Neuropharmacologic Basis for Clozapine's Unique Profile

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.¹ In recent months, three distinct neurochemical hypotheses to explain clozapine's unique profile have been discussed in the Archives.^2-4 Farde et al² propose that clozapine's lower D₂ dopamine receptor binding may explain the infrequent extrapyramidal syndromes (EPSs), and its higher D₁ dopamine receptor binding may explain its superior efficacy. Meltzer and Stockmeier³ suggest that clozapine's significant serotonin (5-HT₂) antagonist activity may explain both its unique properties. Pickar et al⁴ propose that clozapine's potent α₂-noradrenergic antagonist activity (in addition to its anti-5-HT₂ activity) may be relevant to its unique profile. Clozapine's greater affinity for the D₄ dopamine receptor site⁵ has been implicated as well. Recent data