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

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.

Escaping the Long Shadow Cast by Agranulocytosis

“…The initial draft of this article was written by the first author and focused on a VigiBase article by Montastruc et al 13 presenting poor clozapine outcomes in the United Kingdom; other authors helped by proposing ways of looking directly to the UK pharmacovigilance agency on clozapine outcomes, [15][16][17][18] and others insisted on balancing the article by presenting the better clozapine outcomes in the Scandinavian registries. [7][8][9][10][11][12]…”

“…There are 2 major sources of international data on clozapinerelated outcome regarding lethality, the Scandinavian national registries, [7][8][9][10][11][12] and the pharmacovigilance databases [13][14][15][16][17][18] including VigiBase, which receives data from all national agencies. The initial draft of this article was written by the first author and focused on a VigiBase article by Montastruc et al 13 presenting poor clozapine outcomes in the United Kingdom; other authors helped by proposing ways of looking directly to the UK pharmacovigilance agency on clozapine outcomes, [15][16][17][18] and others insisted on balancing the article by presenting the better clozapine outcomes in the Scandinavian registries.…”

“…44 We hope that slower personalized titration with CRP monitoring may decrease clozapine-induced myocarditis and other clozapine-induced inflammations around the world, but even in countries with exemplary low fatal outcomes such as Denmark, there may still be some room for improvement during titrations using slower titrations for PMs, and CRP monitoring may help in preventing aspiration pneumonia and early identifying pneumonia not associated with aspiration. 12 Because it is possible that the UK pharmacovigilance agency has a more sensitive system in picking up clozapine ADRs than in other countries, it may be important that drug regulators from other countries encourage better reporting of clozapine ADRs by patients and healthcare professionals. In that regard, China 38 and Russia 39 are countries with large populations and very frequent use of clozapine, yet send very few reports to VigiBase; prescribers in these countries may be ignoring major clozapine ADRs including myocarditis.…”

“…Whereas Leung et al 4 offered a perspective focused on the United States, this article offers the perspective of an international group of collaborators that focuses on worldwide outcomes of clozapine that may be disproportionate and influenced by differing frequencies of clozapine ADRs. We briefly summarize (1) clozapine outcomes in Scandinavian national registries [7][8][9][10][11][12] and (2) clozapineassociated fatal outcomes according to recent pharmacovigilance studies [13][14][15][16][17][18] suggesting that outcomes may vary across countries based on current use. The discussion elaborates on (1) the relatively low contribution of agranulocytosis to current clozapine-associated lethality, (2) pneumonia as the leading cause of death worldwide in clozapine-treated patients, and (3) myocarditis as possibly the second leading cause worldwide, although it may be the top cause in some countries.…”

Will ChatGPT3 Substitute for us as Clozapine Experts?

“…The authors tested ChapGPT3 on February 18, 2023, and repeated the test on February 25, 2023. Their test was done using their expertise on a very specific topic that has been the focus of their research since 2019, the effects of ethnic ancestry on the stratification of clozapine dosing 3 . To appreciate the ChatGPT3 responses, a brief summary of what is known about clozapine metabolism as a function of race is needed.…”