An International Adult Guideline for Making Clozapine Titration Safer by Using Six Ancestry-Based Personalized Dosing Titrations, CRP, and Clozapine Levels
Authors: de Leon Jose , Schoretsanitis Georgios , Smith Robert L. , Molden Espen , Solismaa Anssi , Seppälä Niko , Kopeček Miloslav , Švancer Patrik , Olmos Ismael , Ricciardi Carina , Iglesias-Garcia Celso , Iglesias-Alonso Ana , Spina Edoardo , Ruan Can-Jun , Wang Chuan-Yue , Wang Gang , Tang Yi-Lang , Lin Shih-Ku , Lane Hsien-Yuan , Kim Yong Sik , Kim Se Hyun , Rajkumar Anto P. , González-Esquivel Dinora F. , Jung-Cook Helgi , Baptista Trino , Rohde Christopher , Nielsen Jimmi , Verdoux Hélène , Quiles Clelia , Sanz Emilio J. , De Las Cuevas Carlos , Cohen Dan , Schulte Peter F.J. , Ertuğrul Aygün , Anıl Yağcıoğlu A. Elif , Chopra Nitin , McCollum Betsy , Shelton Charles , Cotes Robert O. , Kaithi Arun R. , Kane John M. , Farooq Saeed , Ng Chee H. , Bilbily John , Hiemke Christoph , López-Jaramillo Carlos , McGrane Ian , Lana Fernando , Eap Chin B. , Arrojo-Romero Manuel , Rădulescu Flavian Ş. , Seifritz Erich , Every-Palmer Susanna , Bousman Chad A. , Bebawi Emmanuel , Bhattacharya Rahul , Kelly Deanna L. , Otsuka Yuji , Lazary Judit , Torres Rafael , Yecora Agustin , Motuca Mariano , Chan Sherry K.W. , Zolezzi Monica , Ouanes Sami , De Berardis Domenico , Grover Sandeep , Procyshyn Ric M. , Adebayo Richard A. , Kirilochev Oleg O. , Soloviev Andrey , Fountoulakis Konstantinos N. , Wilkowska Alina , Cubała Wiesław J. , Ayub Muhammad , Silva Alzira , Bonelli Raphael M. , Villagrán-Moreno José M. , Crespo-Facorro Benedicto , Temmingh Henk , Decloedt Eric , Pedro Maria R. , Takeuchi Hiroyoshi , Tsukahara Masaru , Gründer Gerhard , Sagud Marina , Celofiga Andreja , Ignjatovic Ristic Dragana , Ortiz Bruno B. , Elkis Helio , Pacheco Palha António J. , LLerena Adrián , Fernandez-Egea Emilio , Siskind Dan , Weizman Abraham , Masmoudi Rim , Mohd Saffian Shamin , Leung Jonathan G. , Buckley Peter F. , Marder Stephen R. , Citrome Leslie , Freudenreich Oliver , Correll Christoph U. , Müller Daniel J. 
Published: December 2021

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.