353). Ten studies contributed data towards the regression analysis, illustrated in Figure 3. Patients in one study [Boachie and McGinnity, 1997] displayed a particularly high

seizure incidence at doses of 200–400 mg (although these were patients with learning disability who have a higher propensity to seizures). Figure 3. Proportion of patients with seizures versus mean dose of clozapine. There was wide variation across the studies with regards to an association of clozapine dose and seizures. In the main, clozapine dose was found to be closely correlated with seizure incidence: the higher the dose; Inhibitors,research,lifescience,medical the greater the risk of seizures, even though our regression analysis did not find this to be statistically PF-02341066 in vivo significant. The majority of case studies reported clozapine-induced seizures in patients Inhibitors,research,lifescience,medical taking doses greater than 600 mg a day [Karper et al. 1992; Baker and Conley, 1991; Haller and Binder, 1990; Simpson and Cooper, 1978]. However, a post-marketing study [Pacia and Devinsky, 1994] did not find a dose-related risk for seizures. The low-dose group had a surprisingly high frequency of seizures. This was attributed to a number of factors; seizures unrelated to clozapine therapy, a pre-existing seizure disorder, organic brain injury or a combination of epileptogenic medication [Wilson and Claussen, 1994;

Devinsky et al. 1991; Haller and Inhibitors,research,lifescience,medical Binder, 1990], and initiating clozapine on a more-rapid dose titration (12 days) contrary to manufacturer recommendations of 2–3 weeks [Wilson and Claussen, 1994; Devinsky et al. 1991]. One study found most seizures occurring soon after a clozapine dose increase (mean

± SD increase Inhibitors,research,lifescience,medical = 54 ± 26 mg/day) [Wilson and Claussen, 1994], although Inhibitors,research,lifescience,medical the authors suggested this was more likely to be related to an associated rapid increase in clozapine plasma levels rather than dose per se. Similarly Haller and Binder reported an increase in seizures following large dose increments (accidental increase of 350 mg and Oxymatrine ingestion of an additional 1200 mg as a suicide attempt). Also, seizures are reported to be more common during the initiation phase (when doses are gradually increased) [Sajatovic and Meltzer, 1996; Pacia and Devinsky, 1994; Wilson and Claussen, 1994; Devinsky et al. 1991]: Pacia and Devinsky recorded the median time to develop seizures was 42 days for the entire group, similar to Sajatovic and Meltzer who reported that half of the seizures occurred within the first 34 days of clozapine treatment. Relationship between clozapine plasma level and occurrence of seizures Our review only found three case reports (four patients) reporting plasma level and seizure incidence. Relevant case reports are summarized in Table 4. There were not enough data to allow a metaregression analysis to be performed.