CLINICAL HANDBOOK OF SCHIZOPHRENIA

18. Clozapine 179Plasma concentrations show large interindividual variation, with average steadystatepeak plasma concentrations occurring at approximately 2.5 hours (range: 1–6hours) after dosing. Clozapine is 95–97% bound to plasma proteins. The elimination ofclozapine is biphasic, with a mean elimination half-life of 8 hours (range: 4–12 hours)after a single 75 mg dose and 12 hours (range: 4–66 hours) after reaching steady statewith 100 mg twice-daily dosing. This suggests the possibility of concentration-dependentpharmacokinetics. However, at steady state, the area under the curve (AUC) and peakand trough plasma concentrations increase linearly in a dose-related fashion.Clozapine is almost completely metabolized prior to excretion, and only traceamounts of unchanged drug are detected in the urine and feces. Approximately 50% ofthe administered dose is excreted in the urine, and 30% in the feces. The desmethylmetabolite has only limited activity while the hydroxylated and N-oxide derivatives areinactive. The metabolism of clozapine occurs via multiple cytochrome P450 (CYP450)enzymes. However, clozapine is primarily a substrate for CYP450 1A2.A correlation between clozapine plasma levels and clinical response has been suggested.Optimal response appears to be reached in individuals whose clozapine plasmalevel is at least 350 ng/ml.TREATMENT STUDIES IN SCHIZOPHRENIAApproximately 30% of patients with schizophrenia do not respond to conventionalantipsychotic agents and are labeled as treatment resistant. Clozapine is considered thetreatment of choice for this refractory patient population. Clozapine has been comparedto conventional antipsychotics in patients with schizophrenia in over 30 studies involvingmore than 2,500 patients. These studies have largely been of short duration (< 13 weeks)and have included mostly young (mean age, 38 years) men. Although there were no differencesin mortality, ability to work, or suitability for discharge at the end of the studies,clinical improvement was seen more frequently in those taking clozapine both in theshort and long term. In the short-term trials, patients on clozapine had fewer relapses.Symptom assessment scales showed a greater reduction of symptoms in clozapine-treatedpatients. Patients were more satisfied with clozapine, and it was more acceptable in thelong-term treatment compared to conventional antipsychotic agents. However, clozapinewas associated with more hypersalivation, temperature increase, and drowsiness, butfewer motor side effects and dry mouth. The clinical efficacy in terms of clinical improvementand symptom reduction was most prominent in those patients who were resistant toconventional antipsychotics. Approximately one-third of patients with treatment-resistantillness improved with clozapine treatment. More recently, a multicenter, randomized, internationalstudy compared the risk for suicidal behavior in patients treated with clozapineversus olanzapine in 980 patients with schizophrenia/schizoaffective disorder (Meltzer etal., 2003). The major finding from this randomized study was that clozapine therapydemonstrated superiority to olanzapine in reducing key measures of suicidality in patientswith schizophrenia/schizoaffective disorder, who are at high risk for suicide.IDENTIFICATION OF THE INDIVIDUAL WHOIS A GOOD CANDIDATE FOR CLOZAPINE THERAPYThe FDA-approved indications for use of clozapine include (1) treatment of severely illpatients with schizophrenia who fail to show an acceptable response to adequate course