This international guideline proposes improving clozapine package inserts worldwide by using ancestry-based dosing and titration. Adverse drug reaction (ADR) databases suggest that clozapine is the third most toxic drug in the United States (US), and it produces four times higher worldwide pneumonia mortality than that by agranulocytosis or myocarditis. For trough steady-state clozapine serum concentrations, the therapeutic reference range is narrow, from 350 to 600 ng/mL with the potential for toxicity and ADRs as concentrations increase. Clozapine is mainly metabolized by CYP1A2 (female non-smokers, the lowest dose; male smokers, the highest dose). Poor metabolizer status through phenotypic conversion is associated with co-prescription of inhibitors (including oral contraceptives and valproate), obesity, or inflammation with C-reactive protein (CRP) elevations. The Asian population (Pakistan to Japan) or the Americas’ original inhabitants have lower CYP1A2 activity and require lower clozapine doses to reach concentrations of 350 ng/mL. In the US, daily doses of 300–600 mg/day are recommended. Slow personalized titration may prevent early ADRs (including syncope, myocarditis, and pneumonia). This guideline defines six personalized titration schedules for inpatients: 1) ancestry from Asia or the original people from the Americas with lower metabolism (obesity or valproate) needing minimum therapeutic dosages of 75–150 mg/day, 2) ancestry from Asia or the original people from the Americas with average metabolism needing 175–300 mg/day, 3) European/Western Asian ancestry with lower metabolism (obesity or valproate) needing 100–200 mg/day, 4) European/Western Asian ancestry with average metabolism needing 250–400 mg/day, 5) in the US with ancestries other than from Asia or the original people from the Americas with lower clozapine metabolism (obesity or valproate) needing 150–300 mg/day, and 6) in the US with ancestries other than from Asia or the original people from the Americas with average clozapine metabolism needing 300–600 mg/day. Baseline and weekly CRP monitoring for at least four weeks is required to identify any inflammation, including inflammation secondary to clozapine rapid titration.

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This retrospective cohort study aimed to investigate the longitudinal changes in clozapine dose over a 5-year period in patients with treatment-resistant schizophrenia (TRS). Patients with TRS who were administered clozapine at a hospital between April 2012 and December 2016 and continued treatment with clozapine for at least 1 year were included. Clozapine doses were compared at the dose-fixation point, defined as when the same regimen of clozapine had been continued for 8 weeks or longer, and the post-dose-fixation phase, at 12, 36 and 60 months after clozapine initiation. We included 103 patients and found no significant differences in clozapine dose between the dose-fixation point and post-dose-fixation phase. Approximately half of the patients were categorized into an unchanged group at 12 months after clozapine initiation, whereas approximately 40% of patients were categorized into either the decreased or increased group at 60 months. Multivariable regression analysis revealed that the change in clozapine dose between the dose-fixation point and 60 months after clozapine initiation was negatively associated with clozapine dose at the dose-fixation point. On average, the clozapine dose was unchanged during long-term treatment in patients with TRS, although the dose was decreased or increased in approximately 40% of the patients.