, tolerability, ease of use, applicability, and cost. The drugs approved for ADHD in the Netherlands were included in the analysis, namely: atomoxetine, immediate-release methylphenidate, and various formulations of slow-release methylphenidate (Concerta, Equasym and Medikinet). Most studies are of limited quality, duration, and size. In one study, Concerta was more effective than atomoxetine. Although no relevant differences were seen in other comparative studies, the clinical experience with atomoxetine is still limited and unexpected toxicity cannot be excluded; few studies have been published with Equasym and Medikinet. No major differences were seen in general tolerability between the drugs. The ease of use of immediate-release methylphenidate is less than for the other drugs. The acquisition cost of immediate-release methylphenidate is considerably lower than that of the slow-release formulations. Atomoxetine is the most expensive drug. The InforMatrix program is available in an interactive format. It enables the user to judge both the importance of the selection criteria and the properties of each therapeutic option per criterion on the basis of his or her own personal expertise and/or the present document.

Use of antipsychotic drugs among Dutch youths between 1997 and 2005.

OBJECTIVE: The authors examined prevalence, incidence, and duration of antipsychotic drug use in the northern and eastern regions of the Netherlands between 1997 and 2005 among youths in regard to age, gender, and class of drug. METHODS: Prescription drug dispensing data were collected from community pharmacies in the northern Netherlands (www.iadb.nl). Prevalence, incidence, and duration of use were studied among roughly 100,000 youths ranging in age from infancy to age 19 years, calculated by age group (zero to four years, five to nine years, ten to 14 years, and 15 to 19 years), for boys and girls, and for first- and second-generation antipsychotics. Duration of use was compared between youths who started antipsychotic treatment in 1998-1999 and those who started in 2001-2002. RESULTS: From 1997 to 2005, prevalence increased from 3.0 to 6.8 per thousand. Prevalence was highest among ten-year-olds to 14-year-olds (11 per thousand), especially among boys (17 per thousand). The increased prevalence was mainly attributable to an increased use of second-generation antipsychotics and to a longer duration of use. Median duration of use doubled from .8 year in 1998-1999 to 1.6 years in 2001-2002. CONCLUSIONS: Second-generation antipsychotic drugs were increasingly prescribed, and for longer periods of time, to younger children, probably because of new indications. This practice increases the exposure of a young population to (partly unknown) risks.

Long-acting methylphenidate-OROS in youths with attention-deficit hyperactivity disorder suboptimally controlled with immediate-release methylphenidate: a study of cost effectiveness in The Netherlands.

BACKGROUND: Attention-deficit hyperactivity disorder (ADHD) is the most common mental health disorder in youths. Stimulants are the drugs of first choice in the treatment of ADHD. It has been suggested that full costs associated with the treatment of ADHD may be reduced by once-daily administration regimens of stimulants. OBJECTIVES: To estimate the cost effectiveness of treatment with long-acting methylphenidate osmotic release oral system (OROS) [Concerta] for youths with ADHD for whom treatment with immediate-release (IR) methylphenidate is suboptimal. STUDY DESIGN: We developed a Markov model to obtain an incremental cost-effectiveness ratio (ICER). The analysis covered 10 years, with a Markov cycle of 1 day. Costs (in 2005 euros ) included medication, consultations and treatment interventions, and additional costs for attending special education. Quality-adjusted life-years (QALYs) were used as the effectiveness measure. Outcome probabilities were taken from the medical literature and an expert panel of five child psychiatrists and paediatricians. Univariate sensitivity analyses were performed to assess the robustness of the base-case estimate. Multivariate sensitivity analysis was used to estimate a worst- and best-case ICER. RESULTS: The ICER of methylphenidate-OROS treatment in youths with ADHD for whom treatment with IR methylphenidate is suboptimal was euro 2004 per QALY. Total costs after 10 years were euro 15,739 for the IR methylphenidate pathway and euro 16,015 for the methylphenidate-OROS pathway. In the univariate sensitivity analysis, the ICER was sensitive to changes in resource use and the probability of stopping stimulant treatment in favour of IR methylphenidate. An ICER of 0 was reached with a 6.2% price reduction of methylphenidate-OROS. CONCLUSION: Methylphenidate-OROS is a cost-effective treatment for youths with ADHD for whom treatment with IR methylphenidate is suboptimal. Higher medication costs of methylphenidate-OROS were compensated for by savings on resource use, yielding similar 10-year costs compared with treatment with IR methylphenidate. Our analysis is sensitive to both clinical parameters and (differences in) resource utilization and costs between the groups modelled, warranting further research within clinical trials and observational databases, and into the full scope of costs.

Atomoxetine for attention-deficit/hyperactivity disorder symptoms in children with pervasive developmental disorders: a pilot study.

OBJECTIVE: This pilot study examined the effects of atomoxetine on attention-deficit/hyperactivity disorder (ADHD) symptoms and autistic features in children with pervasive developmental disorders (PDD). METHOD: Twelve children (aged 6-14 years) with PDD accompanied by ADHD symptoms entered a 10-week open-label study with atomoxetine (1.19 +/- 0.41 mg/kg/day). Response was assessed by using parent and clinician rating scales with change in the ADHD-Rating Scale (ADHDRS) as primary outcome measure. RESULTS: Atomoxetine reduced ADHD-symptoms as measured by the ADHDRS (44% decrease vs. baseline, p < 0.003), the Conners' Parent Rating Scale-R:S (CPRS-R) (25% in the subscale "Cognitive Problems," p < 0.028; 32% in "Hyperactivity," p < 0.030; and 23% in "ADHD index," p < 0.023). We found a reduction of 21% (p = 0.071) for changes in the subscale "Hyperactivity" of the Aberrant Behavior Checklist (ABC). No change was found in any of the other ABC subscales, nor in the subscale "Oppositional" of the CPRS-R. Five patients (42%) discontinued because of side effects. Gastrointestinal symptoms, irritability, sleep problems, and fatigue were the most frequent side effects. CONCLUSIONS: These preliminary findings indicate that atomoxetine may be a promising new agent in the treatment of ADHD symptoms in children with PDD. However, children with PDD may have a higher vulnerability for some of the known side-effects of atomoxetine.

Parents report on stimulant-treated children in the Netherlands: initiation of treatment and follow-up care.

OBJECTIVES: The aim of this study was to describe current practices around initiation and follow-up care of stimulant treatment among stimulant-treated children in a nationwide survey among parents. METHODS: A total of 115 pharmacies detected current stimulant users <16 years old in their pharmacy information system and sent parents a questionnaire regarding their child's stimulant treatment. RESULTS: Parents returned 924 of 1,307 questionnaires (71%). The median age of the stimulant users was 10 years and 85% were boys. In all, 91% were diagnosed with attention-deficit/hyperactivity disorder (ADHD). In 77% of the cases, the child or parents received other therapies besides stimulants-21% received psychotropic co-medication, with melatonin (11%) and antipsychotics (7%) being mentioned most frequently. Stimulant use was primarily initiated by child psychiatrists (51%) and pediatricians (32%), but most children received repeat prescriptions from general practitioners (61%). Of these 924 children, 19% did not receive any follow-up care, and transfer of prescribing responsibility increased the risk of not receiving follow-up care. The 732 children (79%) who were monitored visited a physician approximately twice a year. During follow-up visits, pediatricians performed physical check ups significantly more often. CONCLUSION: Stimulant treatment in The Netherlands is initiated mainly by specialists such as child psychiatrists and pediatricians. In the current study, follow-up care for stimulant-treated children in The Netherlands appeared to be poor, suggesting an urgent need for improvement.

A comparison of North American versus non-North American ADHD study populations.

Few large, prospective clinical studies in Europe have assessed the validity and applicability of research methods used to study ADHD in North America. To assess comparability of study populations, we examined baseline patient characteristics from a group of North American studies against those of a large European/African/Australian study. All studies used identical diagnostic assessments and inclusion criteria, with ADHD diagnosis and the presence of comorbid psychiatric conditions confirmed using the KSADS-PL. Raters were trained and assessed to ensure uniform diagnostic and symptom severity rating standards. Six hundred and four patients (mean age = 10.2 years) enrolled in the non-North American study, and 665 patients (mean age = 10.4 years) enrolled in the North American study. The proportion of girls was higher in the North American studies (29.2% vs. 10.4%, p < 0.001). In both groups, most patients had a positive family history of ADHD and previous stimulant treatment. Fewer had the inattentive subtype of ADHD, and mean severity was slightly higher in the non-North American study. Results demonstrate that, when a uniform set of rigorous, standardized diagnostic criteria are used by skilled clinicians, the patient populations identified are generally similar. This supports the practice of generalizing results from treatment studies across geographies.