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Psychopharmacology

, Volume 152, Issue 1, pp 80–86 | Cite as

Long-term therapeutic drug monitoring of clozapine and metabolites in psychiatric in- and outpatients

  • Michael Dettling
  • Christoph Sachse
  • Jürgen Brockmöller
  • Jürgen Schley
  • Bruno Müller-Oerlinghausen
  • Ines Pickersgill
  • Arndt Rolfs
  • Rainer T. Schaub
  • Jürgen Schmider
Original Investigation

Abstract.

Rationale: Clozapine is a unique antipsychotic drug, outstanding for its lack of extrapyramidal side-effects and its superior efficacy in refractory schizophrenia. However, an unambiguous concentration-response relationship has not yet been established. Objective: We investigated serum concentrations of clozapine, norclozapine and clozapine-N-oxide in psychiatric in- and outpatients to identify particular metabolic patterns in clozapine responders and non-responders and putative threshold levels for clozapine response. Methods: Psychiatric assessments, CYP2D6 genotype, and weekly serum concentrations of clozapine, norclozapine and clozapine-N-oxide were obtained in 34 adult schizophrenic in-and outpatients (18 men, 16 women) during 10 weeks of clozapine treatment with a naturalistic dose design. Results: Responders (n=21) displayed significantly lower serum concentrations of clozapine corrected for dose compared to non-responders (n=13; P<0.05), while none of the other parameters (absolute clozapine concentration, metabolite ratios, gender) were different. Smokers had significantly lower dose-corrected clozapine concentrations. A positive correlation was observed between age and average steady state clozapine concentrations. Conclusions: These findings indicate a possible link between CYP activity and response to clozapine that is not mediated through differences in serum concentrations. No clinically meaningful pattern in serum parameters could be identified that differentiates responders from non-responders. Thus, clozapine TDM seems ineffective for predicting clinical response. Smoking behavior is a major determinant of clozapine clearance while CYP2D6 genotype does not impact clozapine disposition.

Clozapine TDM Metabolite ratio 

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Copyright information

© Springer-Verlag 2000

Authors and Affiliations

  • Michael Dettling
    • 1
  • Christoph Sachse
    • 3
  • Jürgen Brockmöller
    • 3
  • Jürgen Schley
    • 2
  • Bruno Müller-Oerlinghausen
    • 2
  • Ines Pickersgill
    • 2
  • Arndt Rolfs
    • 4
  • Rainer T. Schaub
    • 5
  • Jürgen Schmider
    • 3
  1. 1.Department of Psychiatry, University Clinic Charité, Humboldt University, Schumannstr. 20/21, 10117 BerlinGermany
  2. 2.Department of Psychiatry, University Clinic Benjamin Franklin, Freie Universität, BerlinGermany
  3. 3.Institute for Clinical Pharmacology, Charité, Humboldt Universität, BerlinGermany
  4. 4.Department of Neurology, University Clinic RostockGermany
  5. 5.Department of Psychiatry, University Clinic GreifswaldGermany

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