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

Research output: Contribution to journalReview articlepeer-review

19 Scopus citations


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 com-pare 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 dos-ing; 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.

Original languageEnglish
Pages (from-to)183-195
Number of pages13
JournalPsychiatry Investigation
Issue number3
StatePublished - Mar 2023

Bibliographical note

Publisher Copyright:
© 2023 Korean Neuropsychiatric Association 183.


  • Asian continental ancestry group
  • CYP1AMyocarditis/chemically induced
  • Clozapine/adverse effects
  • Clozapine/therapeutic use
  • Mortality/drug effects

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Biological Psychiatry


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