Clozapine ultrarapid metabolism during weak induction probably exists but requires careful diagnosis. A literature review, five new cases and a proposed definition

Georgios Schoretsanitis, A. Elif Anıl Yağcıoğlu, Can Jun Ruan, Chin B. Eap, Espen Molden, Trino Baptista, Scott R. Clark, Emilio Fernandez-Egea, Se Hyun Kim, Hsien Yuan Lane, Jonathan Leung, Olalla Maroñas Amigo, Mariano Motuca, Ismael Olmos, Susanna Every-Palmer, Ric M. Procyshyn, Christopher Rohde, Suhas Satish, Peter F.J. Schulte, Edoardo SpinaHiroyoshi Takeuchi, Hélène Verdoux, Christoph U. Correll, Jose de Leon

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

During weak induction (from smoking and/or valproate co-prescription), clozapine ultrarapid metabolizers (UMs) need very high daily doses to reach the minimum therapeutic concentration of 350 ng/ml in plasma; clozapine UMs need clozapine doses higher than: 1) 900 mg/day in patients of European/African ancestry, or 2) 600 mg/day in those of Asian ancestry. Published clozapine UMs include 10 males of European/African ancestry, mainly assessed with single concentrations. Five new clozapine UMs (two of European and three of Asian ancestry) with repeated assessments are described. A US double-blind randomized trial included a 32-year-old male smoking two packages/day with a minimum therapeutic dose of 1,591 mg/day from a single TDM during open treatment of 900 mg/day. In a Turkish inpatient study, a 30-year-old male smoker was a possible clozapine UM needing a minimum therapeutic dose of 1,029 mg/day estimated from two trough steady-state concentrations on 600 mg/day. In a Chinese study, three possible clozapine UMs (all male smokers) were identified. The clozapine minimum therapeutic dose estimated with trough steady-state concentrations >150 ng/ml was: 1) 625 mg/day, based on a mean of 20 concentrations in Case 3; 2) 673 mg/day, based on a mean of 4 concentrations in Case 4; and 3) 648 mg/day, based on a mean of 11 concentrations in Case 5. Based on these limited studies, clozapine UMs during weak induction may account for 1-2% of clozapine-treated patients of European ancestry and <1% of those of Asian ancestry. A clozapine-to-norclozapine ratio <0.5 should not be used to identify clozapine UMs.

Original languageEnglish
JournalSchizophrenia Research
DOIs
StateAccepted/In press - 2023

Bibliographical note

Publisher Copyright:
© 2023 Elsevier B.V.

Keywords

  • Asian continental ancestry group
  • CYP1A2
  • Clozapine/blood
  • Clozapine/metabolism
  • Clozapine/therapeutic use
  • Smoking

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Biological Psychiatry

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