Reflections on the Lack of Consideration of Ethnic Ancestry to Stratify Clozapine Dosing

de Leon, Jose

doi:2023.20.3.183

Psychiatry Investig > Volume 20(3); 2023 > Article

Review Article

Psychiatry Investigation 2023;20(3):183-195.
DOI: https://doi.org/10.30773/pi.2022.0293 Published online February 28, 2023.

Reflections on the Lack of Consideration of Ethnic Ancestry to Stratify Clozapine Dosing

Jose de Leon^1,2

^¹Mental Health Research Center, Eastern State Hospital, Lexington, KY, USA
^²Biomedical Research Centre in Mental Health Net (CIBERSAM), Santiago Apostol Hospital, University of the Basque Country, Vitoria, Spain

Correspondence: Jose de Leon ,Tel: +1-859-846-8440, Fax: +1-859-846-8446, Email: jdeleon@uky.edu

Received: October 8, 2022 Revised: December 17, 2022 Accepted: December 26, 2022 Published online: February 28, 2023

Abstract

This review article argues against trusting standard clozapine references, including the US package insert, because they do not include advances in the sciences of pharmacokinetics and pharmacovigilance and ignore the effects of ethnic ancestry on therapeutic dosing. The minimum therapeutic dose leading to the minimum therapeutic concentration of 350 ng/mL in serum/plasma can be used to compare individuals/groups with treatment-resistant schizophrenia. The US clozapine package insert recommends targeting doses of 300– 450 mg/day and, subsequently, increments of up to 100 mg with a maximum dose of 900 mg/day. Ethnic ancestry is defined by DNA ancestry group. Asians (people with ancestry ranging from Pakistan to Japan) and Indigenous Americans are similar in clozapine dosing; their average clozapine minimum therapeutic dose ranged from 166 mg/day (female non-smokers) to 270 mg/day (male smokers). For those with European ancestry, average clozapine minimum therapeutic doses ranged from 236 mg/day (female non-smokers) to 368 mg/day (male smokers). Based on limited studies, Black (African sub-Saharan ancestry) patients may be treated with typical US doses (300–600 mg/day), assuming no poor metabolism (PM) status. Ancestry’s impact on clozapine lethality in four countries is discussed (two countries with highly homogenous populations, Denmark and Japan, and two countries with increasingly heterogenous populations due to immigration, Australia and the UK). An international guideline with 104 authors from 50 countries/regions was recently published, providing 6 personalized clozapine titration schedules for adult inpatients (3 ancestry groups and PM/non-PM schedules) and recommending c-reactive protein monitoring at baseline and weekly for 4 weeks.

Key words Asian continental ancestry group; Clozapine/adverse effects; Clozapine/therapeutic use; CYP1A2; Myocarditis/chemically induced; Mortality/drug effects