Clozapine and the dopamine hypothesis of schizophrenia, a critical appraisal

This paper discusses some of the pharmacological and neurochemical properties of clozapine, and the special attributes that differentiate clozapine from the classical neuroleptics. The question as to whether or not clozapine blocks DA-receptors--a crucial point in regard to the dopamine hypothesis of schizophrenia--has received particular attention. Neurochemical, neuropharmacological, and endocrinological evidence is presented which speaks against a DA-receptor blockade by clozapine in pharmacologically relevant doses. These findings are difficult to reconcile with the dopamine hypothesis which proposes a direct relationship between antipsychotic effect and DA-receptor blockade.