Franck Schürhoff

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.

Early and late onset bipolar disorders: two different forms of manic-depressive illness?

BACKGROUND Conflicting results in genetic studies of bipolar disorders may be due to the clinical and genetic heterogeneity of the disease. Age at onset of bipolar disorders may be a key indicator for identifying more homogeneous clinical subtypes. We tested whether early onset and late onset bipolar illness represent two different forms of bipolar illness in terms of clinical features, comorbidity and familial risk. METHODS Among a consecutively recruited sample of 210 bipolar patients, we compared early onset (n=58) and late onset (n=39) bipolar patients; the cut-off points were age at onset before 18 years and after 40 years for the two subgroups. The subgroups were compared by independent t tests and a contingency table by raw chi-square test. Morbid risk among first-degree relatives was measured by the survival analysis method. RESULTS The early onset group had the most severe form of bipolar disorder with more psychotic features (P=0.03), more mixed episodes (P=0.01), greater comorbidity with panic disorder (P=0.01) and poorer prophylactic lithium response (P=0.04). First degree relatives of early onset patients also had a higher risk of affective disorders (P=0.0002), and exhibit the more severe phenotype, i.e bipolar disorder. CONCLUSION Our data suggest that early and late onset bipolar disorders differ in clinical expression and familial risk and may therefore be considered to be different subforms of manic-depressive illness.

Executive dysfunctions as potential markers of familial vulnerability to bipolar disorder and schizophrenia

Attentional and executive impairments have been found both in patients with schizophrenia and in their unaffected first-degree relatives, suggesting that they might be considered as familial vulnerability markers. Several studies have shown that the performance of bipolar patients does not significantly differ from that of schizophrenic patients, so that executive and attentional deficits might not be specific to schizophrenia. In the present study, we aimed to identify executive dysfunctions in schizophrenia and bipolar disorder that might be vulnerability trait markers specific to one or common to both of these diseases. We assessed cognitive performance of euthymic bipolar and schizophrenic patients, their unaffected first-degree relatives and a healthy control group, using neuropsychological tasks to test different components of executive function: the Verbal Fluency Test, the Stroop Word Colour Test, the Wisconsin Card Sorting Test and the Trail Making Test. The two groups of patients and their unaffected relatives demonstrated disproportionately increased slowness on the Stroop test in comparison to the normal healthy group. Patients with schizophrenia performed poorly on all the tests in comparison to the normal healthy subjects, while no other impairment was observed in the bipolar patients and in the relatives of schizophrenic and bipolar patients. Enhanced susceptibility to interference and reduced inhibition could be transnosographical markers for a shared familial vulnerability common to schizophrenia and bipolar disorders.

Conscious and subliminal conflicts in normal subjects and patients with schizophrenia: The role of the anterior cingulate

The human anterior cingulate cortex (ACC), which is active during conflict-monitoring tasks, is thought to participate with prefrontal cortices in a distributed network for conscious self-regulation. This hypothesis predicts that conflict-related ACC activation should occur only when the conflicting stimuli are consciously perceived. To dissociate conflict from consciousness, we measured the behavioral and brain imaging correlates of a motor conflict induced by task-irrelevant subliminal or conscious primes. The same task was studied in normal subjects and in patients with schizophrenia in whom the ACC and prefrontal cortex are thought to be dysfunctional. Conscious, but not subliminal, conflict affected anterior cingulate activity in normal subjects. Furthermore, patients with schizophrenia, who exhibited a hypoactivation of the ACC and other frontal, temporal, hippocampal, and striatal sites, showed impaired conscious priming but normal subliminal priming. Those findings suggest that subliminal conflicts are resolved without ACC contribution and that the ACC participates in a distributed conscious control network that is altered in schizophrenia.

Serotonin transporter gene polymorphisms in patients with unipolar or bipolar depression

To explore the involvement of serotonin transporter (5HTT) in mood disorder, we studied two polymorphisms of the 5HTT gene (a variable number of tandem repeats in the second intron (VNTR) and a 44 bp insertion/deletion in the 5HTT linked polymorphic region (5-HTTLPR)) in a sample of unipolar and bipolar patients and controls. Homozygosity for the short variant of the 5-HTTLPR was significantly more frequent in bipolar patients than in controls (chi2 = 4.68, d.f. = 1, P = 0.03) whereas there was no difference between bipolar patients and controls for allele distribution, suggesting a recessive effect. The interaction between the two markers suggests that the two polymorphisms probably have independent effects to determine the susceptibility to affective disorder. Further studies are required to identify the precise phenotype associated with 5HTT polymorphisms in depressed patients.

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.

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.

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: 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. Copyright

Admixture analysis of age at onset in schizophrenia.

In schizophrenia, clinical, familial and biological characteristics according to age at onset (AAO) suggest that AAO is a valid candidate symptom for genetic studies. However, none of the various thresholds used to define AAO subgroups in schizophrenia has been validated. We aim to define different AAO subtypes by admixture analysis in a sample of prospectively recruited subjects with schizophrenia. Consecutive inpatients and outpatients (N=141) meeting DSM IV criteria for schizophrenia were included. We used admixture analysis to investigate whether the observed AAO distribution consisted of a mixture of gaussian distributions and then compared clinical features and familial risks in the various groups of subjects. The model that best fitted the observed AAO distribution was a mixture of two gaussian distributions (mean+/-S.D.): (19.91+/-3.56 years) and (33.48+/-8.2 years), with a cutoff point at 28 years. The existence of two subgroups according to AAO was further confirmed by the different clinical and familial profiles of these subgroups. The early-onset group consisted predominantly of male patients, with non-paranoid subtypes and with a higher familial risk of schizophrenia spectrum disorders and affective disorders. The late-onset group of patients presented predominantly paranoid subtype, preponderance of females; they were more likely to be married and to have children. We identified two subgroups of schizophrenic subjects with different clinical and familial profiles. This study provides a mathematical validation of the existence of two subgroups defined by an onset of schizophrenia before or after 28 years. These results may have important implications for the search for schizophrenia susceptibility factors. Working with homogeneous subgroups defined on the basis of AAO may facilitate the identification of genetic vulnerability factors in schizophrenia.