Pharmacopsychiatry 2022; 55(02): 73-86
DOI: 10.1055/a-1625-6388
Review

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

1   Mental Health Research Center, Eastern State Hospital, Lexington, KY, USA
2   Department of Psychiatry, University of Kentucky, Lexington, KY, USA
3   Psychiatry and Neurosciences Research Group (CTS-549), Institute of Neurosciences, University of Granada, Granada, Spain
4   Biomedical Research Centre in Mental Health Net (CIBERSAM), Santiago Apostol Hospital, University of the Basque Country, Vitoria, Spain
,
5   Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zürich, Zürich, Switzerland
6   The Zucker Hillside Hospital, Psychiatry Research, Northwell Health, Glen Oaks, New York, USA
,
7   Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway
,
7   Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway
8   Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, Oslo, Norway
,
9   Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
10   Department of Psychiatry, Tampere University Hospital, Tampere, Finland
,
11   Department of Psychiatry, Satasairaala, Finland
,
12   National Institute of Mental Health, Klecany, Czech Republic
13   Department of Psychiatry, Charles University, Third Faculty of Medicine, Prague, Czech Republic
,
12   National Institute of Mental Health, Klecany, Czech Republic
13   Department of Psychiatry, Charles University, Third Faculty of Medicine, Prague, Czech Republic
,
14   Clinical Pharmacology Unit and Pharmacy Department, Vilardebó Hospital, Administración de Servicios de Salud, Montevideo, Uruguay
,
15   Clinical Pharmacology Unit and Outpatient Clinic, Vilardebó Hospital, Administración de Servicios de Salud, Montevideo, Uruguay
,
16   Universidad de Oviedo. CIBERSAM. INEUROPA. ISPA-FIMBA, Oviedo, Spain
17   Hospital Valle del Nalón, Langreo, Spain
,
18   Hospital Universitario Central de Asturias, Oviedo, Spain
,
19   Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
,
20   Laboratory of Clinical Psychopharmacology, Beijing Anding Hospital, Capital Medical University, Beijing, China
21   The National Clinical Research Centre for Mental Disorders & Beijing Key Lab of Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, China
,
21   The National Clinical Research Centre for Mental Disorders & Beijing Key Lab of Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, China
22   Department of Psychiatry, Beijing Anding Hospital, Capital Medical University, Beijing, China
,
Gang Wang
21   The National Clinical Research Centre for Mental Disorders & Beijing Key Lab of Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, China
,
23   Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia, USA
24   Substance Abuse Treatment Program, Atlanta VA Medical Center, Decatur, Georgia, USA
,
25   Department of Psychiatry, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
26   Department of Psychiatry, School of Medicine, Taipei Medical University, Taipei, Taiwan
,
27   Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
28   Department of Psychiatry and Brain Disease Research Center, China Medical University Hospital, Taichung, Taiwan
29   Department of Psychology, College of Medical and Health Sciences, Asia University, Taichung, Taiwan
,
30   Department of Neuropsychiatry, Nowon Eulji Medical Center, Eulji University, School of Medicine, Seoul, Korea
,
31   Department of Psychiatry, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
,
32   Department of Psychiatry, Christian Medical College, Vellore, India
33   Institute of Mental Health, Jubilee Campus, University of Nottingham, Triumph Road, Nottingham, United Kingdom
,
34   Instituto Nacional de Neurología y Neurocirugía, México City, México
,
34   Instituto Nacional de Neurología y Neurocirugía, México City, México
35   Facultad de Química, Universidad Nacional Autónoma de México (UNAM), México City, México
,
36   Department of Physiology, Los Andes University Medical School, Mérida, Venezuela
,
37   Department of Affective Disorders, Aarhus University Hospital - Psychiatry, Aarhus, Denmark
38   Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
,
39   Mental Health Centre Glostrup, Copenhagen University Hospital, Copenhagen, Denmark
,
40   Univ. Bordeaux, Inserm, Bordeaux Population Health Research Center, Team Pharmacoepidemiology, UMR 1219, F-33000 Bordeaux, France
,
40   Univ. Bordeaux, Inserm, Bordeaux Population Health Research Center, Team Pharmacoepidemiology, UMR 1219, F-33000 Bordeaux, France
,
41   Department of Physical Medicine and Pharmacology, School of Medicine, Universidad de La Laguna, Canary Islands, Spain
42   Hospital Universitario de Canarias, Tenerife, Spain
,
43   Department of Internal Medicine, Dermatology and Psychiatry, School of Medicine, and Instituto Universitario de Neurociencia (IUNE), University of La Laguna, Canary Islands, Spain
,
44   Dutch Clozapine Collaboration Group, Castricum, The Netherlands
45   FACT-team in Heerhugowaard, Department of Severe Mental Illness, Mental Health Services North-Holland North, The Netherlands
,
44   Dutch Clozapine Collaboration Group, Castricum, The Netherlands
46   Mental Health Team Alkmaar, Mental Health Services Noord-Holland-Noord, Alkmaar, The Netherlands
,
47   Department of Psychiatry, Hacettepe University Faculty of Medicine, Ankara, Turkey
,
47   Department of Psychiatry, Hacettepe University Faculty of Medicine, Ankara, Turkey
,
48   Addictions Division, Centre for Addiction and Mental Health, Toronto, Canada
49   Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
,
50   Eastern State Hospital, Lexington, Kentucky, USA
,
2   Department of Psychiatry, University of Kentucky, Lexington, KY, USA
50   Eastern State Hospital, Lexington, Kentucky, USA
,
23   Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia, USA
,
Arun R. Kaithi
51   Hazelwood Center, Louisville, Kentucky, USA
,
6   The Zucker Hillside Hospital, Psychiatry Research, Northwell Health, Glen Oaks, New York, USA
52   Department of Psychiatry and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Hempstead, New York, USA
,
53   School of Medicine, Keele University, Staffordshire, and Midlands Partnership NHS Foundation Trust, Staffordshire, United Kingdom
,
54   Department of Psychiatry, The University of Melbourne, Melbourne, Victoria, Australia
,
55   Department of Psychiatry, Washington University in St. Louis, St. Louis, Missouri, USA
,
56   Department of Psychiatry and Psychotherapy, University Medical Center of Mainz, Germany
,
57   Grupo de Investigación en Psiquiatría GIPSI, Departamento de Psiquiatría, Facultad de Medicina, Universidad de Antioquia, Medellin, Colombia
58   Programa Trastornos del Ánimo, Hospital Universitario San Vicente Fundación, Medellín, Colombia
,
59   Department of Pharmacy Practice, University of Montana, Missoula, USA
,
60   Institute of Neuropsychiatry and Addictions (INAD), Parc de Salut Mar, Barcelona, Spain
61   Department of Psychiatry, Autonomous University of Barcelona, Spain
,
62   Unit of Pharmacogenetics and Clinical Psychopharmacology, Center for Psychiatric Neurosciences, Lausanne University Hospital and University of Lausanne, Switzerland
63   Center for Research and Innovation in Clinical Pharmaceutical Sciences, Lausanne University Hospital and University of Lausanne, Switzerland
64   School of Pharmaceutical Sciences, University of Geneva, Switzerland
65   Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, University of Lausanne, Switzerland
,
Manuel Arrojo-Romero
66   Department of Psychiatry, Complejo Hospitalario Universitario de Santiago, Santiago de Compostela, Spain
,
Flavian Ş. Rădulescu
67   Center for Drug Sciences, Faculty of Pharmacy, University of Medicine and Pharmacy Carol Davila, Bucharest, Romania
,
Erich Seifritz
5   Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zürich, Zürich, Switzerland
,
68   Te Korowai Whāriki Central Regional Forensic Service, Capital and Coast District Health Board, Wellington, New Zealand
69   Department of Psychological Medicine, University of Otago, Wellington, New Zealand
,
70   Departments of Medical Genetics, Psychiatry, Physiology & Pharmacology, and Community Health Sciences University of Calgary, Alberta, Canada
,
71   Faculty of Medicine, University of Montreal, Montreal, Canada
72   Department of Pharmacy, Hôpital du Sacré-Cœur de Montréal, Montreal, Canada
,
73   East London NHS Foundation Trust, London, United Kingdom
74   Honorary Clinical Senior Lecturer, Barts and the London School of Medicine, Queen Mary University of London, United Kingdom
,
75   Department of Psychiatry, School of Medicine, Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, Maryland, USA
,
76   Department of Psychiatry, Asahi General Hospital, Chiba, Japan
,
77   National Institute of Mental Health, Neurology and Neurosurgery, Budapest, Hungary
,
Rafael Torres
78   Department of Psychiatry, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
,
Agustin Yecora
79   Secretaría de Salud Mental y Adicciones, Ministerio de Salud de la Provincia de Jujuy, San Salvador de Jujuy, Argentina
,
80   Instituto Vilapriño, Center for Studies, Assistance and Research in Neurosciences, Mendoza, Argentina
,
81   Department of Psychiatry, LSK Faculty of Medicine, The University of Hong Kong, Hong Kong SAR
82   State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Hong Kong SAR
,
83   College of Pharmacy, QU Health, Qatar University, Doha, Qatar
,
84   Department of Psychiatry, Hamad Medical Corporation, Doha, Qatar
,
85   NHS, Department of Mental Health, “G. Mazzini” Hospital, Teramo, Italy
,
86   Department of Psychiatry, Post Graduate Institute of Medical Education and Research, Chandigarh, India
,
87   British Columbia Mental Health and Substance Use Research Institute, Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada
,
88   Federal Neuropsychiatric Hospital Yaba, Lagos, Nigeria
,
89   Department of Clinical Pharmacology, Astrakhan State Medical University, Astrakhan, Russian Federation
,
90   Department of Psychiatry and Clinical Psychology, Northern State Medical University, Arkhangelsk, Russia
,
91   3rd Department of Psychiatry, Division of Neurosciences, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Greece
,
92   Department of Psychiatry, Medical University of Gdańsk, Gdańsk, Poland
,
92   Department of Psychiatry, Medical University of Gdańsk, Gdańsk, Poland
,
93   Department of Psychiatry, Queens University, Kingston, Canada
,
94   Psychiatry Department, Centro Hospitalar Universitário de S. João, Porto, Portugal
95    Faculdade de Medicina da Universidade do Porto, Porto, Portugal
,
Raphael M. Bonelli
96    Sigmund Freud University, Vienna, Austria
,
97    Department of Neurosciences, Jerez University Hospital, Andalusian Health Service, University of Cadiz, Jerez, Spain
,
98    Department of Psychiatry, School of Medicine, University Hospital Virgen del Rocio-IBIS, Sevilla, Spain
99    Spanish Network for Research in Mental Health (CIBERSAM), Sevilla, Spain
,
100   Department of Psychiatry and Mental Health, University of Cape Town, Valkenberg Hospital, Western Cape, Cape Town, South Africa
,
101   Division of Clinical Pharmacology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
,
102   Hospital Central de Maputo, Maputo, Mozambique
,
103   Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan
,
104   Department of Psychiatry, Okayama Psychiatric Medical Center, Okayama, Japan
,
105   Central Institute of Mental Health, Department of Molecular Neuroimaging, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
,
106   Department of Psychiatry, School of Medicine, University of Zagreb, Zagreb, Croatia
107   Department for Psychiatry and Psychological Medicine, University Hospital Center Zagreb, Croatia
,
108   Department of Psychiatry, University Medical Centre Maribor, Maribor, Slovenia
,
109   University of Kragujevac, Faculty of Medical Sciences, Department of Psychiatry, Kragujevac, Serbia
,
110   Group of Resistant Schizophrenia (GER), Schizophrenia Program (Proesq), Federal University of Sao Paulo, SP, Brazil
,
111   Department and Institute of Psychiatry, University of São Paulo Medical School (FMUSP), Sao Paulo, Brazil
,
112   Department and Institute of Psychiatry and Mental Health, Oporto Faculty of Medicine, Oporto, Portugal
113   Casa de Salidedo Som Jesus (Psychiatric Hospital), Oporto, Portugal
,
114   INUBE Biosanitary Research Institute of Extremadura. Extremadura University Hospital and Medical School, Badajoz, Spain
115   Spanish Network for Research in Mental Health (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain
,
116   Cambridge Psychosis Centre, Cambrigeshire and Peterborough NHS Foundation Trust & Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom
,
117   Metro South Addiction and Mental Health Service, Brisbane, Australia
118   Queensland Centre for Mental Health Research and School of Clinical Medicine, University of Queensland, Brisbane, Australia
,
119   Research Unit, Geha Mental Health Center and Molecular Psychiatry Laboratory, Felsenstein Medical Research Center, Tel Aviv, Israel
120   Department of Psychiatry Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
,
121   Psychiatry “A” Department, Hedi Chaker University Hospital, Sfax, Tunisia
122   Faculty of Medicine, University of Sfax, Sfax, Tunisia
,
123   Centre for Quality Management of Medicines, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
,
124   Department of Pharmacy, Mayo Clinic, Rochester, MN, USA
,
125   School of Medicine, Virginia Commonwealth University, Richmond, VA, USA
,
126   Semel Institute for Neuroscience at UCLA, Los Angeles, CA, USA
127   VA Desert Pacific Mental Illness Research, Education, and Clinical Center, Los Angeles, CA, USA
,
128   New York Medical College, Department of Psychiatry and Behavioral Sciences, Valhalla, NY, USA
,
129   Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
,
6   The Zucker Hillside Hospital, Psychiatry Research, Northwell Health, Glen Oaks, New York, USA
52   Department of Psychiatry and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Hempstead, New York, USA
130   Charité Universitätsmedizin Berlin, Department of Child and Adolescent Psychiatry, Berlin, Germany
,
48   Addictions Division, Centre for Addiction and Mental Health, Toronto, Canada
49   Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
› Author Affiliations
Funding This study article was prepared without any external funding. No commercial organizations had any role in the writing of this paper for publication.

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.

Supplementary Material



Publication History

Received: 10 June 2021
Received: 23 August 2021

Accepted: 23 August 2021

Article published online:
15 December 2021

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