Inflammation and infection also influence plasma levels [Taylor et al. 2009a]. In addition, the fixed regression analysis we conducted was dominated by the large postmarketing naturalistic study which included 5629 patients [Pacia and Devinsky, 1994]. The mean doses used were not specified in the study and so a middle value for each dose

range was assumed. This approximation greatly reduced the capacity to demonstrate a dose-related effect. Owing to the paucity of useful data, we were unable to conduct a meta-regression Inhibitors,research,lifescience,medical analysis exploring the relationship between clozapine plasma level and AVL301 occurrence of seizures. Studies examining this relationship are scarce and our review only found three case reports, which suggest only that there is very substantial risk of seizures with clozapine plasma levels exceeding 1300 μg/l. Other limitations of our analysis include selection bias (the reporting only or mainly of cases), differences in reporting (case studies,

Inhibitors,research,lifescience,medical case series, retrospective population studies, Inhibitors,research,lifescience,medical study duration), the variability between study populations, the absence of data on patient risk factors (seizure history, neurological abnormalities, smoking status, etc.), the dearth of confirmatory observations of seizure occurrence and type (some seizures were clearly reported by patients or relatives), the subsequent drop-out rates, and the previously Inhibitors,research,lifescience,medical mentioned imprecision in reporting of individual or mean

doses. Can we say when to use an antiepileptic? Our regression model showed that seizure risk increases linearly with dose and that EEG abnormalities increase linearly with dose and plasma level and so there is Inhibitors,research,lifescience,medical no clear exponential rise in risk at any dose or level. Because results showed there was no dose or level at which risk increases at a greater rate, and as there is no safe dose or level at which seizures do not occur, we cannot make a recommendation on basis of risk of seizures except to keep the plasma level as low as possible. Dose, however, is affected by too many variables for a clear risk relationship to be established. not The plasma level for acute response to clozapine is in the range 200–504 μg/l [Taylor et al. 2009a]. In those not responding to clozapine, a plasma level target range of 350–500 μg/l has been suggested. When initiating clozapine, we suggest titrating slowly to 350 μg/l, as seizures are more common during the initiation phase [Pacia and Devinsky, 1994; Wilson and Claussen, 1994; Devinsky et al. 1991]. If there is no response, increase the dose to give a plasma level of 500 μg/l. Consideration should be given to introducing an AED if the clozapine plasma levels are above 500 μg/l, if there are clear epileptiform discharges on EEG, if the patient develops stuttering or speech difficulties, or if seizures occur.