[Clozapine and resistant schizophrenia]

Clozapine is an atypical antipsychotic drug, with distinguishing features from neuroleptics which are believed to exert their therapeutic effect by blocking dopamine receptors in the limbic system. Clozapine is both chemically and pharmacologically distinct from neuroleptics such as chlorpromazine and haloperidol. This tricyclic dibenzodiazepine derivative is moderately active on the dopaminergic pathways, blocking D1 and D2 receptors to the same extent; and chronic treatment with clozapine does not lead to a compensatory increase in the number of striatal D2 receptors in rats. Pharmacological studies showed that clozapine produces psychomotor inhibition but without catalepsy and other typical effects of dopamine receptor blockade. The drug also has adrenergic (alpha 1), histamine (H1), and serotonin (5-HT2) blocking activity and is a potent muscarinic antagonist. The efficacy and side-effect profile of clozapine are unique. Treatment-resistant patients are much more likely to respond to clozapine than to haloperidol or chlorpromazine. In double-blind trials, clozapine has improved both positive and negative psychotic symptoms in schizophrenic patients who were refractory to conventional neuroleptics. Extrapyramidal side-effects are exceptional during therapy and tardive dyskinesia never demonstrated in relationship to clozapine. There is an increased risk of agranulocytosis with clozapine use estimated to be up to 20 cases of agranulocytosis per thousand patients treated during one year. Accordingly, a careful patient selection and regular blood monitoring are mandatory over the treatment period (blood testing to be performed weekly and immediately at the first sign of infection). Generally, this agranulocytosis is reversible with early detection and prompt drug discontinuation.