First, clozapine has a greater activating effect on neuronal activity in the ACC and the middle frontal cortex than do other antipsychotics (specifically haloperidol) (Figure 2). However, clozapine also has a “normalizing” action on the behavior of the ACC during performance of a task that utilizes the ACC (Figure 2). Figure 2. A Coronal statistical parametric map derived from 15O-labeled water positron emission tomography (PET) Inhibitors,research,lifescience,medical scans indicating the difference in regional cerebral blood flow (rCBF) between clozapine-treated and haloperidol-treated
schizophrenic volunteers (SVs). … Drug side effects and human pharmacokinetics Clozapine has a multitude of serious as well as incidental side effects, all of which affect patient use. Given the serious nature of the side effects, it is indeed surprising Inhibitors,research,lifescience,medical that the drug is used at all, and the fact that it is, is a testimony to its superior clinical efficacy. The drug was first noted to produce agranulocytosis after several deaths occurred in a Finnish hospital in the 1960s. The action of clozapine in suppressing granulocyte production in the marrow was described
and its incidence gradually tabulated over time, now known to be 0.5% to 1% with a mortality rate of 3% to 15%. Currently, clozapine use is restricted in the USA to those psychotic Inhibitors,research,lifescience,medical persons who fail to respond to other drugs. Its use is also accompanied by required blood counts, most frequent, (weekly) in the first 6 months of treatment. In addition, clozapine causes weight
gain, hypotension, tachycardia, arrhythmias, sialorrhea, Inhibitors,research,lifescience,medical sedation, and seizures in addition to the putatively more serious agranulocytosis. In reality, it is these “lesser” side effects that most often cause drug discontinuation. However, clozapine fails to cause acute or chronic motor side effects to any notable extent. Clozapine has several major metabolites, at least two of which have CNS activity, norclozapine and UMI-77 desmethyloclozapine. Too little is known about, the actions and kinetics of clozapine and its Inhibitors,research,lifescience,medical metabolites. After a single dose only of clozapine (200 mg), Tmax is 3±1.5 h and Cmax is 386±249 ng/mL. Its elimination half-life is approximately 10.3±2.9 h and its mean half-life is 17.4±7.7 h. Plasma concentrations are linear with dose. Risperidone Risperidone was designed on the basis of the clinical observation that haloperidol combined with a pure serotonin antagonist showed fewer motor side effects than haloperidol alone.32 Risperidone contains both the antidopaminergic and the antiscrotonergic components of the two distinct test drugs. Risperidone was the first drug rationally designed to affect both the dopamine and the serotonin systems, where the antiscrotonergic actions are more potent, than the antidopaminergic actions. Although clozapine possesses these properties, it was not designed as such.