Pharmacogénétique des antipsychotiques dans la schizophrénie

Il n'existe pas, aujourd'hui, de critère objectif de choix entre les différents traitements antipsychotiques disponibles dans la schizophrénie. L'étude pharmacogénétique de l'efficacité et de la tolérance de ces traitements a pour objectif à terme l'optimisation individuelle des traitements médicamenteux. Les recherches en cours n'ont pas encore permis de mettre en évidence de critères utilisables en pratique clinique quotidienne. L'évaluation de cohortes plus importantes, génétiquement homogènes et évaluées prospectivement devrait permettre à l'avenir de mieux prédire la réponse au traitement en particulier en terme de tolérance, de mettre en évidence de nouvelles cibles thérapeutiques et de mieux comprendre le mécanisme d'action des traitements actuels

Memory tests in first-degree adult relatives of schizophrenic patients: a meta-analysis.

BACKGROUND: Memory deficits have been clearly demonstrated in schizophrenic patients. However, studies of memory performances in their relatives compared to normal controls provide conflicting results. A meta-analysis was carried out to synthesize all the published data. Unlike previous meta-analyses, which were based on composite scores, we analyzed each memory test separately. This prevents theoretically questionable choices in grouping variables, leads to results with clearer implications for applied research (e.g. the best choice of a test according to its sensitivity) and is more productive in suggesting explanatory hypotheses. METHOD: We initially selected 77 potentially relevant articles, but only 19 met our inclusion criteria. These articles provided data on eight different tasks, from five different memory tests: four tests from the Wechsler Memory Scale (WMS) and the California Verbal Learning Test (CVLT). For each task, we assessed data homogeneity, identified the outliers if any and then estimated effect sizes and tested publication bias using funnel plots. RESULTS: Adult relatives of schizophrenic patients were significantly impaired on most, but not all, tasks. The largest deficits were observed for the verbal paired associates test, the logical stories the digit span forward test and the digit span backward test. We found no significant differences in tasks of delayed recall, when deficits in immediate conditions (reflecting encoding) were taken into account. CONCLUSIONS: Adult relatives of schizophrenic patients have wide but not severe memory impairments. The size of estimated effects suggests that encoding processes are impaired, whereas storage and retrieval processes are relatively unaffected

Exploring the relationships between tobacco smoking and schizophrenia in first-degree relatives.

International audienceUp to 90% of individuals with schizophrenia suffer from nicotine dependence. Both schizophrenia and nicotine consumption have strong genetic components, which may overlap. The relationship between schizophrenia and nicotine dependence remains unclear, due in part to confounding factors. Studies of the relationship between nicotine consumption and milder schizophrenia-related phenotypes, such as schizotypy, in first-degree relatives of individuals with schizophrenia could help to better understand the relationship between smoking and schizophrenia while avoiding such confounders. We assessed the proportion of smokers, their level of nicotine dependence and their level of schizotypy in a sample of 98 first-degree relatives of schizophrenic subjects and 110 healthy controls. Partial correlation analysis was used to assess the relationship between schizotypal dimensions and smoking dependence. The prevalence of smoking and nicotine dependence levels were higher in the relatives than in the healthy control group. We found no relationship between nicotine dependence and the magnitude of schizotypal features in either group. Our results support the hypothesis that the relationship between schizophrenia and smoking is largely mediated by common familial factors, which may be genetic

A self administered executive functions ecological questionnaire (the Behavior Rating Inventory of Executive Function - Adult Version) shows impaired scores in a sample of patients with schizophrenia

Subjective measurements of cognition have seldom been used in schizophrenia. This is mainly due to the assumption that such measurements lack sensitivity in a disorder characterized by poor insight. We investigated the capacity of BRIEF-A (Behavior Rating Inventory of Executive Function - Adult Version: a self-administered, ecological questionnaire) to identify executive deficits in adults with schizophrenia. The global score and each domain-specific score was significantly lower in patients than in healthy controls. BRIEF-A could be a useful complement to objective measurements, providing a subjective assessment of everyday consequences of executive dysfunction in patients with schizophrenia

Correlations between cognitive performances and psychotic or schizotypal dimensions.

International audienceOBJECTIVE: To test if specific correlations exist between cognitive measures and psychotic dimensions in schizophrenic subjects and if similar correlations, between cognition and schizotypal dimensions, are present in non-psychotic subjects. METHODS: We administered the same battery of cognitive tests (Source Monitoring, Verbal Fluency [VF] and Stroop tests) to schizophrenic subjects (N=54), their first-degree relatives (N=37) and controls (N=41). Scores of negative, positive and disorganisation dimensions were derived from the Signs and Symptoms of Psychotic Illness scale in schizophrenic subjects, and from the Schizotypal Personality Questionnaire in relatives and controls. RESULTS: In schizophrenic subjects, as hypothesised, the negative dimension correlated with performance on VF and disorganisation with performance in the Stroop test. The positive dimension did not correlate with any cognitive measure. With only one exception, the significant correlations observed in non-psychotic subjects did not match correlations seen in schizophrenic subjects. In non-psychotic subjects greater disorganisation was associated with more clustered words in VF suggesting that excessive automatic spreading of activation in semantic networks could underlie this dimension. CONCLUSION: As a whole, data lent partial support to our hypothesis of specific cognitive-clinical correlations in schizophrenic subjects but did not support the existence of similar correlations in non-psychotic subjects

Self-reported childhood trauma correlates with schizotypal measures in schizophrenia but not bipolar pedigrees.

International audienceBACKGROUND: Strong evidence supports the association between childhood trauma and psychotic disorders. In two different high-risk populations, we looked for a correlation between the magnitude of schizotypal dimensions and the importance of self-reported childhood trauma.MethodA sample of 138 unaffected first-degree relatives was recruited (67 relatives of schizophrenic probands and 71 relatives of bipolar probands). The relationship between schizotypal dimensions and childhood trauma scores was analyzed by partial correlations. RESULTS: A positive correlation was found between childhood trauma scores and total schizotypal scores in first-degree relatives of schizophrenic subjects but not in first-degree relatives of bipolar probands. This correlation was primarily due to a strong association with the positive dimension of schizotypy. CONCLUSIONS: The significant correlation between childhood trauma and schizotypal dimensions in subjects at high genetic risk for schizophrenia suggests that susceptibility genes for schizophrenia may interact with childhood trauma to induce the emergence of schizotypal dimensions, mainly positive psychotic features

[Psychometric properties of the French version of the signs and symptoms of psychotic illness (SSPI) scale]

International audienceOBJECTIVE: This report describes the psychometric evaluation of the French translation of the Signs and Symptoms of Psychotic Illness (SSPI) scale. The SSPI scale was designed to assess the five main clusters of symptoms of people suffering from psychotic disorders (psychomotor poverty, reality distortion, disorganisation, depression, and psychomotor excitation) across diagnostic entities. This new tool has been built by Liddle because, in the existing scales assessing psychotic symptoms, individual items cover symptoms that belong to different pathophysiological processes. The SSPI scale comprises 20 items. Its interview is semi-standardised and typically lasts around 25 min. The English version of this scale has shown good psychometric properties (inter-rater reliability, factor structure). METHOD: We used the SSPI ratings of 81 patients with psychotic symptoms to assess its factor structure and concurrent validity with the Clinical Global Impressions (CGI) scale. Twenty-eight videotaped ratings were used to calculate the intra-class correlation coefficient (ICC) as a measure of inter-rater reliability. RESULTS AND DISCUSSION: The sample was composed of 46 schizophrenic subjects, 14 with schizoaffective disorder, three with major depressive episode with psychotic features, nine with manic episode with psychotic features and nine with other psychotic disorders. A principal component analysis was conducted to determine the factor structure. Using the Cattell test, we retained a five-factor solution. This solution explained 56.9% of the variance. After varimax rotation, 18 items were attributed to a unique factor. The five factors were: a psychomotor poverty factor, a reality distortion factor, a disorganised factor, an anxious/depressive factor and a psychomotor excitation factor. This structure is close to the original one. The inter-rater reliability of the French version of the SSPI was satisfactory for 18 items, with a mean ICC of 0.64 for the individual items, and an ICC of 0.76 for the global scale. Only two items had an unsatisfactory ICC. This scale showed a good correlation with the CGI scale, with a correlation coefficient between CGI score and SSPI global score of 0.64. Among the factor scores, reality distortion, disorganisation and depression factor scores exhibited a significant correlation with the CGI score. CONCLUSIONS: The French version of the SSPI scale has good psychometric properties, similar to the English version. Furthermore, its factor structure is similar to the English one. This scale is a robust instrument to rate psychotic symptoms and dimensions across diagnosis entities

Genetic overlap between schizophrenia and bipolar disorder: a study with AKT1 gene variants and clinical phenotypes

International audienceINTRODUCTION: A number of epidemiological and genetic studies suggests an overlap of Schizophrenia and Bipolar disorder across the traditional binary classification. AKT1 gene variants were previously shown to be associated with schizophrenia. In this study, our aim was to determine whether AKT1 gene variants are associated with particular phenotypes for schizophrenia (SCZ) and bipolar disorder (BPD). METHODS: This study included 529 subjects of European ancestry: 364 patients suffering from SCZ, BPD or schizoaffective disorder and 165 healthy controls. BPD patients were additionally subdivided into two groups: BPD with or without psychosis. Six AKT1 variants were assessed in a case-control study and allelic associations were analyzed. Moreover, meta-analyses were performed for those variants found in case-control studies of schizophrenia and schizoaffective disorder. RESULTS: Nominal associations were found for three AKT1 gene variants, namely rs3803300, rs2494732 and rs2498804, in the four phenotypes. Two SNP survived Bonferroni corrections for multiple testing: rs3803300 (p\textless0.001) and rs2498804 (p\textless0.03) in group 1 (BPD without psychosis). In group 2 (BPD with psychosis) and in group 4 (SCZ), rs3803300 was significant but did not survive multiple testing. While rs2494732 was associated with the presence of psychosis (group-2, 3 and 4), rs2498804 was associated with affective symptoms (groups-1, 2 and 3). One meta-analysis found a significant level of association between rs3803300 and schizophrenia in Asian subjects. CONCLUSION: AKT1 gene variations appeared to impact the risk for a class of psychiatric symptoms, comprising SCZ and BPD. Our findings support the view that AKT1 genetic variants are shared by both BPD and SCZ

Genetic and molecular exploration of UHMK1 in schizophrenic patients

International audienceIn two recent papers, polymorphisms located in U2AF homology motif kinase 1 (UHMK1) gene have been associated to schizophrenia. This gene encodes the serine/threonine kinase, kinase interacting with Stathmin, and has been functionally related to RNA metabolism and neurite outgrowth. In this study, we explored the contribution of this gene in schizophrenia susceptibility, using a case-control association study, a mutation screening, a transcription level analysis, and by the investigation of the phosphorylation status of the splicing factor, SF1, in B-lymphoblastoid cell lines of patients and controls. No association was observed in our French cohort, and no amino acid substitution was predicted in the subsample studied for mutation screening. No difference was observed in expression level or in SF1 phosphorylation between patients and controls. Despite a slight difference persisting in the meta-analysis carried out using four European populations, these data suggest, altogether, that UHMK1 does not play a major role in susceptibility to schizophrenia

Familial resemblance for executive functions in families of schizophrenic and bipolar patients.

Executive dysfunctions are considered to be putative markers of familial/genetic vulnerability to both schizophrenia and bipolar disorder. However, familial resemblance must be demonstrated before executive functions are used as a potential endophenotype. The aim of this study was to investigate familial resemblance for executive functions in families of schizophrenic and bipolar subjects. We assessed executive functions by means of two tests - the Wisconsin Card Sorting Test (WCST) and the Trail Making Test (TMT) - in 351 subjects from five populations: schizophrenic patients, bipolar patients, a group of relatives for each patient group and controls. For both tests, cognitive assessment results were consistent with previous studies: schizophrenic patients showed the greatest impairment, followed by bipolar patients and then the two groups of relatives. In families of bipolar patients we observed familial resemblance for the WCST and part A and part B of the TMT. However, by contrast with the classical point of view, considering executive measures to be markers of genetic vulnerability to schizophrenia, we did not demonstrate familial resemblance for either of the two executive tests in families of schizophrenic patients. Thus, executive measures, as assessed by the WCST or the TMT, should not be used as endophenotypes in genetic studies of schizophrenia unless confounders are identified and their effects eliminated