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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Serum concentrations of clozapine and its main metabolite demethylclozapine were measured in 44 schizophrenic inpatients, of whom ten were non-smokers and 34 smokers. When comparing their clozapine dose and body weightrelated serum drug levels, we found that clozapine and demethylclozapine concentrations were about 40Yn lower in the smoking than in the non-smoking group, probably due to an inducing effect of smoking on the cytochrome P450 (CYP) 1A2, which is involved in the metabolism of clozapine. We conclude that dosage adjustment may be necessary in clozapinetreated smokers.Clozapine, an atypical antipsychotic agent, is a well-established alternative in the treatment of treatment-refractory or neuroleptic-intolerant schizophrenic patients (Byerly & DeVane 1996).Clozapine is metabolised to demethylclozapine (norclozapine) and clozapine N-oxide in the liver. The pharmacological activity of these metabolites has been reported to be much lower than that of the parent drug (Jann et al. 1993). CYPIA2 and CYP3A4 are the primary enzymes involved in biotransformation of clozapine in vitro (Eiermann et al. 1997; Fang et al. 1998). In a recent study, the CYPlA2 inhibitor fluvoxamine considerably increased serum clozapine concentrations in schizophrenic patients (Wetzel et al. 1998). In contrast, the potent CYP3A4 inhibitor itraconazole did not affect the pharmacokinetics of clozapine in healthy volunteers (Raaska & Neuvonen 1998), suggesting that CYPlA2 is the principal CYP enzyme mediating the biotransformation of clozapine in humans (Bertilsson et al. 1994). On the other hand, serum clozapine levels can be decreased by drugs inducing CYP enzymes such as carbamazepine (Raitasuo et al. The aim of the present study was to compare dose-and weight-related serum clozapine and demethylclozapine concentrations between smoking and non-smoking schizophrenic patients in Finland. Materials and MethodsSubjects. Steady-state serum concentrations of clozapine and demethylclozapine were measured in 44 schizophrenic inpatients ( 3 1 men and 13 women) in the Tampere University Hospital. The diagnosis was established clinically by two experienced psychiatrists. All patients had received a fixed dosage of clozapine for at least two weeks prior to the study. Patients using drugs possibly affecting serum clozapine concentrations (e.g. omeprazole, selective serotonin reuptake inhibitors (SSRI) and inducers of CYP enzymes such a s carbamazepine) were not included (Centorrino et al. 1996; Spina r f al. 1998). Thirty-four patients (26 men and 8 women) were smokers and 10 (5 men and 5 women) were non-smokers (see table 1 for the characteristics of these two groups). The smokers consumed 10 40 cigarettedday (average 18.0 cigarettedday). The number of cigarettes smoked was counted by the nursing staff.Medication. Clozapine dosage was adjusted according to the therapeutic response and possible side effects. The individual dosage ranged from 150 to 800 mg/day and averaged 5 2 0 t 150 mg/day. The non-smoking patients received lower clozap...