Journal of clinical psychopharmacology · 2025
Plasma Clozapine in Treatment Refractory Schizophrenia: What Is the Target Range?
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Flanagan Robert James, Obee Stephen John, Kim Alice Hyun Min, Every-Palmer Susanna, Sanchez Paula Liren Valbuena, Evans Lauren, Rogers Jonathan, Reeves Suzanne
Аннотация
BACKGROUND: In treatment-refractory schizophrenia (TRS), a predose plasma concentration of 0.35 mg L -1 is suggested to ensure an adequate trial of clozapine, but the target range may differ between smokers and nonsmokers.
METHOD: We studied data from a clozapine therapeutic drug monitoring service, 1993-2017, with respect to age, sex, smoking status, clozapine dose, estimated clozapine treatment duration, plasma clozapine and norclozapine concentrations, and reason for the request.
RESULTS: There were 35,147 and 88,279 samples from 8882 women and 20,378 men, respectively, for which reasons for the request were specified (26,572 samples, 2 reasons; 6421, 3 or more reasons). More samples were sent for analysis due to suspected adverse drug reactions (ADRs) from women (5.3 vs 4.7%, P < 0.001). The median minimum duration of clozapine treatment before the suspected reaction was 156 days shorter in nonsmokers than smokers of either sex ( P < 0.001) and shorter in female than male nonsmokers (189 vs 334 d; P < 0.01). The differences in median plasma clozapine concentrations between suspected ADR (1869/4149 samples from women/men, respectively), and control (10,627/25,848 samples from women/men, respectively) groups were small, averaging 0.03 mg L -1 ( P < 0.01), but the median plasma clozapine in the ADR and baseline groups was 0.15 mg L -1 lower in smokers than nonsmokers ( P < 0.001).
IMPLICATIONS: The target ranges associated with response to clozapine and minimal ADRs in TRS may be 0.35-0.45 and 0.50-0.60 mg L -1 in smokers and in nonsmokers, respectively. ADRs may occur earlier in treatment in nonsmokers, particularly in women, who in general have higher predose plasma clozapine concentrations than men.
METHOD: We studied data from a clozapine therapeutic drug monitoring service, 1993-2017, with respect to age, sex, smoking status, clozapine dose, estimated clozapine treatment duration, plasma clozapine and norclozapine concentrations, and reason for the request.
RESULTS: There were 35,147 and 88,279 samples from 8882 women and 20,378 men, respectively, for which reasons for the request were specified (26,572 samples, 2 reasons; 6421, 3 or more reasons). More samples were sent for analysis due to suspected adverse drug reactions (ADRs) from women (5.3 vs 4.7%, P < 0.001). The median minimum duration of clozapine treatment before the suspected reaction was 156 days shorter in nonsmokers than smokers of either sex ( P < 0.001) and shorter in female than male nonsmokers (189 vs 334 d; P < 0.01). The differences in median plasma clozapine concentrations between suspected ADR (1869/4149 samples from women/men, respectively), and control (10,627/25,848 samples from women/men, respectively) groups were small, averaging 0.03 mg L -1 ( P < 0.01), but the median plasma clozapine in the ADR and baseline groups was 0.15 mg L -1 lower in smokers than nonsmokers ( P < 0.001).
IMPLICATIONS: The target ranges associated with response to clozapine and minimal ADRs in TRS may be 0.35-0.45 and 0.50-0.60 mg L -1 in smokers and in nonsmokers, respectively. ADRs may occur earlier in treatment in nonsmokers, particularly in women, who in general have higher predose plasma clozapine concentrations than men.