Atypical Neuroleptics, Dose-Response Relationships, and Treatment-Resistant Psychosis

To the Editor.—  The important work by Kane and colleagues in the Clozaril Collaborative Study Group¹ has provided evidence that the atypical neuroleptic clozapine may have greater efficacy than other antipsychotic agents in some patients with chronic psychosis. The findings raise interesting questions about the mechanisms by which antipsychotic drugs produce their therapeutic effects.Like most neuroleptics, clozapine is a mixed antagonist of dopamine D1 and D2, norepinephrine α-1, and serotonin receptors. However, unlike most other neuroleptics, while clozapine is a relatively potent antagonist of norepinephrine and serotonin, it is a rather weak dopamine antagonist, producing minimal catalepsy or dopamine receptor upregulation in animals² and minimal parkinsonism in patients.³ Given its weakness as a dopamine antagonist, it is unlikely that clozapine at the doses used in the study by Kane and colleagues¹ produced a direct dopamine blockade equivalent to that produced by the drugs to which its