TYPE Brief Research Report PUBLISHED 16 June 2023 DOI 10.3389/fphar.2023.1157135 Utilisation of drugs for the OPEN ACCESS treatment of psychiatric diseases EDITED BY Eugene Van Puijenbroek, Netherlands Pharmacovigilance Centre in the pediatric population: focus Lareb, Netherlands REVIEWED BY on off-label use Angelo Barbato, Mario Negri Pharmacological Research Institute (IRCCS), Italy Stella Pesiou 1,2, Rafel Barcelo 3, Marc Fradera 2,4, Ferran Torres 3* Diogo Mendes, and Caridad Pontes 2,5,6 University of Coimbra, Portugal 1 European Medicines Agency, Amsterdam, Netherlands, 2Department of Pharmacology, Therapeutics and *CORRESPONDENCE Toxicology, Universitat Autònoma de Barcelona, Edifici M Campus de la UAB, Bellaterra, Spain, Ferran Torres, 3 Departament of Pediatrics, Gynecology and Obstetrics, and Preventive Medicine, Universitat Autònoma Ferran.Torres@uab.cat de Barcelona, Edifici M Campus de la UAB, Bellaterra, Spain, 4Unitat Mixta de Neurociència Traslacional RECEIVED 02 February 2023 I3PT-INc-UAB, Parc Taulí Hospital Universitari, Institut d’Investigació i Innovació Parc Taulí (I3PT-CERCA), ACCEPTED 05 June 2023 Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Sabadell, Spain, 5Department of PUBLISHED 16 June 2023 Medicines, Area of Healthcare Services, Catalan Health Service, Barcelona, Spain, 6Digitalization for the Sustainability of the Healthcare System (DS3), Institut d’Investigacio Biomedica de Bellvitge (IDIBELL), CITATION Barcelona, Spain Pesiou S, Barcelo R, Fradera M, Torres F and Pontes C (2023), Utilisation of drugs for the treatment of psychiatric diseases in the pediatric population: focus on off- label use. Psychotropics are increasingly used in pediatrics, often as off-label medicines. The Front. Pharmacol. 14:1157135. doi: 10.3389/fphar.2023.1157135 guarantees of safety and efficacy are not always granted in clinical practice compared to adult authorised indications. A retrospective observational study was done to COPYRIGHT © 2023 Pesiou, Barcelo, Fradera, Torres estimate the prevalence of psychotropic use in pediatric subjects of Catalonia (Spain). and Pontes. This is an open-access article Anonymised data on dispensation of psychotropics to pediatric patients, distributed under the terms of the demography and other related data were obtained by the local healthcare Creative Commons Attribution License (CC BY). The use, distribution or management for the period 2008–2017. Estimation of off-label use was done reproduction in other forums is through description of drug dispensations with no authorised use related to age permitted, provided the original author(s) range. The prevalence of psychotropics was 40.8–64.2 per 1,000 pediatric and the copyright owner(s) are credited and that the original publication in this inhabitants. Hydroxyzine-only represented two-thirds of dispensations, and when journal is cited, in accordance with removed, the prevalence dropped to 26.4–32.2 per 1,000 pediatric inhabitants. accepted academic practice. No use, Adolescents and boys were more likely to receive a psychotropic. Psychostimulants distribution or reproduction is permitted which does not comply with these terms. had the highest exposure rate, mainly due to methylphenidate. Off-label use was observed in 12% of subjects, corresponding to 4.6% of all dispensed psychotropics with boys being more exposed. The proportion of off-label use vs. labelled use was higher in younger populations. Aripiprazole had the highest off-label frequency. Our data support the frequent reality of off-label use in pediatrics, despite the potential underestimation related to the selected off-label definition. There is an urgent need to systematically ascertain effectiveness and any potential adverse events in the off- label pediatric setting, and to generate valuable information for risk-benefit assessment in these populations where extrapolation from adults is not reliable. KEYWORDS children, adolescents, pediatric, psychiatry, drugs, psychotropics, prevalence, off-label 1 Introduction There is a great relevance in ensuring that appropriate efforts are directed to preserve, promote, restore and protect mental health, as a key axis of the overall subject and community wellbeing and functionality (World Health Organization, 2018). Global estimates suggest that roughly 1 in 5 children and adolescents present with a mental Frontiers in Pharmacology 01 frontiersin.org Pesiou et al. 10.3389/fphar.2023.1157135 health condition, that half of the mental conditions start by the age following a procedure aiming to maintain the data confidentiality via of 14 years old, while suicide is considered the third leading cause of double encryption and removal of personal identifiers. death in adolescents aged 15–19 years old (World Health The extracted data were reviewed for their quality and completion. Organization, 2021; World Health Organization, 2023). Hence, No further action was done concerning the missing data as their the epidemiology of mental disorders in the pediatric population collection was not feasible due to the retrospective design of the still has room for improvement, while few and generally fragmented study. Before the actual analysis, duplicate cases were detected and data are available on the prevalence of the different conditions and deleted. The analysis of the study was descriptive: categorical variables their treatments, since many countries do not have the appropriate were described using frequencies and percentages, while the use of information systems to obtain them. psychotropics was defined as per the pharmacy dispensed number of Children and adolescents have been traditionally considered a medicines following their prescription by a physician and given as neglected population from a therapeutic perspective. Reasons prevalence by 1,000 Catalan inhabitants aged less than 18 years. As include the intrinsic clinical difficulty to identify mental signs psychotropics we included the following ATC groups as defined by and symptoms in pediatric patients along with the developmental WHO: antiepileptics (N03A), antipsychotics (N05A), anxiolytics changes, the lack of awareness on the frequency and importance of (N05B), hypnotics/sedatives (N05C), antidepressants (N06A), mental conditions in children, social stigma on mental disorders psychostimulants (N06B) and drugs used in addictive disorders (World Health Organization, 2013), as well as several other reasons (N07B). The off-label use was approached through analysis of drugs acting as barriers to the development of new drugs and evidence- dispensed out of the authorised age range (if any) for each product as based treatment options for this population (Koelch et al., 2008; defined from products labelling, in a subset of data between 2015 and Hoffman et al., 2014). 2017 and was presented using percentages. The listing of the most Data on the use of drugs are important to understand the frequently off-label dispensed psychotropics was described for 1 year epidemiology of a specific health problem, especially in a (2017). population for which the participation in clinical studies is often The statistical analysis was performed using the statistical not considered ethical or easily manageable. Therefore, real-world package SAS v9.4 (SAS Institute, Cary, NC, United States). evidence can be useful for prescribers and patients by complementing The protocol of this observational study was authorised by the the information derived from randomised clinical trials. Moreover, relevant ethics committee in Catalonia, but no further authorisation or data on effectiveness in clinical practice may complement efficacy and signed patient consents were needed according to national regulation. safety data in groups of patients not included in clinical trials, wider samples and diverse cultural and social settings, allowing to clarify uncertainties and to complete missing information (Lapeyre-Mestre 3 Results et al., 2013). In a literature search for studies describing the use of psychotropics in children and adolescents in Spain, we found only one 3.1 Prevalence of psychotropics use population-based study, but the subjects were of the age of 15 years and above (Barceló et al., 2016). During the study period (2008–2017) 449,196 subjects with at We aimed to describe the use of psychotropics in the pediatric least one psychotropic drug dispensed from the Catalan health population in the region of Catalonia (Spain) and their trends in reimbursement system were identified in the concerned region; time, in order to identify the main areas of exposure to psychotropic 137 patients were excluded as they had potential errors as drugs used in this vulnerable population in our setting. regards the sex variable, and therefore our initial sample was finally of 449,059 pediatric subjects. The annual prevalence of use of psychotropics was between 40.8 and 2 Materials and methods 64.2 per 1,000 pediatric inhabitants with at least one psychotropic dispensed within the 10-year period of this study. Pediatric subjects We conducted a retrospective observational population-based under hydroxyzine-only treatment represented two-thirds of the quantitative study of psychotropic consumption in the population dispensations. After removing the hydroxyzine-only dispensations data, below 18 years of age residing in the region of Catalonia (Spain) and the prevalence of psychotropic use in the pediatric population of this covered by the social security. Pharmacy billing data from the Catalan targeted exposure was between 26.4 and 32.2 per 1,000 pediatric Health Service (CatSalut) for a 10-year period (2008–2017) were used inhabitants. Adolescents and boys were more likely to receive a and linked as per the single identification number of the Catalan psychotropic drug. Table 1 presents in detail the prevalence of use in Health Service to the data contained in the central insurance registry the Catalan pediatric population of our setting in total and per age groups. for demographics and insurance status. The pharmacy Psychostimulants had the highest prevalent exposure in our reimbursement data are considered representative of the region’s setting (Figure 1) and boys were much more exposed compared to population, since all residents in Catalonia (approximately girls. Methylphenidate was found to be the most prevalent 7.72 million, 16.4% of Spain’s total population) (Instituto Nacional psychotropic dispensed to the Catalan pediatric population, but de Estadística, 2018) are covered by the public system. The data used antipsychotics and antidepressants were also highly ranked (see for this analysis were provided by the Agència de Qualitat i Avaluació Supplementary Material S1). Sanitàries de Catalunya (AQuAS) through the PADRIS program (Programa públic d’analítica de dades per a la recerca i la 3.2 Off-label use innovació en salut a Catalunya) upon records linkage, by The subset of the pediatric population used for the off-label personnel not linked to the study team and anonymised the data analysis consisted of 66,824 outpatient pediatric subjects with at Frontiers in Pharmacology 02 frontiersin.org Pesiou et al. 10.3389/fphar.2023.1157135 TABLE 1 Prevalence of psychotropics use in Catalonia’s pediatric population from 2008 to 2017 (per 1,000 pediatric inhabitants). 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 Pediatric inhabitants 1,281,777 1,322,462 1,346,516 1,367,382 1,384,978 1,389,763 1,386,458 1,388,261 1,391,507 1,398,400 Any exposure All 63.7 40.8 53.6 60.7 60.5 56.9 63.7 64.2 62.0 55.2 Girls - Boys 57.6–69.5 33.5–47.6 46.5–60.3 52.4–68.4 52.0–68.4 48.7–64.7 55.8–71.1 56.4–71.4 54.5–68.9 47.7–62.1 Target exposures All 26.4 27.2 30.9 31.3 31.5 31.8 32.2 31.4 30.3 29.6 Girls - Boys 19.4–32.9 19.8–34.1 23.3–37.9 22.9–39.2 22.8–39.6 23.1–39.9 23.9–39.9 23.5–38.9 22.6–37.5 22.2–36.6 < 1 year 0.0 0.0 1.3 1.1 1.7 2.4 2.2 2.1 1.7 1.9 Girls - Boys 0.0–0.0 0.0–0.0 1.3–1.4 0.9–1.3 1.3–2.1 1.9–2.7 1.8–2.5 1.9–2.3 1.6–1.7 1.6–2.3 1–2 years 1.0 4.4 8.3 7.0 5.3 5.0 4.7 4.8 4.9 4.6 Girls - Boys 0.9–1.1 3.9–4.8 7.4–9.1 6.1–7.8 4.7–6.0 4.2–5.9 3.8–5.6 4.0–5.5 4.4–5.3 4.2–4.9 3–5 years 14.9 11.4 12.0 11.0 8.9 7.9 6.7 6.2 5.8 5.6 Girls - Boys 12.2–17.5 9.7–12.9 9.7–14.2 9.0–12.8 6.8–10.9 6.0–9.7 5.5–7.9 5.1–7.3 4.6–6.8 4.4–6.8 6–8 years 21.4 18.4 23.7 22.9 21.0 23.8 22.4 19.9 17.7 16.8 Girls - Boys 17.2–25.5 13.5–23.1 16.1–30.9 14.8–30.5 13.7–27.9 14.4–32.6 13.8–30.5 12.1–27.2 10.9–24.1 10.3–22.8 9–11 years 37.0 38.9 44.4 45.5 43.7 45.4 43.2 40.5 37.5 34.8 Girls - Boys 25.9–47.5 24.8–52.2 28.5–59.4 28.8–61.4 26.9–59.7 27.1–62.6 26.1–59.3 24.2–55.8 22.6–51.4 20.8–47.8 12–14 years 45.6 47.8 50.9 54.2 55.8 57.2 58.8 58.0 55.3 53.2 Girls - Boys 30.6–59.8 29.8–64.8 33.3–67.3 34.9–72.0 36.4–73.9 37.9–75.2 39.8–76.8 39.3–75.6 37.0–72.6 35.9–69.5 15–17 years 48.5 55.3 60.4 62.8 69.2 63.5 66.8 66.1 65.2 63.7 Girls - Boys 36.8–59.5 46.7–63.3 56.1–64.4 55.6–69.6 60.5–77.2 59.3–67.3 63.5–69.7 62.9–69.0 61.1–69.0 59.5–67.6 Bold italic figures refer to the overall (Girls+Boys) data FIGURE 1 Prevalence (per 1,000 inhabitants) of psychotropics use by ATC groups.. least one psychotropic drug dispensed between 2015 and 2017, The proportion of off-label use vs. labelled use was higher in corresponding to 950,395 drug dispensations. Off-label use was younger populations as described in Figure 2. Considering data only observed in 12% of pediatric subjects and was more frequent in in 2017, aripiprazole was the active substance most frequently used boys (Table 2). under an off-label status followed by two other antipsychotics (Table 2). Frontiers in Pharmacology 03 frontiersin.org Pesiou et al. 10.3389/fphar.2023.1157135 FIGURE 2 Off-label use considering labelled age-range, by age groups of subjects. TABLE 2 Off-label use considering labelling age range and most frequently off-label drugs. a. Off-label use considering labelling age (patients) Girls Boys Total n (%) n (%) n (%) In the authorised age range 21,910 (82.93) 36,880 (91.28) 58,790 (87.98) Out of authorised age range 4,510 (17.07) 3,524 (8.72) 8,034 (12.02) Overall 26,420 40,404 66,824 b. Most frequent off-label drugs in 2017 ATC Dispensed psychotropics (n = 310,078) Code Name n % D/Pa N05AX12 aripiprazole 5,496 1.77 4.8 N05AH04 quetiapine 4,380 1.41 3.9 N05AH03 olanzapine 2,654 0.86 3.6 N06AB10 escitalopram 1,165 0.38 3.6 N05BA12 alprazolam 1,036 0.33 1.8 N05AX13 paliperidone 1,024 0.33 6.7 N05BA09 clobazam 872 0.28 6.6 N06AB04 citalopram 743 0.24 3.5 N06AX11 mirtazapine 659 0.21 2.9 N03AF02 oxcarbazepine 622 0.20 6.5 a Dispensed drug per patient ratio. Frontiers in Pharmacology 04 frontiersin.org Pesiou et al. 10.3389/fphar.2023.1157135 4 Discussion are useful to define the trends and any relevant change throughout the evaluated period. Nonetheless, the extent of information in the 4.1 Psychotropic use in paediatrics present study was limited, since the type of variables available in healthcare databases is predetermined and focused on the We analysed anonymised data on dispensed drugs covered by the management of invoicing and healthcare services (Andersen, national health system of Catalonia. The overall prevalence of 2014). Another limitation from the source of the data used here psychotropic use was between 4.1% and 6.4% in Catalonia and is the fact that databases of reimbursements are limited to drugs in was led by a high rate of short-term use of hydroxyzine, an need of prescription; since in Spain all psychotropics are H1 antihistaminic which is used for several acute indications such prescription-only medications, this limitation is unlikely a source as skin allergies and itching. To focus the analysis on psychotropic use of bias in our study. Linking the use of drugs and the disease for in mental conditions, subsequent analyses excluded patients who had which they have been prescribed, would have permitted to analyse only hydroxyzine dispensations. In the population with this targeted more in depth the proportion of off-label use, considering the exposure, the prevalence of psychotropics use in the pediatric indication of the treatment. However, since these data were not population ranged between 2.6% and 3.2%, and was more frequent available for the current study, we approached the off-label analysis in adolescents as well as in boys, mostly due to the use of through the perspective of the age range only. psychostimulants. A significant amount of the dispensed psychotropic drugs was used out of the authorised age range, with higher proportions of the overall use being not covered by labelling 4.2 Off-label use of psychotropics age range in younger patients. Aripiprazole was the most frequent drug dispensed off-label, since in Europe it is authorised for use in Medication used under an off-label status is often considered a children older than 13 years of age. common practice in pediatric patients which imposes this vulnerable The rates of exposure to psychotropic drugs in Catalonia were population into a high-risk situation due to uncertainties in the found to be within the ratio reported in other European countries as efficacy and safety of the concerned treatments. Psychotropic well as the United States of America (Zito et al., 2003; Safer et al., medication is often not studied in underaged patients due to a 2004; Zito et al., 2008; Zoëga et al., 2009). A study in France reported large list of reasons like barriers regarding pharmacological a lower prevalence for the year 2010 compared to Catalonia (25.0 vs. treatments to obtain evidence-based treatment options for children 30.9 per 1,000 respectively) (Kovess Masfety et al., 2015). The (Koelch et al., 2008) or lower epidemiology of mental health disorders current study also demonstrated that boys are more exposed to as opposed to adults. The lack of research for many decades has led to psychotropics than girls, confirming the trend that has been a situation where many drugs currently used in children are lacking reported in previous studies (Zito et al., 2003; Zito et al., 2008; clinical evidence in pediatric conditions, and physicians need to Kovess Masfety et al., 2015; Hartz et al., 2016; Piovani et al., 2016). extrapolate their practice from the adult studies or the knowledge Psychostimulants use rate was 15.88 per 1,000 inhabitants, similar to acquired by clinical experience along the years, to be able to treat their the rates reported in Germany (7.1–22.0 per 1,000) (Zito et al., 2008; pediatric patients (Kern, 2009). Bachmann et al., 2017), the Netherlands (1.5–39.0 per 1.000) The off-label use in both Spain (and subsequently Catalonia) is (Schirm et al., 2001; Faber et al., 2005; Zito et al., 2008; somehow regulated, as there are legal measures in place to regulate Bachmann et al., 2017) and Israel (7.0–25.0 per 1,000) (Vinker requirements for an off-label use. A law established in 2009 states et al., 2006), slightly higher than Denmark (0.9–15.0 per 1,000) that a drug could be given as off-label in both hospitals and primary (Pottegård et al., 2012; Bachmann et al., 2017) and lower than the care settings, provided that physicians justify the need and absence ones reported in Iceland (21.7–28.4 per 1,000) (Zoëga et al., 2009), of commercialised alternatives suitable for the patient, as well as they whereas in France (2.0 per 1,000) (Kovess Masfety et al., 2015), Italy should obtain the consent from the patient after informing him or (0.1–1.9 per 1,000) (Piovani et al., 2016) and the United Kingdom her on the benefits and risks (Ministerio de SanidadPolítica Social, (3.0–5.0 per 1,000) (Bachmann et al., 2017), the reported prevalence 2009). In certain circumstances for repeated uses, physician’s rates for psychostimulants were lower. obligations may be waived if approved protocols are in place We had exhaustive information on drug dispensation from the (Ministerio de SanidadPolítica Social, 2009). However, available public healthcare in Catalonia for a period of 10 years, which can be evidence in Europe demonstrates that there is a relationship considered representative for the region since the system covers between off-label use in children and an increased percentage almost all inhabitants and was fully available across the whole study and severity of adverse drug reactions (ADRs); in particular, period (Modol et al., 2017). Prescription data might be a better neuro-psychiatric ADRs are detected more frequently in children option to describe the use of drugs, since they may involve compared to adults (European Medicines Agency, 2004). According information on indication. Advantages of using pharmacy to other studies, between 23% and 60% of all ADRs in children may invoicing data render the observations to be more representative be related to drugs used out of their authorised conditions (Neubert of the actual exposure in specific drugs, considering that these data et al., 2004; Cuzzolin et al., 2006; Fabiano et al., 2012). enclose information on patients that have actually collected the The off-label use of psychotropics in pediatric population has prescribed treatment. Hence, data on reimbursement can define been previously reported in several countries. The extent of off- better the prevalence on the use of a drug, even though one cannot label use depends on the setting and the applied off-label still be reassured in absolute terms about the actual adherence to the definition: small studies used to focus on a given indication or dispensed medications. While the actual use may differ compared to drug, provide more detailed descriptions and include information the purchase of drugs and may also change in time, invoicing data on formulation, dose and indication that allow a more accurate Frontiers in Pharmacology 05 frontiersin.org Pesiou et al. 10.3389/fphar.2023.1157135 definition of the off-label use, hence leading to higher rates of off- Data availability statement label use than the ones identified in our study (Braüner et al., 2016; Deng et al., 2018; Kornø and Aagaard, 2018). In the present study, The raw data supporting the conclusions of this article will be the data did not permit a very precise definition of off-label use, made available by the authors, without undue reservation. since they did not allow linking dispensed medications to a clinical indication. In addition, information on the age of the subjects was received as being aggregated into fixed age groups due to Author contributions confidentiality purposes. Therefore, we had to limit the analysis of the off-label use to the age range for which each active substance CP contributed to conception and design of the study. SP was approved, leading to a partial description of the off-label rates and MF organized the database and informed the analyses to be driven only by the approved age and not by the approved conducted. BR and FT performed the statistical analysis. CP and indication of psychotropics. SP wrote the first draft of the manuscript. All Considering all these limitations, we observed that 12% of authors contributed to the article and approved the Catalan pediatric subjects received at least one psychotropic as submitted version. off-label related to any pediatric approval of at least one product with the same active substance. Our study results may be compared only to one study reporting the off-label psychotropic prescriptions Funding in the Icelandic pediatric population (Zoëga et al., 2009). Nonetheless, the much higher off-label use in Iceland compared A part of the study was partially funded with grants by the to the one described in our sample, can be explained by our methods Generalitat de Catalunya (grant number SLT006/17/216) with main based on age only and the study periods that do not coincide. objective to map the use of psychotropic drugs in the pediatric To date there is still a huge need of appropriate and consistent population in Catalonia. regulatory information for the use of available psychotropic drugs in children and adolescents. We have shown that such use of available drugs is far from being rare, but this off-label use is currently done Acknowledgments empirically and in the absence of the regulatory guarantees that are granted through strict product labelling processes (Christiansen We would like to acknowledge the contributions of Narcis et al., 2022). The present study provide an overview on the Cardoner and Ximena Goldberg during the initiation of the psychotropic use and highlights that pediatric patients are in project. need of special attention. The data generated in this study could be a basis to start working towards an improved environment for pediatric healthcare with treatments having the guarantees of Conflict of interest quality, safety and efficacy for pediatric patients at the same level as the ones existing for adults. Our study could be considered as a The authors declare that the research was conducted in the starting point to identify the most frequent off-label use in pediatric absence of any commercial or financial relationships that could be mental healthcare, in order to inform guidelines on how construed as a potential conflict of interest. psychotropic off-label use can be minimised, especially for those substances with no robust evidence in the particularly vulnerable underaged patient group. Moreover, the information described in Publisher’s note our study could be also useful to regulatory authorities in order to define if there is still a need to further harmonise the requests for All claims expressed in this article are solely those of the authors granting or extending an authorisation in psychiatric indications for and do not necessarily represent those of their affiliated the pediatric population, and subsequently to foster further the organizations, or those of the publisher, the editors and the implementation of the pediatric regulation in Europe which was reviewers. Any product that may be evaluated in this article, or recently under revision (European Medicines Agency, 2021). Real- claim that may be made by its manufacturer, is not guaranteed or world evidence data could also play an important part to fill in the endorsed by the publisher. gap especially for all those medicines that are used for a long period under an off-label status in this patient population. Finally, our data could support actions aimed to align the incentives for Supplementary material pharmaceutical industry with the needs to extend the labelling of existing psychotropics, many under an off-patent status and The Supplementary Material for this article can be found online approved for use only in adults, and thus to regulate current at: https://www.frontiersin.org/articles/10.3389/fphar.2023.1157135/ established uses and patient age groups (Lepola et al., 2020). full#supplementary-material Frontiers in Pharmacology 06 frontiersin.org Pesiou et al. 10.3389/fphar.2023.1157135 References Andersen, M. (2014). Research on drug safety and effectiveness using Lapeyre-Mestre, M., Sapède, C., Moore, N., Bilbault, P., Blin, P., Chopy, D., et al. pharmacoepidemiological databases. J. Intern Med. 275 (6), 548–550. doi:10.1111/ (2013). Pharmacoepidemiology studies: What levels of evidence and how can they be joim.12235 reached? 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