Neuropharmacologic Basis for Clozapine's Unique Profile

Abstract

To the Editor.— In comparison with standard neuroleptics, clozapine is more effective in decreasing positive and negative symptoms in treatmentrefractory schizophrenic patients, and causes significantly fewer parkinsonian side effects and less tardive dyskinesia.¹In recent months, three distinct neurochemical hypotheses to explain clozapine's unique profile have been discussed in theArchives.^2-4Farde et al²propose that clozapine's lower D₂dopamine receptor binding may explain the infrequent extrapyramidal syndromes (EPSs), and its higher D₁dopamine receptor binding may explain its superior efficacy. Meltzer and Stockmeier³suggest that clozapine's significant serotonin (5-HT₂) antagonist activity may explain both its unique properties. Pickar et al⁴propose that clozapine's potent α₂-noradrenergic antagonist activity (in addition to its anti-5-HT₂activity) may be relevant to its unique profile. Clozapine's greater affinity for the D₄dopamine receptor site⁵has been implicated as well. Recent data