DARWIN EU® - Antipsychotic prescribing in children in Europe: a descriptive analysis of trends and patient characteristics

Study type

• Study topic:
  Human medicinal product
• Study type:
  Non-interventional study
• Scope of the study:
  Drug utilisation
• Data collection methods:
  Secondary use of data

Non-interventional study

• Non-interventional study design:
  Cohort

Study drug and medical condition

• Medicinal product name, other:
  All antipsychotics under the ATC code N05A (all, and by grouped by typical/atypical); ; and eleven prespecified drug substances: risperidone, aripiprazole, olanzapine, ; quetiapine, paliperidone, chlorprothixene, clozapine, methotrimeprazine ; (levomepromazine), pipamperone, sulpiride, and promazine.
• Anatomical Therapeutic Chemical (ATC) code:
  (N05A) ANTIPSYCHOTICS

  ANTIPSYCHOTICS

Population studied

• Short description of the study population:
  The study cohort will comprise all paediatric individuals between 1- and 18-years old present in the database during the study period (i.e., 2013-2023). ; Additional eligibility criteria for patient-level antipsychotic characterisation and drug utilisation, and for the calculation of incidence rates will be applied, where a minimum follow-up of 365 days of data availability will be required to exclude individuals with a prior use of the respective drug of interest: ; - When overall, no prior use of any of the common antipsychotics will be required. ; In other words, users with prior use of any of the antipsychotics of interest will be excluded from the analysis.; - When stratified by specific antipsychotic drug, no prior use of the specific antipsychotic will be required. ; In other words, users with prior use of the same antipsychotic will be excluded from the analysis.

Study design details

• Study design:
  Retrospective cohort studies will be conducted using routinely collected health data from 7 databases.
• Main study objective:
  1. To characterise children with a first prescription of an antipsychotic in each database in terms of age, sex, comorbidities and indication of use.; 2. To measure trends in the incidence/prevalence of antipsychotic prescribing in children overall, by typical/atypical grouping and separately for 11 drug substances in each database. Results would be stratified by calendar year, age and sex.; 3. To characterise first use of antipsychotic initiation in children (overall, by typical/atypical use, and by the 11 prespecified drug substances) in terms of dose and duration in each database. Results will be stratified by age and sex.
• Data analysis plan:
  Statistical analysis ; 1. Patient-level new user characterisation: characterisation of patient-level features for new users of antipsychotics was calculated for all (all antipsychotic drugs), by typical/atypical, and separately for the 11 pre-specified drug substances for each database. Analyses included the description of age at index date (date of first prescription of the antipsychotic of interest), pre-defined comorbidities of interest recorded within 30 days or any time before index date, and potential indications based on the record of pre-defined conditions of interest recorded within 7 days, 30 days, or any time before index date. ; 2. Population-level drug utilisation: annual incidence and annual period prevalence estimates were; calculated for antipsychotic treatment for all, by typical/atypical and for the 11 pre-specified drug substances for each database. ; 3. Patient-level drug utilisation: prescribed initial and cumulative dose of antipsychotics, and median treatment duration were described for all antipsychotic use, for typical/atypical antipsychotics, and for the 11 pre-specified drug substances for each database. ; For all analyses, a minimum cell counts of 5 was used when reporting results, with any smaller counts noted ; as <5.
• Summary results:
  Trends in antipsychotic use in children increased in Spain, the Netherlands, Germany, and Croatia. These increases were driven by atypical antipsychotic prescribing, with the highest incidence and prevalence use observed in Spain. All antipsychotic use in Denmark was stable, driven by an increase in atypical use and a decrease in typical use. Typical antipsychotic prescribing also decreased in Croatia, the Netherlands, and Norway over the study period; but increased in Germany and increased or remained stable in Spain depending on database. Antipsychotic prescribing was more common in children aged 12–18 years but occurred in all age groups. Quetiapine, risperidone, and aripiprazole tended to be the most frequently prescribed antipsychotics. Between 38.3% of children in BIFAP (Spain) to 78.2% of children in DK-DHR (Denmark) had recorded at least one condition linked to a potential clinical indication for antipsychotic use in children. Most frequently recorded conditions linked to potential clinical indications were depression in Croatia and Germany, anxiety in Spain, autism in the Netherlands, and sleep disorders in Denmark and Norway. Whilst a limited number of the 11-pre-selected substances have been formally centrally licensed in Europe for use in children to treat the most commonly observed conditions in this population, some products might have been authorised nationally. Further work may be required to better characterise the clinical indications for antipsychotic use in children and to establish the proportion of exposure that is on- versus off-label. Future studies could focus on comparing new diagnoses of conditions linked to potential clinical indications for antipsychotic use with the number of children receiving pharmaceutical interventions. This could help distinguish between over treatment with medication instead of first trying lifestyle interventions, and an increase in prescriptions that simply reflects more new diagnoses