Plasma Clozapine in Treatment Refractory Schizophrenia: What Is the Target Range?

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.

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.

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).

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.