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Multicenter Study
. 2025 Feb;132(2):295-312.
doi: 10.1007/s00702-024-02819-6. Epub 2024 Nov 2.

Therapeutic drug monitoring in children and adolescents with schizophrenia-spectrum, affective, behavioural, tic and other psychiatric disorders treated with aripiprazole: results of the TDM-VIGIL pharmacovigilance study

Jessica Riegger #  1 , Karin Maria Egberts #  2 , Hans-Willi Clement  1 , Katja Schneider-Momm  1 , Regina Taurines  3 , Stefanie Fekete  3 , Christoph Wewetzer  4   5 , Andreas Karwautz  6 , Christoph U Correll  7   8   9 , Paul L Plener  6   10 , Uwe Malzahn  11 , Peter Heuschmann  11   12   13 , Stefan Unterecker  14 , Maike Scherf-Clavel  14 , Hans Rock  14 , Gisela Antony  14 , Wolfgang Briegel  3   15 , Tobias Banaschewski  16 , Tobias Hellenschmidt  17 , Michael Kaess  18   19 , Michael Kölch  20   21 , Tobias Renner  22 , Christian Rexroth  23 , Gerd Schulte-Körne  24 , Susanne Walitza  25   26   27 , Manfred Gerlach  3 , Marcel Romanos  3 , Christian Fleischhaker  28
Affiliations
Multicenter Study

Therapeutic drug monitoring in children and adolescents with schizophrenia-spectrum, affective, behavioural, tic and other psychiatric disorders treated with aripiprazole: results of the TDM-VIGIL pharmacovigilance study

Jessica Riegger et al. J Neural Transm (Vienna). 2025 Feb.

Abstract

Aripiprazole is approved for various severe mental disorders in adults and adolescents. However, off-label prescribing is common, especially in children and adolescents (youth) in whom aripiprazole therapeutic serum level reference ranges are lacking for any disorders. The aim of the study was to evaluate the relationship between aripiprazole dose and serum concentrations and provide further knowledge on the use of aripiprazole in order to improve drug safety and effectiveness in the treatment of minors. The clinical course of youth treated with aripiprazole in the multicentre pharmacovigilance study TDM-VIGIL was systematically followed and serum concentrations measured. Sex, age, weight and comedications were analysed to identify possible effect modifiers. A preliminary therapeutic reference range was estimated for youth with schizophrenia-spectrum disorders, affective disorders and behavioural/emotional/tic disorders coded as treatment responders based on a Clinical-Global Impressions-Improvement (CGI-I) score of much or very much improved. In 93 youth (mean age = 15.2 ± 2.6, range = 7.4-18.2 years, females = 53%, CGI-Severity = 4.4 ± 1.1, responders = 64%), a positive, moderate correlation between the weight-normalized daily dose (WNDD) and aripiprazole serum concentration (=0.791, p < 0.0001) was found. The WNDD and co-medications that interact with CYP2D6 and CYP3A4 affected aripiprazole serum levels, explaining 64% of the variance. In patients within the preliminary therapeutic ranges determined by interquartile ranges (IQRs), slightly better outcomes and fewer adverse drug reactions were found versus patients within preliminary therapeutic ranges determined by the mean ± SD. The preliminary reference range for paediatric patients with schizophrenia-spectrum disorders calculated by the IQR showed an identical lower threshold (100-230 ng/ml) compared to adult schizophrenia-spectrum disorders patients (100-350 ng/ml). The preliminary therapeutic ranges for patients with affective disorders was: 60-160 ng/ml and for patients with behavioural/tic disorders 60-140 ng/ml. The therapeutic reference ranges for aripiprazole in youth estimated via the 25th and 75th IQRs may result in more clinically relevant therapeutic windows. Further studies need to confirm these results, especially in patients with affective and behavioural/tic disorder diagnoses.

Keywords: Affective disorder; Aripiprazole; Children and adolescents; Schizophrenia; Serum concentration; Therapeutic drug monitoring.

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Conflict of interest statement

Declarations. Conflict of interest: KE, MR, RT and PP received grant research support from BfArM. MR currently receives a research grant from Kids-Safe, Innovation Committee of the German Federal Joint Committee (G-BA grant number 01NVF16021). PP receives grant research support from the German Federal Ministry of Education and Research (BMBF) and was involved in clinical trials from Servier and Lundbeck; he received an advisor honorarium from Boehringer Ingelheim and speaker’s honoraria from Shire, Infectopharm and Gerot Lannach. CUC has been a consultant and/or advisor to or has received honoraria from: AbbVie, Acadia, Alkermes, Allergan, Angelini, Aristo, Biogen, Boehringer-Ingelheim, Cardio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Darnitsa, Denovo, Gedeon Richter, Hikma, Holmusk, IntraCellular Therapies, Janssen/J&J, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Neurelis, Newron, Noven, Novo Nordisk, Otsuka, Pharmabrain, PPD Biotech, Recordati, Relmada, Reviva, Rovi, Seqirus, SK Life Science, Sunovion, Sun Pharma, Supernus, Takeda, Teva, and Viatris. He provided expert testimony for Janssen and Otsuka. He served on a Data Safety Monitoring Board for Compass Pathways, Denovo, Lundbeck, Relmada, Reviva, Rovi, Sage, Supernus, Tolmar and Teva. He has received grant support from Janssen and Takeda. He received royalties from UpToDate and is also a stock option holder of Cardio Diagnostics, Mindpax, LB Pharma, PsiloSterics and Quantic. TB received personal fees from serving as an advisor or consultant to from eye level, Infectopharm, Lundbeck, Medice, Neurim Pharmaceuticals, Oberberg GmbH, Roche and Takeda; receiving conference attendance support, conference support, or speaking fees from or speaker’s fee by Janssen, Medice and Takeda; and receiving royalties from Hogrefe, Kohlhammer, CIP-Medien, and Oxford University Press. S.W.has received in the last 5 years royalties from Thieme, Hogrefe, Kohlhammer, Springer, Beltz. In 2023 she will receive speakers honorary from Takeda and Medice. Her work was supported in the last years by the Swiss National Science Foundation (SNF), diff. EU FP7s, HSM Hochspezialisierte Medizin of the Kanton Zurich, Switzerland, Bfarm Germany, ZInEP, Hartmann Müller Stiftung, Olga Mayenfisch, Gertrud Thalmann, Vontobel, Unicentia, Erika Schwarz, Heuberg Fonds, National Government of Health (BAG), Gesundheitsförderung Schweiz and Horizon Europe. Outside professional activities and interests are declared under the link of the University of Zurich www.uzh.ch/prof/ssl-dir/interessenbindungen/client/web/ MKoe receives royalties from publishing companies as an author of books. He served as PI or CI in clinical trials of Lundbeck, Pascoe and Janssen-Cilag. He served as scientific advisor for Janssen. The present work is unrelated to the above grants and relationships. The other authors (JC, HC, KSM, RT, SF, CW, AK, KR, UM, PH, SU, MSC, HR, GA, WB, TH, MKae, CR, GS, MG, and CF) declare no conflict of interest.

Figures

Fig. 1
Fig. 1
Correlation between aripiprazole serum concentrations and weight-adjusted doses of all patients and different diagnostic groups, taking in to account CYP2D6 and CYP3A4 inhibitors
Fig. 2
Fig. 2
Non-significant correlation between the serum concentrations and the clinical effectiveness of aripiprazole measured by the NET-CGI for diagnosis schizophrenia-spectrum disorders (p = 0.61), affective disorders (p = 0.26), personality disorders (p = 0.70) and behavioural/tic disorders (p = 0.30)
Fig. 3
Fig. 3
Preliminary therapeutic reference ranges calculated for responders without inhibiting comedication for aripiprazole in children and adolescents with different diagnoses in comparison to recently proposed therapeutic reference ranges for schizophrenia and the recommended therapeutic reference range for adults with schizophrenia. *Schizophrenia spectrum disorders (SSD)
See this image and copyright information in PMC

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