Clozapine

Abstract

Background: Guidance on clozapine dosing in treatment refractory schizophrenia is based largely on data from young adult male White patients.Aim: This study aimed to audit the plasma clozapine and N-desmethylclozapine (norclozapine) concentrations attained in male and female patients of different ethnicity and smoking habit. Method:The effect of dose, sex, ethnicity, age, body weight, and smoking habit on plasma clozapine and norclozapine concentrations were studied using data from a therapeutic drug monitoring service, 1993 to 2017.Results: There were 371,610 samples (48,098 patients, 32,855 male). Ethnicity was recorded for 763 Afro-Caribbean, 536 Asian, and 7940 White patients. Males were prescribed significantly higher median doses than females but attained significantly lower median plasma clozapine and norclozapine concentrations. Asian and Afro-Caribbean males were prescribed significantly lower and higher median doses, respectively, than White males but attained significantly higher and lower median plasma clozapine and norclozapine concentrations, respectively. Data from 78,431 samples (23,516 patients) were analyzed using a linear mixed model. The predicted dose to attain a predose plasma clozapine concentration of 0.35 mg/L in a nonsmoking White male aged 40 years, with weight of 70 kg, and plasma clozapine-norclozapine ratio of 1.32 was 344 mg/d (95% confidence interval, 227-526 mg/d). The predicted dose was 33% higher and 20% lower in otherwise analogous Afro-Caribbean and Asian patients, respectively. In all cases, the predicted dose was increased by 36% in smokers and decreased by 22% in females. Conclusions:Research is needed to further investigate the complex relationships between dose, sex, ethnicity, plasma clozapine and norclozapine concentrations, and clinical outcome such as weight gain.

Impact of sex on antidepressant discontinuation in groups of similar cytochrome P450 phenotypes

“… 22 Multiple publications also highlight a lower dose requirement of clozapine for females as compared with men. 23–25 These findings identify that there could be sex differences in CYP450 enzymes impacting drug metabolism. Furthermore, alterations in CYP450 enzyme phenotypes may contribute to alterations in drug metabolism that predispose patients to side effects, intolerance, and/or treatment failure.…”

Ethnopsychopharmacology: Clinical and scientific writing pearls

“…All of the publications supported the trend of the need for lower clozapine doses for patients of Asian ancestry and higher doses for certain African populations. 18 , 19 , 21 As an example, one of these studies predicted that a 300-mg clozapine dose would be required for patients of sub-Saharan ancestry to reach a therapeutic value (defined as 350 ng/mL), vs 220 mg for patients of European ancestry and 112 mg for patients of East Asian ancestry. 18 Potentially worrisome is that those authors also reported that patients of sub-Saharan ancestry actually had doses of clozapine similar to those of patients of European ancestry and were approximately half as likely to reach a clozapine concentration of 350 ng/mL.…”