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Pre-clinical Pharmacology of Atypical Antipsychotic Drugs: A Selective Review

Published online by Cambridge University Press:  06 August 2018

Herbert Y. Meltzer
Herbert Y. Meltzer*
Affiliation:
Case Western Reserve University School of Medicine, University Hospitals, Cleveland, USA
*
Professor Herbert Y. Meltzer, University Hospitals of Cleveland, Hanna Pavilion, Room B-68, 11100 Euclid Avenue, Cleveland, OH, 44106-5000, USA
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Extract

The primary basis for the action of neuroleptic drugs has been suggested to be a blockade of D2 receptors in the mesolimbic system, with subsequent decrease in the firing rate of ventral tegmental (A10) dopamine neurons by the process of depolarisation inactivation (Matthyssee, 1974; Bunney et al, 1991). The main evidence for this hypothesis is that: the affinities for the D2 receptor of all effective antipsychotic drugs are positively correlated with their average clinical dose (Seeman & Lee, 1975; Creese et al, 1976); and chronic administration of antipsychotic drugs produces nearly complete inhibition of the firing of ventral tegmental (A10) dopamine neurons that project to the limbic forebrain (Chiodo & Bunney, 1983). Clozapine, the prototypical atypical antipsychotic drug, also satisfies both criteria (Seeman & Lee, 1975; Chiodo & Bunney, 1985). However, the demonstration that clozapine is more effective than other neuroleptics for the treatment of both schizophrenic patients who are responsive to typical neuroleptics (Meltzer, 1992) as well as those who are resistant (Kane et al, 1988) suggests that this simple dopamine hypothesis of neuroleptic drug action is insufficient. Indeed, there is evidence that clozapine at clinically effective doses produces less D2 receptor occupancy and, hence, less antagonism of D2 receptors in the striatum, and probably also in the limbic system, than typical neuroleptic drugs (Farde et al, 1992); this further challenges the adequacy of the dopamine hypothesis to explain the greater efficacy of clozapine. This leaves the need to consider what else besides a D2 receptor blockade may explain the action of clozapine and, indeed, whether limited blockade is superior to a more complete one.

Type
Research Article
Information
The British Journal of Psychiatry , Volume 168 , Issue S29: Current Issues in the Development of Atypical Antipsychotic Drugs , May 1996 , pp. 23 - 31
Copyright
Copyright © 1996 The Royal College of Psychiatrists 

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