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CC BY-NC-ND 4.0 · Pharmacopsychiatry 2023; 56(01): 32-39
DOI: 10.1055/a-1963-7631
Original Paper

Serious Adverse Drug Reactions to Antipsychotics in Minors with Multiple Disabilities: Preventability and Potential Cost Savings by Therapeutic Drug Monitoring

Stefanie Fekete
1   Department Child and Adolescent Psychiatry, Psychosomatic and Psychotherapy, Center of Mental Health, University Hospital Wuerzburg, Wuerzburg, Germany
2   AGNP-Work group ‘Child and Adolescent Psychopharmacology’
,
Tim Güntzel
1   Department Child and Adolescent Psychiatry, Psychosomatic and Psychotherapy, Center of Mental Health, University Hospital Wuerzburg, Wuerzburg, Germany
,
Karin Egberts
1   Department Child and Adolescent Psychiatry, Psychosomatic and Psychotherapy, Center of Mental Health, University Hospital Wuerzburg, Wuerzburg, Germany
2   AGNP-Work group ‘Child and Adolescent Psychopharmacology’
3   AGNP-Work group Therapeutic Drug Monitoring
4   Competence network for Therapeutic Drug Monitoring in child and adolescent psychiatry
,
Julia Geissler
1   Department Child and Adolescent Psychiatry, Psychosomatic and Psychotherapy, Center of Mental Health, University Hospital Wuerzburg, Wuerzburg, Germany
,
Antje Neubert
5   Department of Paediatrics and Adolescent Medicine, University Hospital Erlangen, Erlangen, Germany
,
Manfred Gerlach
1   Department Child and Adolescent Psychiatry, Psychosomatic and Psychotherapy, Center of Mental Health, University Hospital Wuerzburg, Wuerzburg, Germany
2   AGNP-Work group ‘Child and Adolescent Psychopharmacology’
3   AGNP-Work group Therapeutic Drug Monitoring
4   Competence network for Therapeutic Drug Monitoring in child and adolescent psychiatry
,
Marcel Romanos
1   Department Child and Adolescent Psychiatry, Psychosomatic and Psychotherapy, Center of Mental Health, University Hospital Wuerzburg, Wuerzburg, Germany
2   AGNP-Work group ‘Child and Adolescent Psychopharmacology’
3   AGNP-Work group Therapeutic Drug Monitoring
,
Regina Taurines
1   Department Child and Adolescent Psychiatry, Psychosomatic and Psychotherapy, Center of Mental Health, University Hospital Wuerzburg, Wuerzburg, Germany
3   AGNP-Work group Therapeutic Drug Monitoring
› Author Affiliations Funding Information Innovation Fund of the Federal Joint Committee (G-BA) — 01NVF16021
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Abstract

Introduction Children and adolescents with multiple disabilities and mental disorders (CAMD) are frequently treated with antipsychotic drugs. However, CAMD are particularly susceptible to serious adverse drug reactions (sADRs). This retrospective study examined the frequency of sADRs to antipsychotics in CAMD. Further, the potential preventability of these sADRs through therapeutic drug monitoring (TDM) and the potential socio-economic benefits of TDM were explored.

Methods Routine clinical data of all patients treated at a specialized psychiatric clinic for CAMD between January 2017 and December 2018 were retrospectively examined. Data on the occurrence of sADRs (definition according to the European Medicines Agency), their causality with antipsychotics, as well as their preventability (Schumock criteria) were extracted from patient files. The prolongation of the hospital stay due to sADRs was calculated, and the cost savings were estimated if TDM had been applied. The data were based on a subsample of the KiDSafe project, supported by the Innovation Fund of the Joint Federal Committee, grant number 01NVF16021.

Results One hundred two CAMD who were administered at least one antipsychotic drug during inpatient treatment were identified. Of these patients, 22 (21.6%) sADRs with a possible causal relationship with the antipsychotic treatment were documented. Eleven sADRs (50%) could potentially have been prevented through TDM. Mitigating sADRs through TDM likely would have prevented prolonged hospital stays and thus conferred considerable savings for health insurance companies.

Discussion The routine implementation of TDM is urgently recommended for antipsychotic treatment in CAMD to increase drug therapy safety.

Key words

pharmacovigilance - drug safety - psychotropic drugs - intellectual and developmental disorders - children


Publication History

Received: 06 July 2022
Received: 02 September 2022

Accepted: 13 October 2022

Article published online:
04 November 2022

© 2022. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).

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  • References

  • 1 Buckley N, Glasson EJ, Chen W. et al. Prevalence estimates of mental health problems in children and adolescents with intellectual disability: A systematic review and meta-analysis. Aust N Z J Psychiatry 2020; 54: 970-984
    CrossrefPubMedGoogle Scholar
  • 2 Brophy S, Kennedy J, Fernandez-Gutierrez F. et al. Characteristics of children prescribed antipsychotics: Analysis of routinely collected data. J Child Adolesc Psychopharmacol 2018; 28: 180-191
    CrossrefPubMedGoogle Scholar
  • 3 Brauner JV, Johansen LM, Roesbjerg T. et al. Off-label prescription of psychopharmacological drugs in child and adolescent psychiatry. J Clin Psychopharmacol 2016; 36: 500-507
    CrossrefPubMedGoogle Scholar
  • 4 Sharma AN, Arango C, Coghill D. et al. BAP position statement: Off-label prescribing of psychotropic medication to children and adolescents. J Psychopharmacol 2016; 30: 416-421
    CrossrefPubMedGoogle Scholar
  • 5 Correll CU, Carlson HE. Endocrine and metabolic adverse effects of psychotropic medications in children and adolescents. J Am Acad Child Adolesc Psychiatry 2006; 45: 771-791
    CrossrefPubMedGoogle Scholar
  • 6 De Hert M, Detraux J, van Winkel R. et al. Metabolic and cardiovascular adverse effects associated with antipsychotic drugs. Nat Rev Endocrinol 2011; 8: 114-126
    CrossrefPubMedGoogle Scholar
  • 7 Kryzhanovskaya LA, Xu W, Millen BA. et al. Comparison of long-term (at least 24 weeks) weight gain and metabolic changes between adolescents and adults treated with olanzapine. J Child Adolesc Psychopharmacol 2012; 22: 157-165
    CrossrefPubMedGoogle Scholar
  • 8 Arnold LE. Clinical pharmacological issues in treating psychiatric disorders of patients with mental retardation. Ann Clin Psychiatry 1993; 5: 189-197
    CrossrefPubMedGoogle Scholar
  • 9 European Medicines Agency. Guideline on Good Pharmacovigilance Practices (GVP). 2017
    PubMed
  • 10 Hiemke C, Bergemann N, Clement HW. et al. Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017. Pharmacopsychiatry 2018; 51: 9-62
    Article in Thieme ConnectPubMedGoogle Scholar
  • 11 Gerlach M, Egberts K, Dang SY. et al. Therapeutic drug monitoring as a measure of proactive pharmacovigilance in child and adolescent psychiatry. Expert Opin Drug Saf 2016; 15: 1477-1482
    CrossrefPubMedGoogle Scholar
  • 12 Kloosterboer SM, Vierhout D, Stojanova J. et al. Psychotropic drug concentrations and clinical outcomes in children and adolescents: A systematic review. Expert Opin Drug Saf 2020; 19: 873-890
    CrossrefPubMedGoogle Scholar
  • 13 Egberts K, Fekete S, Hage A. et al. Therapeutic drug monitoring to optimize psychopharmacotherapy in children and adolescents – Update and guidelines for practice. Z Kinder Jugendpsychiatr Psychother 2021; 50: 133-152
    PubMedGoogle Scholar
  • 14 Fekete S, Hiemke C, Gerlach M. Dose-related concentrations of neuroactive/psychoactive drugs expected in blood of children and adolescents. Ther Drug Monit 2020; 42: 315-324
    CrossrefPubMedGoogle Scholar
  • 15 Ulrich S, Baumann B, Wolf R. et al. Therapeutic drug monitoring of clozapine and relapse – a retrospective study of routine clinical data. Int J Clin Pharmacol Ther 2003; 41: 3-13
    CrossrefPubMedGoogle Scholar
  • 16 Gaertner I, Gaertner HJ, Vonthein R. et al. Therapeutic drug monitoring of clozapine in relapse prevention: A five-year prospective study. J Clin Psychopharmacol 2001; 21: 305-310
    CrossrefPubMedGoogle Scholar
  • 17 Fellows L, Ahmad F, Castle DJ. et al. Investigation of target plasma concentration-effect relationships for olanzapine in schizophrenia. Ther Drug Monit 2003; 25: 682-689
    CrossrefPubMedGoogle Scholar
  • 18 Mauri MC, Laini V, Boscati L. et al. Long-term treatment of chronic schizophrenia with risperidone: A study with plasma levels. Eur Psychiatry 2001; 16: 57-63
    CrossrefPubMedGoogle Scholar
  • 19 Mauri MC, Maffini M, Di Pace C. et al. “Long-acting” olanzapine in maintenance therapy of schizophrenia: A study with plasma levels. Int J Psychiatry Clin Pract 2015; 19: 99-105
    CrossrefPubMedGoogle Scholar
  • 20 Simmons SA, Perry PJ, Rickert ED. et al. Cost-benefit analysis of prospective pharmacokinetic dosing of nortriptyline in depressed inpatients. J Affect Disord 1985; 8: 47-53
    CrossrefPubMedGoogle Scholar
  • 21 Lundmark J, Bengtsson F, Nordin C. et al. Therapeutic drug monitoring of selective serotonin reuptake inhibitors influences clinical dosing strategies and reduces drug costs in depressed elderly patients. Acta Psychiatr Scand 2000; 101: 354-359
    CrossrefPubMedGoogle Scholar
  • 22 March JK O, Chrisman A. CAPTN: The Pediatric Adverse Event Rating Scale. In Edited by: Novins DK, DeYoung, eds. The Scientific Proceedings of the 2007 Annual Meeting of the American Academy of Child and Adolescent Psychiatr. 23-28 October 2007. Boston; 2007: 241
    Google Scholar
  • 23 Organization UMCotWH. WHO-UMC-Causality Assessment. 2013 https://www.who.int/publications/m/item/WHO-causality-assessment
    PubMed
  • 24 Schumock GT, Thornton JP. Focusing on the preventability of adverse drug reactions. Hosp Pharm 1992; 27: 538
    PubMedGoogle Scholar
  • 25 Egberts KM, Gerlach M, Correll CU. et al. Serious adverse drug reactions in children and adolescents treated on- and off-label with antidepressants and antipsychotics in clinical practice. Pharmacopsychiatry 2022; DOI: 10.1055/a-1716-1856.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 26 DGKJP, Häßler FC F, Hoffmann K, Irblich D, Mall V, Mendes U, Romanos M, Voß T. S2k Praxisleitlinie Intelligenzminderung. 2021
    PubMed
  • 27 Sporn AL, Vermani A, Greenstein DK. et al. Clozapine treatment of childhood-onset schizophrenia: Evaluation of effectiveness, adverse effects, and long-term outcome. J Am Acad Child Adolesc Psychiatry 2007; 46: 1349-1356
    CrossrefPubMedGoogle Scholar
  • 28 Wohkittel C, Gerlach M, Taurines R. et al. Relationship between clozapine dose, serum concentration, and clinical outcome in children and adolescents in clinical practice. J Neural Transm (Vienna) 2016; 123: 1021-1031
    CrossrefPubMedGoogle Scholar
  • 29 Morselli PL, Bianchetti G, Durand G. et al. Haloperidol plasma level monitoring in pediatric patients. Ther Drug Monit 1979; 1: 35-46
    CrossrefPubMedGoogle Scholar
  • 30 Alfaro CL, Wudarsky M, Nicolson R. et al. Correlation of antipsychotic and prolactin concentrations in children and adolescents acutely treated with haloperidol, clozapine, or olanzapine. J Child Adolesc Psychopharmacol 2002; 12: 83-91
    CrossrefPubMedGoogle Scholar
  • 31 Migliardi G, Spina E, D’Arrigo C. et al. Short- and long-term effects on prolactin of risperidone and olanzapine treatments in children and adolescents. Prog Neuropsychopharmacol Biol Psychiatry 2009; 33: 1496-1501
    CrossrefPubMedGoogle Scholar
  • 32 Kloosterboer SM, de Winter BCM, Reichart CG. et al. Risperidone plasma concentrations are associated with side effects and effectiveness in children and adolescents with autism spectrum disorder. Br J Clin Pharmacol 2021; 87: 1069-1081
    CrossrefPubMedGoogle Scholar
  • 33 Taurines R, Fekete S, Preuss-Wiedenhoff A. et al. Therapeutic drug monitoring in children and adolescents with schizophrenia and other psychotic disorders using risperidone. J Neural Transm (Vienna) 2022; 129: 689-701
    CrossrefPubMedGoogle Scholar
  • 34 Sallee FR, Gilbert DL, Vinks AA. et al. Pharmacodynamics of ziprasidone in children and adolescents: Impact on dopamine transmission. J Am Acad Child Adolesc Psychiatry 2003; 42: 902-907
    CrossrefPubMedGoogle Scholar
  • 35 Fekete S, Egberts K, Preissler T. et al. Estimation of a preliminary therapeutic reference range for children and adolescents with tic disorders treated with tiapride. Eur J Clin Pharmacol 2021; 77: 163-170
    CrossrefPubMedGoogle Scholar
  • 36 Klampfl K, Taurines R, Preuss A. et al. Serum concentrations, therapeutic response and side effects in children and adolescents with impulsive-aggressive symptoms during risperidone therapy. Pharmacopsychiatry 2010; 43: 58-65
    Article in Thieme ConnectPubMedGoogle Scholar
  • 37 Kloosterboer SM, Egberts KM, de Winter BCM. et al. Pipamperone population pharmacokinetics related to effectiveness and side effects in children and adolescents. Clin Pharmacokinet 2020; 59: 1393-1405
    CrossrefPubMedGoogle Scholar
  • 38 Hiemke C, Haen E, Paulzen M. et al. Heidelberg: Springer-Verlag GmbH; 2022. www.psiac.de
  • 39 Ostad Haji E, Mann K, Dragicevic A. et al. Potential cost-effectiveness of therapeutic drug monitoring for depressed patients treated with citalopram. Ther Drug Monit 2013; 35: 396-401
    CrossrefPubMedGoogle Scholar