Clinical utility of the Multiple Errands Test in schizophrenia: A preliminary assessment.

Schizophrenia (SZ) is a chronic, severe disease, which results in misperception of reality, major social withdrawal, and cognitive disturbances. One type of cognitive disturbance, known as executive dysfunction, is widely considered as a primary determinant of functional outcome. However, classic neuropsychological measures of executive functioning (EF) poorly represent patients' functional outcome, and thus seem inappropriate for evaluating the real-world functional impact of diseases such as SZ. We hypothesized that the Multiple Errands Test (MET), an ecological assessment of executive function would show greater ability to measure everyday adaptive functioning SZ, compared to conventional EF assessment methods. 100 clinically stable SZ patients were administered the MET, Wisconsin Card Sorting Test - 64 and a paper version of MET. Correlation analyses were performed between each EF measure and functional outcome, as measured by the Social Autonomy Scale (SAS). After adjusting for age, education, IQ and illness duration, SAS was significantly predicted by MET global score. No other EF measure correlated with SAS. Results from this study suggest that MET offers a valuable prediction of daily life functional outcome in this large sample of SZ patients. Therefore, it could be used as a complementary measure to improve the identification of executive dysfunctions prior to psychosocial interventions.

Exome sequencing in 53 sporadic cases of schizophrenia identifies 18 putative candidate genes.

Schizophrenia (SCZ) is a severe, debilitating mental illness which has a significant genetic component. The identification of genetic factors related to SCZ has been challenging and these factors remain largely unknown. To evaluate the contribution of de novo variants (DNVs) to SCZ, we sequenced the exomes of 53 individuals with sporadic SCZ and of their non-affected parents. We identified 49 DNVs, 18 of which were predicted to alter gene function, including 13 damaging missense mutations, 2 conserved splice site mutations, 2 nonsense mutations, and 1 frameshift deletion. The average number of exonic DNV per proband was 0.88, which corresponds to an exonic point mutation rate of 1.7×10(-8) per nucleotide per generation. The non-synonymous-to-synonymous mutation ratio of 2.06 did not differ from neutral expectations. Overall, this study provides a list of 18 putative candidate genes for sporadic SCZ, and when combined with the results of similar reports, identifies a second proband carrying a non-synonymous DNV in the RGS12 gene.

Comparative analysis of anti-toxoplasmic activity of antipsychotic drugs and valproate.

Recent studies have shown a strong link between Toxoplasma gondii infection and psychiatric disorders, especially schizophrenia and bipolar disorders (odd ratio ≈2.7 for each disorder). Antipsychotic drugs and mood stabilizers may have anti-toxoplasmic activity that potentially may be associated with better effectiveness in these disorders, but previous results have been few in number and conflicting. We therefore sought to determine which daily prescribed antipsychotics and mood stabilizer have the best anti-toxoplasmic activity during the development phase of the parasite. In the present study, we examined the effects of commonly used antipsychotic drugs (amisulpride, cyamemazine, fluphenazine, haloperidol, levomepromazine, loxapine, olanzapine, risperidone and tiapride) and one mood-stabilizing agent (valproate) on toxoplasmic activity. We replicated that fluphenazine has a high anti-toxoplasmic activity, but it does not seem to be a phenothiazine-specific class effect: indeed, we found that another first-generation antipsychotic, zuclopenthixol, has a high anti-toxoplasmic activity. Valproate, tiapride and amisulpride have no anti-toxoplasmic activity on parasite growth, and the other antipsychotic drugs showed low or intermediate anti-toxoplasmic activity. As it is not possible to know the intracellular concentrations of antipsychotics in the brain, further clinical studies are warranted to determine whether these in vitro findings have potential implications in treatment of toxo-positive patients with schizophrenia. These findings may be potentially relevant for the choice of the first-line antipsychotic drug or mood stabilizer in previously infected patients.

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.

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

Up 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.

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

INTRODUCTION: 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<0.001) and rs2498804 (p<0.03) 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.

In 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.

Clinical predictors of response to olanzapine or risperidone during acute episode of schizophrenia.

The study attempted to identify clinical variables which could predict the response to a second-generation antipsychotic treatment during acute episodes among schizophrenic patients. Socio-demographic, premorbid and clinical variables were studied in a population of 95 diagnosed with schizophrenia, as defined in the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSMIV), during an acute treated phase, in a multicentre prospective study. Patients were assigned to olanzapine or risperidone treatment in an open design. Clinical evaluations were performed at D0, D42 and D180. Good response to treatment was defined as a Positive and Negative Syndrome Scale (PANSS) reduction greater than 20% and a Brief Psychiatric Rating Scale (BPRS) score lower than 35. Univariate analysis revealed earlier age at onset of schizophrenia and earlier age at first prescription of antipsychotic among non-responders compared with good responders at D42. Non-responders also had a clinical profile at the onset of antipsychotic treatment characterised by more severe forms of the acute episode as shown by higher scores at the positive, general and overall PANSS scale and on CGI-S and BPRS scores. With a multivariate logistic regression model, age at onset and overall duration of illness remained the only clinical criteria identified as predictors of response to antipsychotic treatment at D42. Clinical variables do not clearly appear to be good predictors of treatment efficacy.

Pharmacogenetic of response efficacy to antipsychotics in schizophrenia: pharmacodynamic aspects. Review and implications for clinical research.

Pharmacogenetics constitutes a new and growing therapeutic approach in the identification of the predictive factors of the response to antipsychotic treatment. This review aims to summarize recent finding into pharmacodynamic approach of pharmacogenetics of antipsychotics and particularly second generation. Studies were identified in the MEDLINE database from 1993 to July 2008 by combining the following Medical Subject Heading search terms: genetic, polymorphism, single nucleotide polymorphism, pharmacogenetics, antipsychotics, and response to treatment as well as individual antipsychotics names. Only pharmacodynamics studies were analyzed and we focused on efficacy studies. We also reviewed the references of ll identified articles. Most studies follow a polymorphism-by-polymorphism approach, and concern polymorphisms of genes coding for dopamine and serotonin receptors. Haplotypic approach has been considered in some studies. Few have studied the combinations of polymorphisms of several genes as a predictive factor of the response to antipsychotics. We present this gene-by-gene approach while detailing the features of the polymorphisms being studied (functionality, linkage disequilibrium) and the features of the studies (studied treatment(s), prospective/retrospective study, pharmacological dosage). We discuss the heterogeneity of the results and their potential clinical implications and extract methodological suggestions for the future concerning phenotype characterization, genotypes variants studied and methodological and statistical approach.

Correlations between cognitive performances and psychotic or schizotypal dimensions.

OBJECTIVE: 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.

[Pharmacogenetics of antipsychotics in schizophrenia]. / Pharmacogénétique des antipsychotiques dans la schizophrénie.

There are no objective criterion of choice between the various antipsychotic treatments available in schizophrenia today. The final aim of the pharmacogenetic study of the efficacy and the tolerance of these treatments is the individual optimization of the drug treatments. Research in progress did not make it possible yet to highlight criteria usable in daily clinical practice. The assessment of larger cohorts, genetically homogeneous and prospectively evaluated should in the future make it possible to better predict the response to the treatment in particular in term of tolerance, to highlight new therapeutic targets and to better understand the mechanism of action of the current treatments.

Longitudinal studies of cognition in schizophrenia: meta-analysis.

BACKGROUND: A wide range of cognitive deficits have been demonstrated in schizophrenia, but their longitudinal course remains unclear. AIMS: To bring together all the available information from longitudinal studies of cognitive performance in people with schizophrenia. METHOD: We carried out a meta-analysis of 53 studies. Unlike previous reviewers, we included all studies (regardless of the type of medication), analysed each variable separately and compared results with data from controls. RESULTS: Participants with schizophrenia showed a significant improvement in most cognitive tasks. The available data for controls showed, with one exception (the Stroop test), a similar or greater improvement. Performance in semantic verbal fluency remained stable in both individuals with schizophrenia and controls. CONCLUSIONS: Participants with schizophrenia displayed improvement in most cognitive tasks, but practice was more likely than cognitive remediation to account for most of the improvements observed. Semantic verbal fluency may be the best candidate cognitive endophenotype.

Executive deficits in psychotic and bipolar disorders - implications for our understanding of schizoaffective disorder.

OBJECTIVE: Schizoaffective disorder could be considered as a form of schizophrenia, a form of bipolar disorder, an independent disorder or a disorder intermediate between bipolar disorder and schizophrenia, within a psychotic continuum. The study of cognitive deficits in subjects with those diagnoses could help differentiate between these possibilities. METHODS: We compared cognitive performances of schizoaffective (SZAff) subjects with those of subjects with schizophrenia (SZ), bipolar disorder with psychotic symptoms (life-time) (BDP), bipolar disorder without life-time occurrence of psychotic symptoms (BD) and normal controls (NC). We used two tests of executive functions - the Wisconsin Card Sorting Test (WCST) and the Trail-making Test (TMT) - that are known to be impaired in those disorders. RESULTS: The number of perseverative errors on WCST was highest in SZ subjects and gradually decreased in SZAff, BDP and, finally in BD subjects. By contrast, SZ and SZAff subjects obtained similar scores in the TMT, as did BD and BDP patients. CONCLUSIONS: These results suggest that, for some deficits, there may be a continuum between SZ, SZAff and affective disorders, whereas SZAff patients most closely resemble SZ patients for other deficits. This implies that different conceptual views about schizoaffective disorder should be seen as complementary, rather than mutually exclusive.

Tardive dyskinesia and glucid metabolism.

UNLABELLED: A role of insulin-dependent diabetes in the onset of tardive dyskinesia has been reported and relies on weak physiopathological evidence. OBJECTIVE: To study the relationship between the occurrence of tardive dyskinesia and variations in glucose levels in a population of patients under typical antipsychotic treatment. METHODS: Sixty-nine patients with a schizophrenic disorder and who had been receiving continuous neuroleptic treatment for at least 2 years were included. Tardive dyskinesias were assessed by the Abnormal Involuntary Movements Scale (AIMS) and glucose levels by glucose oxidase method. RESULTS: No significant differences in values of fasting glucose (FG) levels, post-prandial glucose (PPG) levels and glycosylated haemoglobin between the groups with and without tardive dyskinesia were found. In the sub-group with normal FG, comparison of post-prandial delta glucose levels (difference between PPG and FG) between the two group with and without tardive dyskinesia showed a significant difference (p < 0.05). This comparison also showed a correlation between post-prandial delta glucose levels and the AIMS score in the group with tardive dyskinesia (r = 0.482, p < 0.05). CONCLUSION: Glucose metabolism could be involved in patients with tardive dyskinesia. Various factors outside antipsychotic treatment can favour a disturbance of glucose metabolism, which may not be severe.

Schizotypal dimensions: an intermediate phenotype associated with the COMT high activity allele.

BACKGROUND: Although catechol-O-methyltransferase (COMT) has long been suggested to be implicated in the pathogenesis of schizophrenia, association studies have generated discrepant results concerning the involvement of the COMT gene in schizophrenia. As several studies have suggested that schizotypal traits might be genetically related to schizophrenia, increased statistical power to detect gene effects could be obtained by using dimensional personality traits in unaffected relatives. METHODS: We tested the hypothesis that the functional Val158Met COMT polymorphism might contribute to the variance of self-reported schizotypal scores in a sample of 106 unaffected subjects, composed of controls (N = 57), first-degree relatives of schizophrenic (N = 27) and of bipolar (N = 22) probands. We also looked for specific associations between COMT polymorphisms and the three dimensions of schizotypy (positive, negative, disorganized) assessed by the Schizotypal Personality Questionnaire (SPQ). RESULTS: We found that self-reported SPQ scores are related to COMT genotype (P = 0.01), with individuals homozygous for the high activity allele having the highest scores. This association is primarily due to specific associations with the positive (P = 0.001) and negative (P = 0.04) dimensions. CONCLUSIONS: Our data support the hypothesis that the functional COMT polymorphism could be involved in different psychotic dimensions. This confirms that studying specific schizotypal dimensions can help to identify the genes involved in the pathogenesis of psychosis.

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.

Schizotypal dimensions: continuity between schizophrenia and bipolar disorders.

BACKGROUND: Family studies have suggested that schizophrenia and bipolar disorders share some susceptibility factors. Schizotypal personality disorder (SPD) may be an intermediate phenotype common both to schizophrenia and bipolar disorders. We explored the familiality of schizotypal dimensions by comparing the magnitude of schizotypal dimensions between schizophrenic and bipolar relatives. We also looked for intra-familial resemblance for these dimensions, and for an increased familial risk of schizophrenia and/or bipolar disorders associated with a particular schizotypal dimension. METHODS: We used the Schizotypal Personality Questionnaire (SPQ) to study the three schizotypal dimensions (disorganization, negative and positive) in a sample of unaffected first-degree relatives of schizophrenic (N=85), psychotic bipolar (N=63) and bipolar (N=32) probands. Differences between groups were tested using a two-tailed t-test or ANOVA for continuous variables and a chi-squared test for discrete variables. We used the intraclass correlation method to study the intra-familial correlation. Linear mixed models were used to measure the familial risk. RESULTS: The disorganization dimension appears to be common to relatives of both schizophrenia and psychotic bipolar disorders, but not in the relatives of non-psychotic bipolar probands. This dimension also increases the familial risk of these two disorders. The negative dimension shows intra-familial resemblance (R=0.29), we failed to observe the expected familiality for the disorganized dimension. CONCLUSIONS: The shared nature of the disorganization dimension shown by a similar familial risk for schizophrenia and psychotic bipolar disorders suggests that same genetic background may underlie psychotic disorders. Although, negative dimension is familial, it is not associated for an increased familial risk for both disorders.

Tests of executive functions in first-degree relatives of schizophrenic patients: a meta-analysis.

BACKGROUND: Executive dysfunctions in relatives of schizophrenic patients may be trait markers of genetic liability and thus help us to elucidate the aetiology of schizophrenia. As a large amount of data has been published, a synthesis through a meta-analysis was needed to demonstrate the existence of executive impairments in relatives of schizophrenic patients and to assess their magnitude. METHOD: We conducted a meta-analysis of articles that compared performances of controls and relatives of schizophrenic patients on the four tests most frequently used to assess executive functions: the Wisconsin Card Sorting Test (WCST), the Trail Making Test (TMT), the Stroop Test and the Verbal Fluency (VF) Test. When needed and possible, published data were supplemented with information from the authors. After assessing the homogeneity of the data, effect sizes were estimated and publication bias was tested by use of funnel plots. RESULTS: Relatives of schizophrenic patients performed less well than controls on all executive tests analysed. Effect estimates were in the small to moderate range (from 0.26 to 0.49) for Stroop, WCST and TMT, but were greater for the fluency tests (0.65 for phonological and 0.87 for semantic VF). CONCLUSION: Relatives of schizophrenic patients appear to have wide, although not severe, executive dysfunctions. As the sensitivity of the different tests for impairments in relatives is not the same, the choice of test and method used should be carefully assessed.