Promoting safer clozapine dosing in the Americas

Leon, José de; Baptista, Trino; Motuca, Mariano; Ruan, Changgeng; Schoretsanitis, Georgios; Cuevas, Carlos De las

doi:10.47626/1516-4446-2021-0041

Cited by 3 publications

(5 citation statements)

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“…The original inhabitants of the Americas are descendants of East Asians and, therefore, for clozapine metabolism, they behave like the patients with Asian ancestry 71 . Countries in Latin America have populations of very mixed ancestry 72 . Different countries have different percentages of patients with predominant ancestry from the Americas, Europe, or Africa and different levels of mixed ancestry 72 .…”

Section: Discussionmentioning

confidence: 99%

“…Countries in Latin America have populations of very mixed ancestry 72 . Different countries have different percentages of patients with predominant ancestry from the Americas, Europe, or Africa and different levels of mixed ancestry 72 . Recently, Baptista et al 73 reviewed all published clozapine research in South America and only found a myocarditis study from Venezuela, which was published in English and Spanish 74 and 3 case reports from other countries published in languages other than English 73 .…”

Section: Discussionmentioning

confidence: 99%

“…72 Different countries have different percentages of patients with predominant ancestry from the Americas, Europe, or Africa and different levels of mixed ancestry. 72 Recently, Baptista et al 73 reviewed all published clozapine research in South America and only found a myocarditis study from Venezuela, which was published in English and Spanish 74 and 3 case reports from other countries published in languages other than English. 73 A search of the international pharmacovigilance database for clozapine ADRs through January 15, 2021, identified only two myocarditis cases from Latin American countries, both from Venezuela.…”

Section: Clozapine-associated Myocarditis In Latin Americamentioning

confidence: 99%

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Can slow personalized titration using C-Reactive Protein monitoring decrease the high rates and mortality of clozapine-associated myocarditis seen in some countries? A call for research

de Leon

2024

J Clin Psychopharmacol

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Purpose/Background The hypothesis that slower personalized titration may prevent clozapine-associated myocarditis and decrease the disproportion incidence of 3% found in Australia was not described in a recent Australian article in this journal. Methods Six countries in addition to Australia have published information suggesting a similar incidence of clozapine-associated myocarditis. On September 19, 2023, PubMed searches were updated for articles from the United States, Korea, Japan, Canada, New Zealand, and Turkey. Findings/Results An incidence of 3.5% (4/76) was found in a US hospital, but US experts were the first to propose that clozapine-associated myocarditis may be a hypersensitivity reaction associated with rapid titration and possibly preventable. Koreans and Japanese are of Asian ancestry and need lower minimum therapeutic doses for clozapine than patients of European ancestry. A 0.1% (2/1408) incidence of myocarditis during clozapine titration was found in a Korean hospital, but pneumonia incidence was 3.7% (52/1408). In 7 Japanese hospitals, 34% (37/110) of cases of clozapine-associated inflammation were found during faster titrations (based on the official Japanese titration) versus 13% (17/131) during slower titrations (based on the international titration guideline for average Asian patients). Recent limited studies from Canada, New Zealand, and Turkey suggest that slower personalized titration considering ancestry may help prevent clozapine-associated myocarditis. Implications/Conclusions Other countries have very limited published data on clozapine-associated myocarditis. Based on a recent Australian case series and these non-Australian studies, the author proposes that Australia (and other countries) should use slow personalized titration for clozapine based on ancestry and c-reactive protein monitoring.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Clozapine-associated Myocarditis In Latin Americamentioning

confidence: 99%

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Can slow personalized titration using C-Reactive Protein monitoring decrease the high rates and mortality of clozapine-associated myocarditis seen in some countries? A call for research

de Leon

2024

J Clin Psychopharmacol

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“…Clarifications for patients of mixed ancestry have also been suggested. 31 The international guideline is being translated into Chinese, Croatian, Korean, Japanese, Russian, and Spanish and being disseminated in summary articles in psychiatric journals of national distribution across multiple countries/regions. 3,21,31,70,76,100,141,[173][174][175]…”

Section: Update Of the International Titration Guidelinementioning

confidence: 99%

“…• Individuals or groups can be compared using their minimum clozapine therapeutic dose. 27,28 Definition of clozapine PM • A clozapine PM needs approximately half of the minimum therapeutic dose compared with their ancestry group and sex-smoking subgroup, the doses range from: [29][30][31] -75 (♀ non-smokers) to 150 mg/day (♂ smokers) in patients of Asian ancestry, and -75 (♀ non-smokers) to 200 mg/day (♂ smokers) in patients of European ancestry. 31 Limited a knowledge 30 of clozapine genetic and non-genetic PMs…”

Section: Supplementary Table 1 the Need For An Open-minded Readermentioning

confidence: 99%

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

León

2023

Psychiatry Investig

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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.

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Clozapine-induced myocarditis in children and adolescents: a pharmacovigilance study using VigiBase and a systematic literature review

Cuevas

Arrojo-Romero

Ruan

et al. 2022

Expert Opinion on Drug Metabolism & Toxicology

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Promoting safer clozapine dosing in the Americas

Cited by 3 publications

References 5 publications

Can slow personalized titration using C-Reactive Protein monitoring decrease the high rates and mortality of clozapine-associated myocarditis seen in some countries? A call for research

Can slow personalized titration using C-Reactive Protein monitoring decrease the high rates and mortality of clozapine-associated myocarditis seen in some countries? A call for research

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

Clozapine-induced myocarditis in children and adolescents: a pharmacovigilance study using VigiBase and a systematic literature review

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