An International Adult Guideline for Making Clozapine Titration Safer by Using Six Ancestry-Based Personalized Dosing Titrations, CRP, and Clozapine Levels

de Leon J 1 , Schoretsanitis G 2 , Smith RL 3 , Molden E 3 , Solismaa A 4 , Seppälä N 5 Show all authors , Kopeček M 6 , Švancer P 6 , Olmos I 7 , Ricciardi C 8 , Iglesias-Garcia C 9 , Iglesias-Alonso A 10 , Spina E 11 , Ruan CJ 12 , Wang CY 13 , Wang G 13 , Tang YL 14 , Lin SK 15 , Lane HY 16 , Kim YS 17 , Kim SH 18 , Rajkumar AP 19 , González-Esquivel DF 20 , Jung-Cook H 20 , Baptista T 21 , Rohde C 22 , Nielsen J 23 , Verdoux H 24 , Quiles C 24 , Sanz EJ 25 , De Las Cuevas C 26 , Cohen D 27 , Schulte PFJ 27 , Ertuğrul A 28 , Anıl Yağcıoğlu AE 28 , Chopra N 29 , McCollum B 30 , Shelton C 31 , Cotes RO 14 , Kaithi AR 32 , Kane JM 33 , Farooq S 34 , Ng CH 35 , Bilbily J 36 , Hiemke C 37 , López-Jaramillo C 38 , McGrane I 39 , Lana F 40 , Eap CB 41 , Arrojo-Romero M 42 , Rădulescu FŞ 43 , Seifritz E 2 , Every-Palmer S 44 , Bousman CA 45 , Bebawi E 46 , Bhattacharya R 47 , Kelly DL 48 , Otsuka Y 49 , Lazary J 50 , Torres R 51 , Yecora A 52 , Motuca M 53 , Chan SKW 54 , Zolezzi M 55 , Ouanes S 56 , De Berardis D 57 , Grover S 58 , Procyshyn RM 59 , Adebayo RA 60 , Kirilochev OO 61 , Soloviev A 62 , Fountoulakis KN 63 , Wilkowska A 64 , Cubała WJ 64 , Ayub M 65 , Silva A 66 , Bonelli RM 67 , Villagrán-Moreno JM 68 , Crespo-Facorro B 69 , Temmingh H 70 , Decloedt E 71 , Pedro MR 72 , Takeuchi H 73 , Tsukahara M 74 , Gründer G 75 , Sagud M 76 , Celofiga A 77 , Ignjatovic Ristic D 78 , Ortiz BB 79 , Elkis H 80 , Pacheco Palha AJ 81 , LLerena A 82 , Fernandez-Egea E 83 , Siskind D 84 , Weizman A 85 , Masmoudi R 86 , Mohd Saffian S 87 , Leung JG 88 , Buckley PF 89 , Marder SR 90 , Citrome L 91 , Freudenreich O 92 , Correll CU 33 , Müller DJ 29

Affiliations 

  • 1 Mental Health Research Center, Eastern State Hospital, Lexington, KY, USA
  • 2 Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zürich, Zürich, Switzerland
  • 3 Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway
  • 4 Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
  • 5 Department of Psychiatry, Satasairaala, Finland
  • 6 National Institute of Mental Health, Klecany, Czech Republic
  • 7 Clinical Pharmacology Unit and Pharmacy Department, Vilardebó Hospital, Administración de Servicios de Salud, Montevideo, Uruguay
  • 8 Clinical Pharmacology Unit and Outpatient Clinic, Vilardebó Hospital, Administración de Servicios de Salud, Montevideo, Uruguay
  • 9 Universidad de Oviedo. CIBERSAM. INEUROPA. ISPA-FIMBA, Oviedo, Spain
  • 10 Hospital Universitario Central de Asturias, Oviedo, Spain
  • 11 Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
  • 12 Laboratory of Clinical Psychopharmacology, Beijing Anding Hospital, Capital Medical University, Beijing, China
  • 13 The National Clinical Research Centre for Mental Disorders & Beijing Key Lab of Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, China
  • 14 Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia, USA
  • 15 Department of Psychiatry, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
  • 16 Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
  • 17 Department of Neuropsychiatry, Nowon Eulji Medical Center, Eulji University, School of Medicine, Seoul, Korea
  • 18 Department of Psychiatry, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
  • 19 Department of Psychiatry, Christian Medical College, Vellore, India
  • 20 Instituto Nacional de Neurología y Neurocirugía, México City, México
  • 21 Department of Physiology, Los Andes University Medical School, Mérida, Venezuela
  • 22 Department of Affective Disorders, Aarhus University Hospital - Psychiatry, Aarhus, Denmark
  • 23 Mental Health Centre Glostrup, Copenhagen University Hospital, Copenhagen, Denmark
  • 24 Univ. Bordeaux, Inserm, Bordeaux Population Health Research Center, Team Pharmacoepidemiology, UMR 1219, F-33000 Bordeaux, France
  • 25 Department of Physical Medicine and Pharmacology, School of Medicine, Universidad de La Laguna, Canary Islands, Spain
  • 26 Department of Internal Medicine, Dermatology and Psychiatry, School of Medicine, and Instituto Universitario de Neurociencia (IUNE), University of La Laguna, Canary Islands, Spain
  • 27 Dutch Clozapine Collaboration Group, Castricum, The Netherlands
  • 28 Department of Psychiatry, Hacettepe University Faculty of Medicine, Ankara, Turkey
  • 29 Addictions Division, Centre for Addiction and Mental Health, Toronto, Canada
  • 30 Eastern State Hospital, Lexington, Kentucky, USA
  • 31 Department of Psychiatry, University of Kentucky, Lexington, KY, USA
  • 32 Hazelwood Center, Louisville, Kentucky, USA
  • 33 The Zucker Hillside Hospital, Psychiatry Research, Northwell Health, Glen Oaks, New York, USA
  • 34 School of Medicine, Keele University, Staffordshire, and Midlands Partnership NHS Foundation Trust, Staffordshire, United Kingdom
  • 35 Department of Psychiatry, The University of Melbourne, Melbourne, Victoria, Australia
  • 36 Department of Psychiatry, Washington University in St. Louis, St. Louis, Missouri, USA
  • 37 Department of Psychiatry and Psychotherapy, University Medical Center of Mainz, Germany
  • 38 Grupo de Investigación en Psiquiatría GIPSI, Departamento de Psiquiatría, Facultad de Medicina, Universidad de Antioquia, Medellin, Colombia
  • 39 Department of Pharmacy Practice, University of Montana, Missoula, USA
  • 40 Institute of Neuropsychiatry and Addictions (INAD), Parc de Salut Mar, Barcelona, Spain
  • 41 Unit of Pharmacogenetics and Clinical Psychopharmacology, Center for Psychiatric Neurosciences, Lausanne University Hospital and University of Lausanne, Switzerland
  • 42 Department of Psychiatry, Complejo Hospitalario Universitario de Santiago, Santiago de Compostela, Spain
  • 43 Center for Drug Sciences, Faculty of Pharmacy, University of Medicine and Pharmacy Carol Davila, Bucharest, Romania
  • 44 Te Korowai Whāriki Central Regional Forensic Service, Capital and Coast District Health Board, Wellington, New Zealand
  • 45 Departments of Medical Genetics, Psychiatry, Physiology & Pharmacology, and Community Health Sciences University of Calgary, Alberta, Canada
  • 46 Faculty of Medicine, University of Montreal, Montreal, Canada
  • 47 East London NHS Foundation Trust, London, United Kingdom
  • 48 Department of Psychiatry, School of Medicine, Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, Maryland, USA
  • 49 Department of Psychiatry, Asahi General Hospital, Chiba, Japan
  • 50 National Institute of Mental Health, Neurology and Neurosurgery, Budapest, Hungary
  • 51 Department of Psychiatry, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
  • 52 Secretaría de Salud Mental y Adicciones, Ministerio de Salud de la Provincia de Jujuy, San Salvador de Jujuy, Argentina
  • 53 Instituto Vilapriño, Center for Studies, Assistance and Research in Neurosciences, Mendoza, Argentina
  • 54 Department of Psychiatry, LSK Faculty of Medicine, The University of Hong Kong, Hong Kong SAR
  • 55 College of Pharmacy, QU Health, Qatar University, Doha, Qatar
  • 56 Department of Psychiatry, Hamad Medical Corporation, Doha, Qatar
  • 57 NHS, Department of Mental Health, "G. Mazzini" Hospital, Teramo, Italy
  • 58 Department of Psychiatry, Post Graduate Institute of Medical Education and Research, Chandigarh, India
  • 59 British Columbia Mental Health and Substance Use Research Institute, Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada
  • 60 Federal Neuropsychiatric Hospital Yaba, Lagos, Nigeria
  • 61 Department of Clinical Pharmacology, Astrakhan State Medical University, Astrakhan, Russian Federation
  • 62 Department of Psychiatry and Clinical Psychology, Northern State Medical University, Arkhangelsk, Russia
  • 63 3rd Department of Psychiatry, Division of Neurosciences, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Greece
  • 64 Department of Psychiatry, Medical University of Gdańsk, Gdańsk, Poland
  • 65 Department of Psychiatry, Queens University, Kingston, Canada
  • 66 Psychiatry Department, Centro Hospitalar Universitário de S. João, Porto, Portugal
  • 67  Sigmund Freud University, Vienna, Austria
  • 68  Department of Neurosciences, Jerez University Hospital, Andalusian Health Service, University of Cadiz, Jerez, Spain
  • 69  Department of Psychiatry, School of Medicine, University Hospital Virgen del Rocio-IBIS, Sevilla, Spain
  • 70 Department of Psychiatry and Mental Health, University of Cape Town, Valkenberg Hospital, Western Cape, Cape Town, South Africa
  • 71 Division of Clinical Pharmacology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
  • 72 Hospital Central de Maputo, Maputo, Mozambique
  • 73 Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan
  • 74 Department of Psychiatry, Okayama Psychiatric Medical Center, Okayama, Japan
  • 75 Central Institute of Mental Health, Department of Molecular Neuroimaging, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
  • 76 Department of Psychiatry, School of Medicine, University of Zagreb, Zagreb, Croatia
  • 77 Department of Psychiatry, University Medical Centre Maribor, Maribor, Slovenia
  • 78 University of Kragujevac, Faculty of Medical Sciences, Department of Psychiatry, Kragujevac, Serbia
  • 79 Group of Resistant Schizophrenia (GER), Schizophrenia Program (Proesq), Federal University of Sao Paulo, SP, Brazil
  • 80 Department and Institute of Psychiatry, University of São Paulo Medical School (FMUSP), Sao Paulo, Brazil
  • 81 Department and Institute of Psychiatry and Mental Health, Oporto Faculty of Medicine, Oporto, Portugal
  • 82 INUBE Biosanitary Research Institute of Extremadura. Extremadura University Hospital and Medical School, Badajoz, Spain
  • 83 Cambridge Psychosis Centre, Cambrigeshire and Peterborough NHS Foundation Trust & Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom
  • 84 Metro South Addiction and Mental Health Service, Brisbane, Australia
  • 85 Research Unit, Geha Mental Health Center and Molecular Psychiatry Laboratory, Felsenstein Medical Research Center, Tel Aviv, Israel
  • 86 Psychiatry "A" Department, Hedi Chaker University Hospital, Sfax, Tunisia
  • 87 Centre for Quality Management of Medicines, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
  • 88 Department of Pharmacy, Mayo Clinic, Rochester, MN, USA
  • 89 School of Medicine, Virginia Commonwealth University, Richmond, VA, USA
  • 90 Semel Institute for Neuroscience at UCLA, Los Angeles, CA, USA
  • 91 New York Medical College, Department of Psychiatry and Behavioral Sciences, Valhalla, NY, USA
  • 92 Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
Pharmacopsychiatry, 2021 Dec 15.
PMID: 34911124 DOI: 10.1055/a-1625-6388

Abstract

This international guideline proposes improving clozapine package inserts worldwide by using ancestry-based dosing and titration. Adverse drug reaction (ADR) databases suggest that clozapine is the third most toxic drug in the United States (US), and it produces four times higher worldwide pneumonia mortality than that by agranulocytosis or myocarditis. For trough steady-state clozapine serum concentrations, the therapeutic reference range is narrow, from 350 to 600 ng/mL with the potential for toxicity and ADRs as concentrations increase. Clozapine is mainly metabolized by CYP1A2 (female non-smokers, the lowest dose; male smokers, the highest dose). Poor metabolizer status through phenotypic conversion is associated with co-prescription of inhibitors (including oral contraceptives and valproate), obesity, or inflammation with C-reactive protein (CRP) elevations. The Asian population (Pakistan to Japan) or the Americas' original inhabitants have lower CYP1A2 activity and require lower clozapine doses to reach concentrations of 350 ng/mL. In the US, daily doses of 300-600 mg/day are recommended. Slow personalized titration may prevent early ADRs (including syncope, myocarditis, and pneumonia). This guideline defines six personalized titration schedules for inpatients: 1) ancestry from Asia or the original people from the Americas with lower metabolism (obesity or valproate) needing minimum therapeutic dosages of 75-150 mg/day, 2) ancestry from Asia or the original people from the Americas with average metabolism needing 175-300 mg/day, 3) European/Western Asian ancestry with lower metabolism (obesity or valproate) needing 100-200 mg/day, 4) European/Western Asian ancestry with average metabolism needing 250-400 mg/day, 5) in the US with ancestries other than from Asia or the original people from the Americas with lower clozapine metabolism (obesity or valproate) needing 150-300 mg/day, and 6) in the US with ancestries other than from Asia or the original people from the Americas with average clozapine metabolism needing 300-600 mg/day. Baseline and weekly CRP monitoring for at least four weeks is required to identify any inflammation, including inflammation secondary to clozapine rapid titration.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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