Abstract
BackgroundClozapine is widely prescribed and, although effective, can cause weight gain and dysglycemia. The dysmetabolic effects of clozapine are thought to be more prevalent in women with this gender on average attaining 17 % higher plasma clozapine concentrations than men.MethodsWe investigated the relationship between dose, body mass index (BMI), plasma glucose concentration, and plasma clozapine and N-desmethylclozapine (norclozapine) concentrations in 100 individuals with a severe enduring mental illness.ResultsMean (10th/90th percentile) plasma clozapine concentrations were higher for women [0.49 (0.27–0.79) mg/L] compared with men [0.44 (0.26–0.70) mg/L] (F = 2.2; p = 0.035). There was no significant gender difference in the prescribed clozapine dose. BMI was significantly higher in women [mean (95 % CI) = 34.5 (26.0–45.3)] for females compared with 32.5 (25.2–41.0) for males. Overall, BMI increased by 0.7 kg/m2 over a mean follow-up period of 210 days. A lower proportion, 41 % of women had a fasting blood glucose ≤6.0 mmol/L (<6.0 mmol/L is defined by the International Diabetes Federation as normal glucose handling), compared with 88 % of men (χ2 = 18.6, p < 0.0001).ConclusionsWe have shown that mean BMI and blood glucose concentrations are higher in women prescribed clozapine than in men. Women also tended to attain higher plasma clozapine concentrations than men. The higher BMI and blood glucose in women may relate to higher tissue exposure to clozapine, as a consequence of sex differences in drug metabolism.
Highlights
Clozapine is widely prescribed and, effective, can cause weight gain and dysglycemia
A higher proportion of the samples from females had plasma clozapine concentrations of 0.60– 1.00 mg/L (25 % of samples from females compared with 14 % of samples from males) and >1.00 mg/L (11 % of Metabolic investigations body mass index (BMI) was significantly higher in women [mean = 34.5 (26.0–45.3)] for females compared with 32.5 (25.2–41.0) for males; F = 3.8, p = 0.02, Fig. 1b)
Though treatment with clozapine offers significant benefits for many patients with treatment-resistant schizophrenia (TRS), it is associated with a high incidence of substantial weight gain, especially in females
Summary
Clozapine is widely prescribed and, effective, can cause weight gain and dysglycemia. The dysmetabolic effects of clozapine are thought to be more prevalent in women [2] and it has been shown that gender does have an influence on the observed interpatient variability in plasma clozapine concentrations, with women on average attaining 17 % higher plasma clozapine concentrations than men at constant dose irrespective of smoking habit [3]. This is in keeping with already identified gender-related differences in pharmacokinetics for some drugs, including theophylline and several benzodiazepines, known since the 1980s [4]. Therapeutic drug monitoring (TDM) of clozapine and N-desmethylclozapine (norclozapine) is useful when assessing therapeutic effectiveness and for dose optimisation [5, 6] and may be relevant to assessing the metabolic consequences of treatment with clozapine.
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