Can-Jun Ruan1, Chuan-Yue Wang2, Yi-Lang Tang3, Shih-Ku Lin4, Seung-Tae Lee5, Kyung Sue Hong6, Anto P Rajkumar7,8, Kuruthukulangara S Jacob7, Jose de Leon9. 1. From the Laboratory of Clinical Psychopharmacology, The National Clinical Research Centre for Mental Disorders, Beijing Key Laboratory of Mental Disorders. 2. 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. 3. Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta. 4. Department of General Psychiatry, Taipei City, Psychiatric Center. 5. Department of Laboratory Medicine, Yonsei University College of Medicine. 6. Department of Psychiatry, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Korea. 7. Department of Psychiatry, Christian Medical College, Vellore, India. 8. Department of Old Age Psychiatry, Institute of Psychiatry, Psychology, & Neuroscience, King's College London, London. 9. Mental Health Research Center, Eastern State Hospital, Lexington, KY and Psychiatry and Neurosciences Research Group (CTS-549), Institute of Neurosciences, University of Granada, Granada.
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.
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.
Authors: Jose de Leon; Can-Jun Ruan; Georgios Schoretsanitis; Carlos De Las Cuevas Journal: Psychother Psychosom Date: 2020-04-14 Impact factor: 17.659