Clozapine's Multiple Cellular Mechanisms: What Do We Know after More than Fifty Years? a Systematic Review and Critical Assessment of Translational Mechanisms Relevant for Innovative Strategies in Treatment-Resistant Schizophrenia

Bartolomeis, Andrea de; Vellucci, Licia; Barone, Annarita; Manchia, Mirko; Luca, Vincenzo De; Iasevoli, Felice; Correll, Christoph U.

doi:10.2139/ssrn.4089530

Cited by 1 publication

(2 citation statements)

References 719 publications

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“…He dares to propose that trusting these sources may have deleterious effects in the use of clozapine around the world. If the reader is profoundly shocked by this statement and wants to stop reading, he/she needs to read Supplementary Table 1 (in the online-only Data Supplement) [6][7][8][9][10][11][12][13][14][15] that explains that for understanding these or any new ideas the reader needs to be open-minded. As most psychiatrists are not well versed in pharmacokinetics, there is another Supplementary Table 2 (in the online-only Data Supplement) 14,[16][17][18][19][20][21] explaining some basic pharmacokinetic concepts such as poor metabolizers (PMs), who tend to have adverse drug reactions (ADRs) with average doses, while ultrarapid metabolizers (UMs) need high doses for efficacy.…”

Section: A Paradoxical Hypothesis: Major Standard Clozapine Reference...mentioning

confidence: 99%

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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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Section: A Paradoxical Hypothesis: Major Standard Clozapine Reference...mentioning

confidence: 99%

“…• Thus, scientific discussion in psychiatry tends to focus on brain mechanisms. A recent comprehensive review of clozapine cellular mechanisms for the last 50 years has 755 references 15 but ignores most of the pharmacokinetic advances proposed in this article.…”

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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show abstract

Clozapine's Multiple Cellular Mechanisms: What Do We Know after More than Fifty Years? a Systematic Review and Critical Assessment of Translational Mechanisms Relevant for Innovative Strategies in Treatment-Resistant Schizophrenia

Cited by 1 publication

References 719 publications

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

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

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