Objective and subjective extrapyramidal side effects in schizophrenia: their relationships with negative and depressive symptoms.

The aim of this study was to show that objective extrapyramidal symptoms (O-EPS) were strongly correlated to negative and depressive symptoms while subjective extrapyramidal symptoms (S-EPS) were not. Ninety-one schizophrenic patients were evaluated by the Extrapyramidal Symptoms Rating Scale (ESRS), Montgomery and Asberg Depression Rating Scale (MADRS) and Scale for the Assessment of Negative Symptoms (SANS). While significant correlations were found between O-EPS and SANS (r = 0.51; p < 0.001) and between O-EPS and MADRS (r = 0.26; p < 0.01), no significant relationship existed between S-EPS and SANS (r = 0.19) or MADRS (r = 0.19). Similar results regarding the relationships between EPS and SANS were found in stabilized and acute subgroups and in deficit and nondeficit subgroups. A stepwise multiple regression showed that 41% of the variance of the SANS scores was due to facial mask and bradykinesia, and that 17% of the variance of the MADRS scores was due to facial mask and akathisia. This study shows the interest of evaluating subjective parkinsonism symptoms over objective ones since they are less interrelated to other symptoms, in particular to negatives ones.

Plasma 3-methoxy-4-hydroxyphenylglycol and homovanillic acid measurements in deficit and nondeficit forms of schizophrenia.

BACKGROUND: Discrepancies in the biochemical research on negative symptoms in schizophrenia may be ascribed to the lack of differentiation into primary and secondary negative symptoms. We have used Carpenter's criteria to define the deficit syndrome of schizophrenia as the presence of enduring and primary negative symptoms and measured catecholaminergic parameters in deficit as compared with nondeficit schizophrenics. METHODS: We have investigated plasma homovanillic acid (pHVA) and 3-methoxy-4-hydroxyphenylglycol (pMHPG) concentrations in 34 DSM-III-R neuroleptic-treated schizophrenic patients who were classified into deficit (n = 14) and nondeficit (n = 20) forms of schizophrenia. All these patients were in a stable clinical and therapeutic status for the preceding 12 months. RESULTS: The 14 deficit schizophrenic patients had lower plasma levels of pHVA and higher plasma concentrations of pMHPG from 9 AM to 12 AM as compared with the 20 nondeficit schizophrenic patients. The two groups did not differ on any demographic, therapeutic, or clinical variable considered. CONCLUSIONS: Our data are consistent with the postulated distinct pathophysiological basis for the deficit syndrome of schizophrenia and suggest that opposite alterations in the pHVA or pMHPG levels may reflect specific changes in noradrenergic and dopaminergic functions in these deficit patients.

Association of DNA polymorphism in the first intron of the tyrosine hydroxylase gene with disturbances of the catecholaminergic system in schizophrenia.

We examined whether there are clinical or biological differences in chronic schizophrenic patients sharing a rare variant allele (a perfect ten tetranucleotide repeats allele of the human TH01 microsatellite) in the tyrosine hydroxylase (TH) gene. For that purpose, clinical parameters (PANSS subscores) and plasma measurements (homovanillic acid and 3-methoxy-4-hydroxy-phenylglycol (MHPG)) were analyzed in five schizophrenic patients sharing the rare allele and 19 schizophrenic patients who did not possess this allele. The mean concentration of plasma HVA and plasma MHPG were significantly lower in the group of schizophrenic patients sharing the rare allele. No other group differences were observed between both groups. These results suggest that this TH gene polymorphism may be associated with disturbances of the catecholaminergic pathway.

[Atypical pharmacologic characteristics of an antipsychotic drug: clozapine]. / Atypicité pharmacologique d'un antipsychotique: la clozapine.

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.

[New antipsychotic agents: new paths of research on the notion of atypical agents]. / Les nouveaux antipsychotiques: nouvelles voies de recherche sur la notion d'atypicité.

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.

[Stability of positive/negative symptoms in schizophrenia]. / Stabilité des symptômes positifs/négatifs des schizophrénies.

The debate concerning the stable or instable aspect of schizophrenic symptomatology has lead the authors to study this phenomenon by taking into account, at the time of inclusion of a schizophrenic patient, such parameters as: the phase of the illness (acute, post-acute or stable) or the course (chronicity) as well as the relationship between the negative symptomatology variation and other symptomatic dimension variation (depression, akinesia, etc.), in follow-up studies. The results of these studies are clearly in favour of taking into consideration all or part of these parameters, to evaluate at best the stability of positive and negative schizophrenic symptoms.

[Identification by typological analysis of distinct groups of schizophrenic patients. Applicability of a disorganized schizophrenia subtype]. / Identification par une analyse typologique de groupes distincts de patients schizophrènes. Pertinence d'un groupe désorganisé.

Since Crow, Andreasen et al. have described schizophrenia in terms of negative and positive symptoms, the dichotomic approach has been well established. As a matter of fact, factor analyses, especially principal components analyses, led with symptomatic specific scales, have proved their validity. But they have shown their limits too : some authors think that the dichotomic model fails to explain all of the schizophrenic psychopathology and that a third dimension including formal thought disorders, most of the time called "disorganization", should systematically be taken into account. In this study, the authors have hypothesized that a categorial approach could describe this "disorganization". Using a cluster analysis they investigated the existence of subtypes in a population including 136 schizophrenic patients assessed with the PANSS (Positive and Negative Syndrome Scale, Kayet al., 1987). The results suggested at least five subtypes: a pure positive subtype, characterized by high scores on items delusions, hallucinatory behavior, suspiciousness/persecution, and by a low score on conceptual disorganization item; a disorganized positive subtype, characterized by high scores on positive items, including conceptual disorganization item, and also high scores on unusual thought content and autistic preoccupation items; a negative subtype, characterized by high scores on negative items and low scores on positive items, including conceptual disorganization item; a mixed subtype, characterized by high scores on the most positive, negative and general psychopathological items; a residual subtype, characterized by low scores on all the positive, negative and general psychopathological items. The good validity of this analysis was showed since differences on a number of clinical characteristics were observed between the five clusters. These results demonstrated the oversimplication of the positive-negative dichotomy and the relevance of a disorganized subtype.

Identifying subtypes of schizophrenia by cluster analyses.

The existence of two subtypes of schizophrenia (positive and negative) is well established. The evidence in favor of other subtypes, particularly a disorganized subtype, is still the subject of some debate. The aim of the study reported in this article is to investigate the possibility of further subtypes of schizophrenia by applying a particular method of cluster analysis to a particular set of data. Ward's method of cluster analysis was applied to the Positive and Negative syndrome Scale (PANSS) scores of 138 patients, defined as having schizophrenia by one of four diagnostic criteria. The validity of the cluster solution was assessed both by examining differences between clusters on a number of clinical characteristics recorded for each patient and by comparing the results obtained from the PANSS with those derived from a cluster analysis using two other instruments (the Scale for the Assessment of Negative Symptoms and the Scale for the Assessment of Positive Symptoms). Results from the cluster analysis suggest the existence of at least four subtypes of schizophrenia: positive, negative, mixed, and disorganized. A fifth subtype includes patients with few symptoms, suggesting the simple schizophrenia named by Bleuler. Evidence for the validity of these subtypes was provided by the differences observed between the clusters on a number of clinical characteristics and by the similarity of the cluster solution obtained from the different instruments. In conclusion, the negative-positive dichotomy in schizophrenia is an oversimplification, and the existence of a more complex structure needs to be taken into account in future research.

Family history and deficit form in schizophrenia.

As no genetic study has been made in deficit patients, characterized by enduring and primary negative symptoms, the aim of the study was to test the involvement of a familial factor in deficit syndrome. The results in 71 schizophrenic patients showed less familial factors but a greater weight in heritage of schizophrenia in deficit than in nondeficit patients.

A comparison of plasma homovanillic acid in the deficit and nondeficit subtypes of schizophrenia.

Plasma homovanillic acid (pHVA) was measured over a 13 hr-period in 16 DMS-III-R schizophrenic patients, all treated with neuroleptic drugs and in a stable clinical and therapeutic status for the preceeding 12 months. Patients were categorized into deficit (n = 9) and nondeficit (n = 7) forms of schizophrenia according to the Schedule for the Deficit Syndrome (SDS) criteria. As compared to the nondeficit group, deficit patients display significantly lower mean pHVA concentrations from 9 AM to 12 AM and a lack of diurnal variations. None of the demographic, clinical, and therapeutic variables can explain these biological differences. These data suggest a specific biochemical basis for the deficit syndrome of schizophrenia as defined by the SDS criteria, that is, primary, enduring, negative symptoms.

[Schedule for evaluation of the deficit syndrome in schizophrenia: Schedule for Deficit Syndrome (SDS) (Kirkpatrick et al.). Importance pertinence of the SDS. Introduction of the French version]. / Instrument d'évaluation du syndrome déficitaire de la schizophrénie: Schedule for the Deficit Syndrome (SDS) (Kirkpatrick et al.). Intérêt et pertinence de la SDS. Présentation de la version française.

The negative symptoms of schizophrenia have generated a great interest leading some authors (Crow, Andreasen, Kay) to delineate schizophrenic subtypes based on their presence or absence. Carpenter et al. have recently proposed another subtype, the deficit syndrome, based on Kraepelin's clinical description. This differs from other proposed negative subtypes and refers to the presence or absence of prominent, enduring and primary negative symptoms. Primary negative symptoms have to be due to psychophrenia itself, in other words, independent of factors such as depression, anxiety, akinesia... Kirkpatrick et al. have proposed the Schedule for the Deficit Syndrome (SDS) to reliably identify this deficit syndrome. Some studies using this instrument have supported the validity of the deficit syndrome concept. Particularly, deficit patients have clinical, neuropsychological, neurological, eye-tracking and brain imaging impairments compared to nondeficit patients. We realized a french translation of SDS and used it to study a biological index (plasma homovanillic acid, pHVA) among deficit and nondeficit schizophrenic patients. Our data suggest a specific biochemical basis for the deficit syndrome, ie, significant lower mean pHVA levels with a lack of diurnal variation for deficit patients. The french version of SDS was validated by Kirkpatrick after english back translation. We present here our psychometric data regarding reliability (assessed by weighted and unweighted kappa coefficients) and cohesiveness of the construct (assessed by rank-order correlations of each negative symptoms with the other five, using Spearman's rho). These data are quite significant and in agreement with the SDS authors.