The average daily doses of clozapine and risperidone have decreased in the last 5 years, while the average daily dose of olanzapine has increased, almost reaching the maximal recommended dose. This current practice does not seem specific to New York State. Stahl3 reported that, in California, the average daily dose in 2002 was 4.0 mg for risperidone, Inhibitors,research,lifescience,medical 20.5 mg for olanzapine, and 316 mg for quetiapine (for patients aged 1 8 to 44). Although the patient populations were not quite comparable between these

two reports, it appears that clinicians use a lower daily dose of risperidone than before, whereas they use higher doses of olanzapine. Table I. Recommended daily Inhibitors,research,lifescience,medical doses of neuroleptics, and neuroleptic doses used in New York State Hospitals. FDA, Food and Drug Administration. Data taken from reference 2. Evidence for an optimal dose of atypical neuroleptics For all atypicals, studies have shown that very low doses are no better than placebo, so the question of finding the optimal dose can be summarized as: is more medication more efficacious? There are two ways to measure the quantity of medication each patient receives: daily dose and plasma level. Usually, when plasma levels are studied, the question that researchers try to answer is: is there a drug plasma level that should be reached in order to obtain an Inhibitors,research,lifescience,medical optimal

response? To answer this, a specific statistical tool is used: the receiver operating characteristics (ROC) curves. These curves are obtained by ranking each patient from the highest plasma level to the lowest, plasma level. Rach case is then plotted Inhibitors,research,lifescience,medical on a graph: the y axis represents the cumulative percentage of responders (which is also Inhibitors,research,lifescience,medical the sensitivity of

the cutoff point), while the x axis represent, the cumulative percentage of nonresponders (which will give the specificity of the cutoff point, by subtracting this number from 1). From the curve, a cutoff point is determined, and a chi-square analysis is undertaken to determine whether the percentage of responders among GSK-3 patients with a plasma level above the cutoff point, is significantly different from the rate of responders with a plasma level under the cutoff point. We will now review the evidence for high dosing for each atypical neuroleptic. Clozapine Several studies4-10 have tried to determine a threshold for the clozapine plasma level, above which a response could be predicted (Table IT). Comparison between these studies is made difficult as they vary greatly in their methodologies. .For example, some used a fixed dose, while others did not (which leads to a lower percentage of responders in the high doses, and thus makes it difficult to identify a threshold). However, it can be Cabozantinib cancer concluded that 350 ng/mL can be considered as a plasma threshold for optimal clozapine therapy.