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Previous case reports suggest the potential benefits of use of clozapine on psychotic symptoms in Huntington's chorea. Clozapine was administered to a 70 years old female patient admitted in the inpatient unit of the Department of Psychiatry for paranoïd delusions, hallucinations, comorbid with Huntington's chorea. Clozapine was administered with increasing regimen ranging from 25 to 200 mg/day after all other medications were discontinued. No other drugs were associated. Clinical evaluation was carried out at days 0, 28, 56, 112, 280 using the PANSS and Psychotic Depression Rating Scale. The clinical improvement was associated with plasma levels of clozapine which have been recognized as in therapeutic ranges by previous studies. Clozapine proved efficient on both positive and negative symptoms as assessed by a decrease of the PANSS ratings (-44%) between day 0 and day 56, (-61%) between day 0 and day 280, and by a decrease of Psychotic Depression ratings (-43%) between day 0 and day 56, (-60%) between day 0 and day 280. It was also effective on choreiform movements. The clinical improvement was associated with plasma levels of clozapine which have been recognized as in therapeutic ranges by previous studies. A lower daily dose than those classically used in schizophrenia was sufficient to obtain efficient treatment.

The discovery of clozapine in the mid-sixties and the demonstration of its clinical efficacy vis-à-vis recalcitrant schizophrenia contributed to the development of specific psychopharmacological research addressing the concept of atypical antipsychotics. The research has a dual aim. First, identifying the action sites, in the brain, specific to clozapine and to conventional neuroleptics, in order to classify those drugs on the basis of the observed differences in pharmacoclinical profile (low incidence of neurological side effects, activity on schizophrenic deficiency symptoms, activity vis-à-vis certain forms of recalcitrant schizophrenia). Recent studies have used tools derived from molecular biology to determine the action sites. The results of those studies suggest that there are at least four classes of antipsychotics (reverse neuroleptics, conventional neuroleptics, atypical neuroleptics and atypical antipsychotics). The second aim of the research is to determine the behavioral effects of each of the recognized classes of medication in order to determine the neurobiological substrates specific to the elementary cognitive operations impaired in schizophrenia. There is preclinical evidence to suggest that, in each area investigated (low incidence of neurological side effects, negative symptoms, cognitive symptoms), clozapine, a "dirty" drug, acts on different neurotransmission systems. The research thus aims to determine the pharmacological profile of the drugs of the future, designed to treat the cognitive deficiencies specific to the various types of schizophrenia.

The synthesis of new compounds called atypical neuroleptics such as amisulpride, clozapine, risperidone and now olanzapine has roused interest in the psychopharmacology of atypical antipsychotics. Since the synthesis of chlorpromazine in the early 1950s, subsequent therapeutic research has had two main goals: to define the mechanism of action of atypical neuroleptics and to search new compounds with both clinical efficacy and fewer side effects. The first one has widely been achieved, as it is clear that classical neuroleptics exert their effects by blockade of dopamine D2 receptors located in the ventral striatum. As a matter of fact, non specific blockade of dopaminergic receptors in the dorsal striatum also predicts extrapyramidal side effects. Moreover, classical neuroleptics have poor effects on negative and cognitive symptoms. That is why the search for new compounds has focused on two main goals: first, understanding the interactions of the neurotransmitters involved by the new drugs, second, characterizing their brain site of action. Achieving these two goals might enable us to precise the notion of atypicity as well as the classification of these new drugs.

Neuroleptics have been held responsible for cognitive impairments and negative symptoms in the course of schizophrenia. On the other hand, recent data suggest that alterations in information processing, cognitive and neuro-psychological functions are present at early stages in the developmental course of the illness. Two recent reviews, by D. King and G. Cassens suggest that, although acute administration of neuroleptics may alter performances in some neuro-psychological functions, there is no convincing evidence so far, to support a significant role of chronic neuroleptic treatment in the development of negative symptoms and cognitive dysfunction in schizophrenia. Despite several methodological limitations, which preclude any definitive statement, experimental and clinical data suggest that chronic neuroleptic treatment might improve neuropsychological functioning and the deficit syndrome, in some groups of schizophrenic patients. These results are examined in the framework of recent theoretical developments, which emphasize the role of cognitive dysfunction in the pathophysiology of schizophrenia.