Exploring the Prevalence of Clozapine Phenotypic Poor Metabolizers in 4 Asian Samples: They Ranged Between 2% and 13%

Can Jun Ruan, Chuan Yue Wang, Yi Lang Tang, Shih Ku Lin, Seung Tae Lee, Kyung Sue Hong, Anto P. Rajkumar, Kuruthukulangara S. Jacob, Jose De Leon

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

Purpose/Background Clozapine clearance is influenced by sex, smoking status, ethnicity, coprescription of inducers or inhibitors, obesity, and inflammation. In 126 Beijing inpatients, we measured repeated trough steady-state serum concentrations and identified 4% (5/126) who were phenotypical poor metabolizers (PMs); none were ultrarapid metabolizers (UMs). They were defined as being 2 SDs beyond the means of total clozapine concentration/dose ratios stratified by sex and smoking. Using this definition, this study explores the prevalence of PMs and UMs using data from 4 already published Asian samples. Three samples were East Asian (Beijing 2, Taipei, and Seoul); one was from South India (Vellore). Findings/Results The prevalence of phenotypical PMs ranged from 2% to 13%, but inflammation was not excluded. The prevalence was 7% (14/191) for Beijing 2, 11% (8/70) for Taipei, 13% (9/67) for Seoul, and 2% (2/101) for the Vellore sample. Five phenotypic PMs appeared to be associated with extreme obesity. Phenotypic UM prevalence ranged from 0% to 1.6% but may be partly explained by lack of adherence. A Vellore phenotypic UM appeared to be associated with induction through high coffee intake. Implications/Conclusions Approximately 10% of Asians may be clozapine PMs and may need only 50 to 150 mg/d to get therapeutic concentrations. Future studies combining gene sequencing for new alleles with repeated concentrations and careful control of confounders including inhibitors, inflammation, and obesity should provide better estimations of the prevalence of phenotypic clozapine PMs across races. Clozapine UM studies require excluding potent inducers, careful supervision of compliance in inpatient settings, and multiple serum concentrations.

Original languageEnglish
Pages (from-to)644-648
Number of pages5
JournalJournal of Clinical Psychopharmacology
Volume39
Issue number6
DOIs
StatePublished - Nov 1 2019

Bibliographical note

Funding Information:
Purpose/Background: Clozapine clearance is influenced by sex, smoking status, ethnicity, coprescription of inducers or inhibitors, obesity, and inflammation. In 126 Beijing inpatients, we measured repeated trough steady-state serum concentrations and identified 4% (5/126) who were phenotypical poor metabolizers (PMs); none were ultrarapid metabolizers (UMs). They were defined as being 2 SDs beyond the means of total clozapine concentration/dose ratios stratified by sex and smoking. Using this definition, this study explores the prevalence of PMs and UMs using data from 4 already published Asian samples. Three samples were East Asian (Beijing 2, Taipei, and Seoul); one was from South India (Vellore). Findings/Results: The prevalence of phenotypical PMs ranged from 2% to 13%, but inflammation was not excluded. The prevalence was 7% (14/191) for Beijing 2, 11% (8/70) for Taipei, 13% (9/67) for Seoul, and 2% (2/101) for the Vellore sample. Five phenotypic PMs appeared to be associated with extreme obesity. Phenotypic UM prevalence ranged from 0% to 1.6% but may be partly explained by lack of adherence. A From the *Laboratory of Clinical Psychopharmacology, The National Clinical Research Centre for Mental Disorders, Beijing Key Laboratory of Mental Disorders; and †Department of Psychiatry, The National Clinical Research Centre for Mental Disorders, Beijing Key Laboratory of Mental Disorders, Beijing Institute for Brain Disorders Center of Schizophrenia, Beijing Anding Hospital, Capital Medical University, Beijing, China; ‡Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta; and Substance Abuse Treatment Program, Atlanta VA Medical Center, Decatur, GA; §Department of General Psychiatry, Taipei City, Psychiatric Center; and Department of Psychiatry, School of Medicine, Taipei Medical University, Taipei, Taiwan; ||Department of Laboratory Medicine, Yonsei University College of Medicine; and ¶Department of Psychiatry, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Korea; #Department of Psychiatry, Christian Medical College, Vellore, India; **Department of Old Age Psychiatry, Institute of Psychiatry, Psychology, & Neuroscience, King's College London, London; and Institute of Mental Health, Jubilee Campus, University of Nottingham, Triumph Road, Nottingham, United Kingdom; and ††Mental Health Research Center, Eastern State Hospital, Lexington, KY; and Psychiatry and Neurosciences Research Group (CTS-549), Institute of Neurosciences, University of Granada, Granada; and Biomedical Research Centre in Mental Health Net (CIBERSAM), Santiago Apóstol Hospital, University of the Basque Country, Vitoria, Spain. Received June 14, 2019; accepted after revision August 21, 2019. Reprints: Jose de Leon, MD, Room 3A15A, Mental Health Research Center, Eastern State Hospital, 1350 Bull Lea Rd, Lexington, KY 40511 (e‐mail: jdeleon@uky.edu). C.-J.R. is supported by a grant to the Beijing Anding Hospital (Beijing Science and Technology Plan Project Z171100001017074). The study at Vellore was supported by Christian Medical College, Vellore, India (fluid research grant no. 22X356 to A.P.R.). See other three original articles for the support that led to completion and publication of the Beijing 2, Taipei, and Seoul studies. Supplemental digital content is available for this article. Direct URL citation appears in the printed text and is provided in the HTML and PDF versions of this article on the journal’s Web site (www.psychopharmacology.com). Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0271-0749 DOI: 10.1097/JCP.0000000000001125 Vellore phenotypic UM appeared to be associated with induction through high coffee intake. Implications/Conclusions: Approximately 10% of Asians may be clozapine PMs and may need only 50 to 150 mg/d to get therapeutic concentrations. Future studies combining gene sequencing for new alleles with repeated concentrations and careful control of confounders including inhibitors, inflammation, and obesity should provide better estimations of the prevalence of phenotypic clozapine PMs across races. Clozapine UM studies require excluding potent inducers, careful supervision of compliance in inpatient settings, and multiple serum concentrations.

Publisher Copyright:
© 2019 Wolters Kluwer Health, Inc.

Keywords

  • Asian continental ancestry group/genetics
  • CYP1A2
  • India
  • clozapine, blood
  • clozapine, pharmacokinetics
  • sex
  • smoking

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Pharmacology (medical)

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