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Relationship between clozapine dose, serum concentration, and clinical outcome in children and adolescents in clinical practice

  • Psychiatry and Preclinical Psychiatric Studies - Original Article
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Abstract

Information on dose- and concentration-related clinical effects of clozapine treatment in children and adolescents is scarce. This study aimed to examine the relationship between dose, serum concentration, and clinical outcome as well as the influencing factors thereof in paediatric patients treated with clozapine. Data from a routine Therapeutic Drug Monitoring (TDM) service between 2004 and 2014 were studied in 68 patients, aged 11–18 years. Severity of illness, therapeutic effectiveness and adverse drug reactions (ADRs) were assessed by standardized means. A relationship between the daily dose (mean 319 mg, 4.9 mg/kg) and serum concentration (mean 387 ng/ml) of clozapine was found with the variation in dose explaining 30 % of the variability in clozapine serum concentrations. Also gender contributed to the variability, however, no influence of age or concomitant medications was detected. Furthermore, a significant association was found between clozapine serum concentration and the occurrence of ADRs. Patients without ADRs had a lower mean serum concentration than those with mild (261.4 vs 407.3 ng/ml, P = 0.018) and moderate ADRs (261.4 vs 416.3 ng/ml, P = 0.028). As clozapine was estimated to be effective in lower blood concentrations, guidance on a possibly lower therapeutic range of clozapine serum levels in paediatric patients is provided. With ADRs increasing under higher concentrations, TDM is strongly recommended in paediatric clozapine therapy for individualized dosing. Dose adjustment in females also might be reasonable according to gender-related differences in serum concentrations. However, regarding the limitations of this study results should be validated in larger studies with more standardized designs.

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References

  • Baumann P, Hiemke C, Ulrich S, Eckermann G, Gaertner I, Gerlach M, Kuss H-J, Laux G, Müller-Oerlinghausen B, Rao ML, Riederer P, Zernig G (2004) The AGNP-TDM expert group consensus guidelines: therapeutic drug monitoring in Psychiatry. Pharmacopsychiatry 37:243–265

    Article  CAS  PubMed  Google Scholar 

  • Centorrino F, Baldessarini RJ, Kando J, Frankenburg FR, Volpicelli SA, Puopolo PR, Flood JG (1994) Serum concentrations of clozapine and its major metabolites: effects of cotreatment with fluoxetine or valproate. Am J Psychiatry 151:123–125

    Article  CAS  PubMed  Google Scholar 

  • Couchman L, Morgan PE, Spencer EP, Flanagan RJ (2010) Plasma clozapine, norclozapine and the clozapine/norclozapine ratio in relation to prescribed dose and other factors: data from a therapeutic drug monitoring service, 1993–2007. Ther Drug Monit 32:438–447

    Article  CAS  PubMed  Google Scholar 

  • Couchman L, Bowskill SVJ, Handley S, Patel MX, Flanagan RJ (2013) Plasma clozapine and norclozapine in relation to prescribed dose and other factors in patients aged <18 years: data from a therapeutic drug monitoring service, 1994–2010. Early Interv Psychia 7:122–130

    Article  Google Scholar 

  • Diaz FJ, de Leon J, Josiassen RC, Cooper TB, Simpson GM (2005) Plasma clozapine concentration coefficients of variation in a long-term study. Schizophr Res 72:131–135

    Article  PubMed  Google Scholar 

  • Egberts K, Mehler-Wex C, Gerlach M (2011) Therapeutic drug monitoring in child and adolescent psychiatry. Pharmacopsychiatry 44:249–253

    Article  CAS  PubMed  Google Scholar 

  • Egberts K, Karwautz A, Plener PL, Mehler-Wex C, Kölch M, Dang SY, Taurines R, Romanos M, Gerlach M (2015) Pharmacovigilance in child and adolescent psychiatry. Z Kinder Jugendpsychiatr Psychother 43:21–28

    Article  PubMed  Google Scholar 

  • Eiermann B, Engel G, Johansson I, Zanger UM, Bertilsson L (1997) The involvement of CYP1A2 and 3A4 in the metabolism of clozapine. Br J Clin Pharmacol 44:439–446

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Findling R, Frazier J, Gerbino-Rosen G, Kranzler H, Kumra S, Kratchovil C (2007) Is there a role for clozapine in the treatment of children and adolescents? J Am Acad Child Adolesc Psychiatry 46:423–428

    Article  PubMed  Google Scholar 

  • Fleischhaker C, Heiser P, Hennighausen K, Herpertz-Dahlmann B, Holtkamp K, Mehler-Wex C, Rauh R, Remschmidt H, Schulz E, Warnke A (2008) Weight gain in children and adolescents during 45 weeks treatment with clozapine, olanzapine and risperidone. J Neural Transm 115:1599–1608

    Article  CAS  PubMed  Google Scholar 

  • Frazier JA, Gordon CT, McKenna K, Lenane MC, Jih D, Rapoport JL (1994) An open trial of clozapine in 11 adolescents with childhood-onset schizophrenia. J Am Acad Child Adolesc Psychiatry 33:658–663

    Article  CAS  PubMed  Google Scholar 

  • Frazier JA, Glassner L, Jacobsen L, Grothe D, Flood J, Baldessarini RJ, Piscitelli S, Kim GS, Rapoport JL (2003) Clozapine pharmacokinetics in children and adolescents with childhood-onset schizophrenia. J Clin Psychopharmacol 23:87–91

    Article  CAS  PubMed  Google Scholar 

  • Gerlach M, Greenhill L, Warnke A (2014) Special features of psychopharmacological therapy in children and adolescents. In: Gerlach M, Warnke A, Greenhill L (eds) Psychiatric drugs in children and adolescents. Basic pharmacology and practical applications. Springer, Wien, pp 61–75

    Google Scholar 

  • Guy W (1976) Ecdeu assessment manual. National Institute of Mental Health, Rockville

    Book  Google Scholar 

  • Hiemke C, Baumann P, Bergemann N, Conca A, Dietmaier O, Egberts K, Fric M, Gerlach M, Greiner C, Gründer G, Haen E, Havemann-Reinecke U, Jaquenoud Sirot E, Kirchherr H, Laux G, Lutz UC, Messer T, Müller MJ, Pfuhlmann B, Rambeck B, Riederer P, Schoppek B, Stingl J, Uhr M, Ulrich S, Waschgler R, Zernig G, The TDM group of the AGNP (2011) AGNP consensus guidelines for therapeutic drug monitoring in psychiatry–update 2011. Pharmacopsychiatry 44:195–235

    Article  Google Scholar 

  • Kane J, Honigfeld G, Singer J, Meltzer H (1988) Clozapine for the treatment- resistant schizophrenic. A double- blind comparison with chlorpromazine. Arch Gen Psychiatry 45:789–796

    Article  CAS  PubMed  Google Scholar 

  • Kant R, Chalansani R, Chengappa KN, Dieringer MF (2004) The off-label use of clozapine in adolescents with bipolar disorder, intermittent explosive disorder, or posttraumatic stress disorder. J Child Adolesc Psychopharmacol 14:57–63

    Article  PubMed  Google Scholar 

  • Kirschbaum KM, Finger S, Vogel F, Burger R, Gerlach M, Riederer P, Hiemke Ch (2008) High performance-liquid chromatography with column-switching and spectro-photometric detection for determination of risperidone and 9-hydroxyrisperidone in human serum. Chromatographia 67:321–324

    Article  CAS  Google Scholar 

  • Kumra S, Frazier JA, Jacobsen LK, McKenna K, Gordon CT, Lenane MC, Hamburger SD, Smith AK, Albus KE, Alaghband-Rad J, Rapoport JL (1996) Childhood onset schizophrenia: a double blind clozapine-haloperidol comparison. Arch Gen Psychiatry 53:1090–1097

    Article  CAS  PubMed  Google Scholar 

  • Lane HY, Chang YC, Chang WH, Lin SK, Tseng YT, Jann MW (1999) Effects of gender and age on plasma levels of clozapine and its metabolites: analyzed by critical statistics. J Clin Psychiatry 60:36–40

    Article  CAS  PubMed  Google Scholar 

  • Lingjaerde O, Ahlfors UG, Bech P, Dencker SJ, Elgen K (1987) The UKU side effect rating scale. A new comprehensive rating scale for psychotropic drugs and a cross-sectional study of side effects in neuroleptic-treated patients. Acta Psychiatr Scand 76(Suppl 334):1–100

    Article  Google Scholar 

  • Mehler-Wex C, Kölch M, Kirchheiner J, Antony G, Fegert JM, Gerlach M (2009) The-rapeutic drug monitoring in child and adolescent psychiatry for improved efficacy and safety of psychopharmacology. Child Adolesc Psychiatry Ment Health 3:14. doi:10.1186/1753-200-3-14

    Article  PubMed  PubMed Central  Google Scholar 

  • Novartis Pharma GmbH (2015) Leponex®: Summary of product characteristics

  • Palego L, Biondi L, Giannaccini G, Sarno N, Elmi S, Ciapparelli A, Cassano GB, Lucacchini A, Martini C, Dell’Osso L (2002) Clozapine, norclozapine plasma levels, their sum and ratio in 50 psychotic patients: influence of patient-related variables. Prog Neuropsychopharmacol Biol Psychiatry 26:473–480

    Article  CAS  PubMed  Google Scholar 

  • Perry PJ, Bever KA, Arndt S, Combs MD (1998) Relationship between patient variables and plasma clozapine concentrations: a dosing nomogram. Biol Psychiatry 44:733–738

    Article  CAS  PubMed  Google Scholar 

  • Pickar D, Owen RR, Litman RE, Konicki E, Gutierrez R, Rapaport MH (1992) Clinical and biologic response to clozapine in patients with schizophrenia. Crossover comparison with fluphenazine. Arch Gen Psychiatry 49:345–353

    Article  CAS  PubMed  Google Scholar 

  • Schimmelmann BG, Mehler-Wex C, Wewetzer Ch (2014) Schizophrenia. In: Gerlach M, Warnke A, Greenhill L (eds) Psychiatric drugs in children and adolescents. Basic pharmacology and practical applications. Springer, Wien, pp 499–506

    Google Scholar 

  • Shaw P, Sporn A, Gogtay N, Overman GP, Greenstein D, Gochman P, Tossell JW, Lenane M, Rapoport JL (2006) Childhood-onset schizophrenia: a double-blind, randomized clozapine-olanzapine comparison. Arch Gen Psychiatry 63:721–730

    Article  CAS  PubMed  Google Scholar 

  • Sporn AL, Vermani A, Greenstein DK, Bobb AJ, Spencer EP, Clasen LS, Tossell JW, Stayer CC, Gochman PA, Lenane MC, Rapoport JL, Gogtay N (2007) Clozapine treatment of childhood-onset schizophrenia: evaluation of effectiveness, adverse effects, and long-term outcome. J Am Acad Child Adolesc Psychiatry 46:1349–1356

    Article  PubMed  Google Scholar 

  • Van der Zwaag C, McGee M, McEvoy JP (1996) Response of patients with treatment-refractory schizophrenia to clozapine within three serum level ranges. Am J Psychiatry 153:1579–1584

    Article  Google Scholar 

  • Whitney Z, Boyda HN, Procyshyn RM, Elbe D, Black T, Eslami A, Barr AM (2015) Therapeutic drug levels of second generation antipsychotics in youth: a systematic review. J Child Adolesc Psychopharmacol 25:234–245

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We gratefully acknowledge Dr. Peter Scheuerpflug’s and Prof. Dr. Christoph Hiemke’s support with the data analysis. The participating hospitals are members in the ‘Competence Network on TDM in Child and Adolescent Psychiatry’, which was supported by the German Federal Ministry of Education and Research (BMBF-FKZ: 01EZ0937) as well as by the ‘Society for performing conferences in neuroscience e.V.’ Paulsborner-Strasse 44, 14193 Berlin. The mentioned multicentre pharmacovigilance study (‘TDM-VIGIL’) is established in cooperation with this network and funded by the German Federal Institute for Drugs and Medical Devices (BfArM), Bonn (BfArM-Reference Number: 73.05/3832-397285/12).

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    Authors and Affiliations

    1. Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Centre for Mental Health, University Hospital of Würzburg, Würzburg, Germany

      Christopher Wohkittel, Manfred Gerlach, Regina Taurines, Diana Schreck, Claudia Mehler-Wex, Marcel Romanos & Karin Egberts

    2. Clinics of the City Cologne GmbH, Clinic for Child and Adolescent Psychiatry and Psychotherapy, Cologne, Germany

      Christoph Wewetzer

    3. HEMERA Private Hospital for Mental Health, Adolescents and Young Adults, Bad Kissingen, Germany

      Claudia Mehler-Wex

    4. Department of Child and Adolescent Psychiatry and Psychotherapy, University Hospital of Ulm, Ulm, Germany

      Claudia Mehler-Wex

    5. Department of Psychiatry, Psychosomatics and Psychotherapy, Centre for Mental Health, University Hospital of Würzburg, Würzburg, Germany

      Stefan Unterecker & Rainer Burger

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    1. Christopher Wohkittel
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    Correspondence to Christopher Wohkittel.

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    C. Wohkittel and M. Gerlach contributed equally.

    C. Mehler-Wex was in University Hospital of Ulm, Department of Child and Adolescent Psychiatry and Psychotherapy, Ulm, Germany, between January 2007 and December 2008.

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    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 123, 1021–1031 (2016). https://doi.org/10.1007/s00702-016-1573-y

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    • DOI: https://doi.org/10.1007/s00702-016-1573-y

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