European Whites May Need Lower Minimum Therapeutic Clozapine Doses Than Those Customarily Proposed

J Clin Psychopharmacol. 2021 Mar-Apr;41(2):140-147. doi: 10.1097/JCP.0000000000001341.


Purpose/background: A nomogram from a British naturalistic study proposed that the clozapine dosing needed to reach a serum concentration of 350 ng/mL ranged from 265 mg/d (female nonsmokers) to 525 mg/d (male smokers). Some European reviews have used these dosing recommendations, which seem greater than what we found in an Italian White sample ranging from 245 mg/d (female nonsmokers) to 299 mg/d (male smokers). Five other published samples of European Whites were added to the Italian sample to estimate clozapine doses recommended for reaching 350 ng/mL.

Methods/procedures: Average clozapine metabolizers were obtained by eliminating outliers with confounding variables: (1) psychiatric inducers and inhibitors; (2) doses less than 100 mg/d; and (3) when possible, patients with inflammation, obesity, or using oral contraceptives. The study included 1363 average metabolizer European Whites: the Italian sample and 5 new samples. Mean averages that reached serum concentration levels of 350 ng/mL were calculated after stratification by sex and smoking status in each sample. Then, weighted mean averages were obtained by combining the 6 samples.

Findings/results: The estimated weighted mean clozapine dosages ranged from 236 to 368 mg/d (236 mg/d in 218 female nonsmokers, 256 mg/d in 340 male nonsmokers, 357 mg/d in 269 female smokers, and 368 mg/d in 546 male smokers).

Implications/conclusions: Our recommended dosages are less than those recommended in Europe. Future studies in European Whites need to replicate these recommended doses for average metabolizer patients after sex and smoking stratification and further explore clozapine dosing for those with relevant clinical confounders.

MeSH terms

  • Adult
  • Antipsychotic Agents / administration & dosage*
  • Antipsychotic Agents / pharmacokinetics
  • Clozapine / administration & dosage*
  • Clozapine / pharmacokinetics
  • Dose-Response Relationship, Drug
  • Female
  • Humans
  • Male
  • Nomograms
  • Sex Factors
  • Smoking / epidemiology*
  • White People*


  • Antipsychotic Agents
  • Clozapine