Therapeutic Drug Monitoring in Children and Adolescents: Findings on Fluoxetine from the TDM-VIGIL Trial

Michael Frey^{1

2}, Lukasz Smigielski³, Elvira Tini³, Stefanie Fekete⁴, Christian Fleischhaker⁵, Christoph Wewetzer⁶, Andreas Karwautz⁷, Christoph U Correll^{8

9

10}, Manfred Gerlach⁴, Regina Taurines⁴, Paul L Plener^{7

11}, Uwe Malzahn¹², Selina Kornbichler², Laura Weninger², Matthias Brockhaus¹³, Su-Yin Reuter-Dang¹⁴, Karl Reitzle¹⁵, Hans Rock¹⁶, Hartmut Imgart¹⁷, Peter Heuschmann^{12

18}, Stefan Unterecker¹⁹, Wolfgang Briegel^{4

20}, Tobias Banaschewski²¹, Jörg M Fegert¹¹, Tobias Hellenschmidt²², Michael Kaess^{23

24}, Michael Kölch^{25

26}, Tobias Renner²⁷, Christian Rexroth²⁸, Susanne Walitza^{3

29

30}, Gerd Schulte-Körne², Marcel Romanos⁴, Karin Maria Egberts⁴

Affiliations

¹ Faculty of Applied Healthcare Science, Deggendorf Institute of Technology, 94469 Deggendorf, Germany.
² Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital, LMU Munich, 80097 Munich, Germany.
³ Department of Child and Adolescent Psychiatry and Psychotherapy, Psychiatric University Hospital Zurich, University of Zurich, 8032 Zürich, Switzerland.
⁴ Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Center for Mental Health, University Hospital of Wuerzburg, 97080 Wuerzburg, Germany.
⁵ Department of Child and Adolescent Psychiatry and Psychotherapy, University Medical Center Freiburg, 79104 Freiburg, Germany.
⁶ KIRINUS Tagesklinik Kinder und Jugendliche, 80639 Munich, Germany.
⁷ Department of Child and Adolescent Psychiatry, Medical University Vienna, 1090 Vienna, Austria.
⁸ Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin Berlin, 13353 Berlin, Germany.
⁹ Department of Psychiatry, The Zucker Hillside Hospital, Northwell Health, Glen Oaks, NY 11004, USA.
¹⁰ Department of Psychiatry and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11549, USA.
¹¹ Department of Child and Adolescent Psychiatry/Psychotherapy, University Hospital Ulm, 89075 Ulm, Germany.
¹² Clinical Trial Center Wuerzburg, University Hospital Wuerzburg, 97080 Wuerzburg, Germany.
¹³ Max-Planck-Institut für Psychiatry, 80804 Munich, Germany.
¹⁴ Specialist Practice and Medical Care Centre for Child and Adolescent Psychiatry Munich, Dr. Epple & Dr. Reuter-Dang, 81241 Munich, Germany.
¹⁵ Specialist Practice and Medical Care Center for Child and Adolescent Psychiatry Munich, 81241 Munich, Germany.
¹⁶ Central Information Office, Department of Neurology, Philipps University of Marburg, 35112 Marburg, Germany.
¹⁷ Parkland-Clinic, Clinic for Psychosomatics and Psychotherapy, Academic Teaching Hospital for the University Gießen, 34537 Bad Wildungen, Germany.
¹⁸ Institute of Clinical Epidemiology and Biometry, University of Wuerzburg, 97080 Wuerzburg, Germany.
¹⁹ Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of Wuerzburg, 97080 Wuerzburg, Germany.
²⁰ Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Leopoldina Hospital, 97422 Schweinfurt, Germany.
²¹ Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, 68159 Mannheim, Germany.
²² Department of Child and Adolescent Psychiatry, Psychotherapy and Psychosomatic medicine, Vivantes Clinic Berlin Neukölln, 12351 Berlin, Germany.
²³ Clinic for Child and Adolescent Psychiatry, Center for Psychosocial Medicine, University Hospital Heidelberg, 69115 Heidelberg, Germany.
²⁴ University Hospital of Child and Adolescent Psychiatry and Psychotherapy, University of Bern, 3000 Bern, Switzerland.
²⁵ Department of Child and Adolescent Psychiatry and Psychotherapy, Brandenburg Medical School Brandenburg, 16816 Neuruppin, Germany.
²⁶ Department of Child and Adolescent Psychiatry, Neurology, Psychosomatics, and Psychotherapy, University Medical Center Rostock, 18147 Rostock, Germany.
²⁷ Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Psychiatry and Psychotherapy Tuebingen, Center of Mental Health Tuebingen, 72076 Tuebingen , Germany.
²⁸ Clinic for Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University of Regensburg at the Regensburg District Hospital, Medbo KU, 93053 Regensburg, Germany.
²⁹ Zurich Center for Integrative Human Physiology, University of Zurich, 8057 Zürich, Switzerland.
³⁰ Neuroscience Center Zurich, University of Zurich and ETH, 8057 Zürich, Switzerland.

PMID: 37765171
PMCID: PMC10534581
DOI: 10.3390/pharmaceutics15092202

Therapeutic Drug Monitoring in Children and Adolescents: Findings on Fluoxetine from the TDM-VIGIL Trial

Michael Frey et al. Pharmaceutics. 2023.

. 2023 Aug 25;15(9):2202.

doi: 10.3390/pharmaceutics15092202.

Authors

Affiliations

¹ Faculty of Applied Healthcare Science, Deggendorf Institute of Technology, 94469 Deggendorf, Germany.
² Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital, LMU Munich, 80097 Munich, Germany.
³ Department of Child and Adolescent Psychiatry and Psychotherapy, Psychiatric University Hospital Zurich, University of Zurich, 8032 Zürich, Switzerland.
⁴ Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Center for Mental Health, University Hospital of Wuerzburg, 97080 Wuerzburg, Germany.
⁵ Department of Child and Adolescent Psychiatry and Psychotherapy, University Medical Center Freiburg, 79104 Freiburg, Germany.
⁶ KIRINUS Tagesklinik Kinder und Jugendliche, 80639 Munich, Germany.
⁷ Department of Child and Adolescent Psychiatry, Medical University Vienna, 1090 Vienna, Austria.
⁸ Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin Berlin, 13353 Berlin, Germany.
⁹ Department of Psychiatry, The Zucker Hillside Hospital, Northwell Health, Glen Oaks, NY 11004, USA.
¹⁰ Department of Psychiatry and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11549, USA.
¹¹ Department of Child and Adolescent Psychiatry/Psychotherapy, University Hospital Ulm, 89075 Ulm, Germany.
¹² Clinical Trial Center Wuerzburg, University Hospital Wuerzburg, 97080 Wuerzburg, Germany.
¹³ Max-Planck-Institut für Psychiatry, 80804 Munich, Germany.
¹⁴ Specialist Practice and Medical Care Centre for Child and Adolescent Psychiatry Munich, Dr. Epple & Dr. Reuter-Dang, 81241 Munich, Germany.
¹⁵ Specialist Practice and Medical Care Center for Child and Adolescent Psychiatry Munich, 81241 Munich, Germany.
¹⁶ Central Information Office, Department of Neurology, Philipps University of Marburg, 35112 Marburg, Germany.
¹⁷ Parkland-Clinic, Clinic for Psychosomatics and Psychotherapy, Academic Teaching Hospital for the University Gießen, 34537 Bad Wildungen, Germany.
¹⁸ Institute of Clinical Epidemiology and Biometry, University of Wuerzburg, 97080 Wuerzburg, Germany.
¹⁹ Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of Wuerzburg, 97080 Wuerzburg, Germany.
²⁰ Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Leopoldina Hospital, 97422 Schweinfurt, Germany.
²¹ Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, 68159 Mannheim, Germany.
²² Department of Child and Adolescent Psychiatry, Psychotherapy and Psychosomatic medicine, Vivantes Clinic Berlin Neukölln, 12351 Berlin, Germany.
²³ Clinic for Child and Adolescent Psychiatry, Center for Psychosocial Medicine, University Hospital Heidelberg, 69115 Heidelberg, Germany.
²⁴ University Hospital of Child and Adolescent Psychiatry and Psychotherapy, University of Bern, 3000 Bern, Switzerland.
²⁵ Department of Child and Adolescent Psychiatry and Psychotherapy, Brandenburg Medical School Brandenburg, 16816 Neuruppin, Germany.
²⁶ Department of Child and Adolescent Psychiatry, Neurology, Psychosomatics, and Psychotherapy, University Medical Center Rostock, 18147 Rostock, Germany.
²⁷ Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Psychiatry and Psychotherapy Tuebingen, Center of Mental Health Tuebingen, 72076 Tuebingen , Germany.
²⁸ Clinic for Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University of Regensburg at the Regensburg District Hospital, Medbo KU, 93053 Regensburg, Germany.
²⁹ Zurich Center for Integrative Human Physiology, University of Zurich, 8057 Zürich, Switzerland.
³⁰ Neuroscience Center Zurich, University of Zurich and ETH, 8057 Zürich, Switzerland.

PMID: 37765171
PMCID: PMC10534581
DOI: 10.3390/pharmaceutics15092202

Abstract

Fluoxetine is the recommended first-line antidepressant in many therapeutic guidelines for children and adolescents. However, little is known about the relationships between drug dose and serum level as well as the therapeutic serum reference range in this age group. Within a large naturalistic observational prospective multicenter clinical trial ("TDM-VIGIL"), a transdiagnostic sample of children and adolescents (n = 138; mean age, 15; range, 7-18 years; 24.6% males) was treated with fluoxetine (10-40 mg/day). Analyses of both the last timepoint and all timepoints (n = 292 observations), utilizing (multiple) linear regressions, linear mixed-effect models, and cumulative link (mixed) models, were used to test the associations between dose, serum concentration, outcome, and potential predictors. The receiver operating curve and first to third interquartile methods, respectively, were used to examine concentration cutoff and reference values for responders. A strong positive relationship was found between dose and serum concentration of fluoxetine and its metabolite. Higher body weight was associated with lower serum concentrations, and female sex was associated with lower therapeutic response. The preliminary reference ranges for the active moiety (fluoxetine+norfluoxetine) were 208-328 ng/mL (transdiagnostically) and 201.5-306 ng/mL (depression). Most patients showed marked (45.6%) or minimal (43.5%) improvements and reported no adverse effects (64.9%). This study demonstrated a clear linear dose-serum level relationship for fluoxetine in youth, with the identified reference range being within that established for adults.

Keywords: TDM; adolescents; antidepressants; depression; pharmacovigilance; reference range; selective serotonin reuptake inhibitors; steady-state concentration.

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Conflict of interest statement

K.E., R.T., M.R., M.G. and P.P. 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). P.P. 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. C.C. 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. T.B. received personal fees from serving as an advisor or consultant to eyelevel, Infectopharm, Lundbeck, Medice, Neurim Pharmaceuticals, Oberberg GmbH, Roche, and Takeda; received conference attendance support, conference support, or speaking fees from Janssen, Medice, and Takeda; and received royalties from Hogrefe, Kohlhammer, CIP-Medien, and Oxford University Press. J.M.F. received research funding in the last five years from European Union, BMG (Federal Ministry of Health), BMBF (Federal Ministry of Education and Research), BMFSFJ (Federal Ministry of Family, Senior Citizens, Women and Youth), DFG (German Research Foundation), G-BA Innovation Fund, State Ministries of Baden-Württemberg and Saarland, State Foundation Baden-Württemberg, Porticus Foundation, and Evangelical-Lutheran Church in Württemberg. He also received travel grants, honoraria, sponsorship for conferences, and medical educational purposes from APK, Adenauer- and Ebertstiftung, Deutschlandfunk, DFG, DJI, DKSB, Infectopharm, med update, UNICEF, professional associations, universities and federal, and state ministries and was a consultant for APK, federal and state ministries industry-sponsored lecture series but has no shareholdings and no participation in pharmaceutical companies. Every grant and every honorarium was declared to the law office of the University Hospital Ulm. M.K (Michael Kölch). receives royalties from publishing companies as an author of books. He served as PI or CI in clinical trials for Lundbeck, Pascoe, and Janssen-Cilag. He served as scientific advisor for Janssen. The present work is unrelated to the above grants and relationships. S.W. has received in the last 5 years royalties from Thieme, Hogrefe, Kohlhammer, Springer, and Beltz. Her work was supported in the last 5 years by the Swiss National Science Foundation, different EU FP7s programs, Hochspezialisierte Medizin of the Kanton Zurich, Switzerland, BfArM, ZInEP, Hartmann Müller Stiftung, Olga Mayenfisch, Gertrud Thalmann, Vontobel, Unicentia, Erika Schwarz Fonds, and Gesundheitsforderung Schweiz. M.F. received royalties from Kohlhammer and Elsevier. The other authors. (L.S., E.T., L.S., C.W., A.K., K.R., U.M., S.U., S.K., M.B., L.W., P.H., W.B., C.F., T.H., H.I., M.K. (Michael Kaess), T.R., C.R., G.S.-K. and S.F.) declare no conflict of interest.

Figures

**Figure 1**
Significant linear associations between fluoxetine (FLX) daily dose (x-axis) and steady-state serum concentrations of FLX, norfluoxetine (NORFLX), and the active moiety (FLX+NORFLX) (y-axis; from left to right). The blue diagonal line is the best-fit line. The black dots represent data points.

See this image and copyright information in PMC

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Therapeutic Drug Monitoring in Children and Adolescents: Findings on Fluoxetine from the TDM-VIGIL Trial

Affiliations

Therapeutic Drug Monitoring in Children and Adolescents: Findings on Fluoxetine from the TDM-VIGIL Trial

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Grants and funding

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