215 - Clozapine dosing regimen

Clozapine dosing regimen

214 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 Table 1.50  Clozapine dose (in mg/day) with the highest likelihood of providing a plasma concentration of 350mcg/L, estimated by extrapolation of concentrations reported for different populations. Patient group Rostami-­Hodjegan3 (ethnicity not described) Schoretsanitis4 (White Europeans) Reeves5 Asian White Afro-­ Caribbean Female non-­smoker 236 225 Female smoker 357 300 Male non-­smoker 256 275 Male smoker 368 375 REFRACTORY SCHIZOPHRENIA AND CLOZAPINE Clozapine initiation schedules Clozapine dosing regimen Many of the adverse effects of clozapine are dose dependent and linked to speed of titration. Adverse effects tend to be more common and severe at the beginning of treatment. Titration is required to allow tolerance to develop to the pharmacological effects of clozapine. The degree to which tolerance ultimately develops is evidenced by the fact that standard maintenance doses would be fatal in a clozapine-­naïve person.1 To minimise adverse effects and maximise the chances of successful titration, it is clearly important to start treatment at a low dose and to increase dosage slowly. There are many different opinions on exactly how slowly clozapine should be titrated. Titration schedules should certainly be individualised. This is something everyone agrees on. There are, however, competing imperatives: the need to establish an effective dose quickly, the need to allow time for the patient to gain tolerance to adverse effects, the need to minimise the risk of myocarditis and the need to account for very different rates of clozapine metabolism. The aim of dose titration is to attain a minimum therapeutic plasma concentration of approximately 350mcg/L over the course of about 3 weeks. The average dose at which this plasma concentration is achieved varies according to sex, smoking status and genetic variability in cytochrome enzyme activity, such as lower CYP1A2 activity for people of Asian or Native American heritage.2 Achieving a therapeutic concentration over a period of 2–3 weeks will require very different titration schedules for people with different metabolic capacities. A dose that will achieve a plasma concentration of 350mcg/L for an individual patient can be estimated by extrapolation of concentrations reported for different populations. This method groups patients according to sex and smoking status to produce predictive models.3–5 Results are summarised in Table 1.50.