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.
White blood cell (WBC) monitoring has reduced clozapine-treated patient deaths associated with agranulocytosis to a rarity. However, clozapine protocols and package inserts worldwide provide no instructions for preventing myocarditis or pneumonia during clozapine titrations. Prescribers worldwide are largely unaware of that. Meanwhile, as they worry about agranulocytosis, their clozapine-treated patients are at risk of dying from pneumonia or myocarditis. Consequently, an international guideline with 104 authors from 50 countries/regions was recently published to provide personalised clozapine titration schedules for adult inpatients. This forum article reviews pneumonia and myocarditis occurring during clozapine titration, as well as the three most innovative aspects of this new guideline: (1) personalised titration, (2) C reactive protein (CRP) measures, and (3) dose predictions based on blood levels. Clozapine metabolism is influenced by 3 levels of complexity: (1) ancestry groups, (2) sex-smoking subgroups, and (3) presence/absence of poor metabolizer status. These 3 groups of variables should determine the maintenance dose and speed of clozapine titration; they are summarised in a table in the full-text. The international clozapine titration guideline recommends measuring CRP levels simultaneously with WBC, at baseline and weekly at least for the first 4 weeks of titration, the highest risk period for clozapine-induced myocarditis.
Although there have been several case reports suggesting the beneficial effect of acetylcholinesterase inhibitors in the cognitive deficits seen in schizophrenia, controlled studies have revealed contradictory results. The aim of this study was to investigate if donepezil could improve cognitive functions in schizophrenia. Twelve schizophrenic patients, who were diagnosed according to DSM-IV criteria and who had been on a stable dose of a high-potency typical antipsychotic for a minimum period of 3 months, participated in this 12-wk double-blind, placebo controlled, cross-over study of donepezil adjunctive treatment. Patients were randomly assigned under double-blind conditions to receive 5 mg/d donepezil or placebo for 6 wk, and then were crossed over to the alternate condition for 6 additional weeks. At baseline, 6 and 12 wk, patients were evaluated with the Positive and Negative Syndrome Scale (PANSS), Calgary Depression Scale, the Wechsler Memory Scale Revised (WMS-R), a test for Verbal Fluency, Trail Making Test, Parts A and B, and Wisconsin Card Sorting Test (WCST). Treatment effect was not significant in any of the cognitive measures. There were also no significant changes in the PANSS and depression scores. Nicotinic receptor desensitization may cause non-responsiveness to acetylcholine as previously suggested, but the most likely explanation appears to be that defects in other neurotransmitter systems account for the cognitive deficits seen in schizophrenic patients.
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