Biomedical subjects

Marion Leboyer

Publications and source records attributed to Marion Leboyer.

At least 37 records · Page 2Linked to original sources

PubMed2005

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.

Cognition Disorders↗

PubMed2005

Platelet serotonergic markers as endophenotypes for obsessive-compulsive disorder.

Although compelling evidence has shown that obsessive-compulsive disorder (OCD) has a strong genetic component, its genetic basis remains to be elucidated. Identifying biological abnormalities in nonaffected relatives is one of the strategies advocated to isolate genetic vulnerability factors in complex disorders. Since peripheral serotonergic disturbances are frequently observed in OCD patients, the aim of this study was to investigate if they could represent endophenotypes, by searching for similar abnormalities in the unaffected parents of OCD patients. We assessed whole blood serotonin (5-HT) concentration, platelet 5-HT transporter (5-HTT) and 5-HT2A receptor-binding characteristics, and platelet inositol trisphosphate (IP3) content in a sample of OCD probands (n = 48) and their unaffected parents (n = 65), and compared them with sex- and age-matched controls (n = 113). Lower whole blood 5-HT concentration, fewer platelet 5-HTT-binding sites, and higher platelet IP3 content were found in OCD probands and their unaffected parents compared to controls. Whole blood 5-HT concentration showed a strong correlation within families (p < 0.001). The only parameter that appeared to discriminate affected and unaffected subjects was 5-HT2A receptor-binding characteristics, with increased receptor number and affinity in parents and no change in OCD probands. The presence of peripheral serotonergic abnormalities in OCD patients and their unaffected parents supports a familial origin of these disturbances. These alterations may serve as endophenotypic markers in OCD, and could contribute to the study of the biological mechanisms and genetic underpinnings of the disorder.

Adolescent↗

PubMed2005

Age at onset in bipolar affective disorders: a review.

Bipolar affective disorder (BPAD) is a multifactorial disorder with various clinical presentations. Etiologic heterogeneity may partly underlie the phenotypic heterogeneity. Efforts to dissect BPAD have been based on the course of the disorders (BP I versus BP II or rapid cycling), comorbidity pattern (panic attacks, suicide attempts, addiction or hyperactivity), differences between the sexes, and clinical pattern (cycloid and puerperal psychosis). The present article provides a comprehensive review of the existing data, showing that age at onset (AAO) identifies homogeneous sub-groups of patients with BPAD. Recent work has demonstrated the existence of three--early, intermediate and late--onset bipolar sub-groups based on AAO, following Kendell's criteria for validity (The American Journal of Psychiatry 2003; 160: 999). We will also show how these distinctions may be of use in the search for genetic vulnerability factors and other pathogenic influences. Following Kendell's criteria, we show that AAO of bipolar disorders has been tested with most of the available strategies for establishing the validity of clinical syndromes. We also present data from genetic epidemiologic studies in bipolar disorder, showing that AAO sub-groups may reduce the underlying genetic heterogeneity. No accurate AAO thresholds to define valid sub-groups have been identified precisely. Until recently, studies defined early- and late-onset as corresponding to early or mid-adulthood, not taking into account juvenile-onset bipolar disorder. A recently proposed theoretical model with three AAO sub-groups (onset age 17, 27 and 46) is discussed.

Adolescent↗

PubMed2005

Early-onset obsessive-compulsive disorder: a subgroup with a specific clinical and familial pattern?

BACKGROUND: The familial nature of obsessive-compulsive disorder (OCD) has been previously demonstrated. The identification of candidate symptoms such as age at onset may help to disentangle the clinical and genetic heterogeneity of the disorder. In this study, the specificity of early-onset OCD was investigated, focusing on the effect of gender, comorbid conditions and familial risk of tics and OCD by studying a population consisting exclusively of patients with early-onset OCD. METHODS: One hundred and forty-four patients having OCD were recruited in the study (108 early-onset probands and 36 late-onset probands). The early-onset probands and 199 of their first-degree relatives were investigated using structured interviews and questionnaires. This sample of early onset was mainly composed of children and adolescents (74 children and adolescents and 34 adults). RESULTS: The average age of onset of OCD is 9.98+/-3.2 years. Forty-four per cent of the probands have a comorbid tic disorder. The age-corrected morbid risk among the first-degree relatives is 17% for OCD and 12% for tics. Morbid risk for OCD and tics was independent of the presence of tics in probands. Only 32.6% of the probands have a positive family history of OCD. CONCLUSIONS: These findings are consistent with other reports in the literature that the morbid risk of OCD is elevated in relatives of probands with early-onset OCD. However, the majority of cases do not have a positive family history of OCD. This result suggests that early onset is not the only specific clinical marker for familial risk in OCD. Thus more work is needed to clearly elucidate other factors related to increased genetic vulnerability for OCD.

Adolescent↗

PubMed2005

Impaired decision making in suicide attempters.

OBJECTIVE: The understanding of suicidal behavior is incomplete. The stress-diathesis model suggests that a deficit in serotonergic projections to the orbitofrontal cortex is involved in susceptibility to suicidal behavior. The orbitofrontal cortex has been implicated in decision making, a cognitive function dealing with complex choices that may be under serotonergic modulation. In this preliminary study, the authors assessed decision making in suicide attempters. METHOD: The authors used the Iowa Gambling Task to investigate patients with a history of violent (N=32) or nonviolent (N=37) suicidal behavior, patients suffering from affective disorders with no history of suicidal behavior (N=25), and healthy comparison subjects (N=82). Patients were assessed when they were not suffering from a current axis I disorder. The authors also assessed the correlation of Iowa Gambling Task performance with psychometric measures of impulsivity, hostility, anger, aggression, and emotional instability. RESULTS: Both groups of suicide attempters scored significantly lower than healthy comparison subjects, and violent suicide attempters performed significantly worse than affective comparison subjects. No significant differences were observed between the groups of suicide attempters or between the two comparison groups. The differences in performance could not be accounted for by age, intellectual ability, educational level, number of suicide attempts, age at first suicide attempt, history of axis I disorder, or medication use. Iowa Gambling Task performances were correlated positively with affective lability and with anger expression but not with impulsivity. CONCLUSIONS: Impaired decision making, possibly due to emotional dysfunction, may be a neuropsychological risk factor for suicidal behavior.

Adult↗

PubMed2004

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.

Adult↗

PubMed2004

Lack of association between 5HT2A receptor gene haplotype, bipolar disorder and its clinical subtypes in a West European sample.

Bipolar affective disorder (BPAD) is a complex psychiatric disorder with a major genetic contribution. Abnormalities in serotonergic function have been implicated in its aetiology. The 5HT2A receptor (5HT2AR) gene is a strong candidate gene for involvement in BPAD, but previous association studies have reported conflicting results. These data are difficult to interpret because most negative results were obtained with small samples. The aim of this study was to test the association between the 5HT2AR gene and BPAD in a large West European sample. We studied the -1438G/A and the His452Tyr polymorphisms, for haplotype analysis to increase both informativity and the likelihood of detecting an association between BPAD and the 5HT2AR gene. We analysed the genotype, allele and haplotype distributions of two 5HT2AR gene variants in a population of 356 BPAD patients, which we compared with 208 healthy controls. We also carried out exploratory analysis in clinical subgroups of patients defined according to personal history of mood disorders, suicidal behaviour, comorbid psychiatric disorders and family history of affective disorders. We found no difference between BPAD patients and controls for allele, genotype and haplotype distributions. Exploratory analysis in subgroups of BPAD patients showed only a marginal difference in haplotype distribution between controls and BPAD patients with antidepressant-induced mania (P = 0.018). This difference was not significant after correction for multiple testing. Our study suggests that the 5HT2AR gene is unlikely to be involved in genetic susceptibility to BPAD but should be further investigated in a pharmacogenetic study.

Adult↗

PubMed2004

Abnormal cortical voice processing in autism.

Impairments in social interaction are a key feature of autism and are associated with atypical social information processing. Here we report functional magnetic resonance imaging (fMRI) results showing that individuals with autism failed to activate superior temporal sulcus (STS) voice-selective regions in response to vocal sounds, whereas they showed a normal activation pattern in response to nonvocal sounds. These findings suggest abnormal cortical processing of socially relevant auditory information in autism.

Adult↗

PubMed2004

No association between DUP25 and anxiety disorders.

Gratacos et al. [2001: Cell 106:367-379] described an interstitial duplication dup(15)q24q26 (DUP25) in patients with anxiety disorders; this duplication was found in approximately 90% of patients and in 7% of controls. In order to determine if DUP25 is present in additional individuals susceptible to panic attacks, we tested 44 patients with anxiety disorders, using probes 251c23 and 216c14 mapping in the 15q24 and 15q26 region. We have not detected any DUP25. Our results suggest that DUP25 is not common in people with anxiety disorders in the population tested here.

Adolescent↗

PubMed2004

Lack of evidence for association between serotonin transporter gene (5-HTTLPR) and obsessive-compulsive disorder by case control and family association study in humans.

Association studies of the serotonin transporter (SLC6A4) gene in obsessive-compulsive disorder (OCD) have generated discrepant results. Here, we genotyped the 5-HTTLPR polymorphism in 106 French OCD patients and 171 healthy controls (case control study). We also performed a family association study on 116 trios including an OCD patient (73 French and 43 German). No association was detected between the 5-HTTLPR polymorphism and OCD in either the case control study or the family study.

Adult↗

PubMed2004

Frequency and transmission of glutamate receptors GRIK2 and GRIK3 polymorphisms in patients with obsessive compulsive disorder.

Several lines of evidence suggest that obsessive compulsive disorder (OCD) could be the consequence of glutamatergic dysfunction. We performed a case-control study in 156 patients and 141 controls and the transmission disequilibrium test in 124 parent-offspring trios to search for association between OCD and two kainate receptors, GRIK2 and GRIK3. Using three single nucleotide polymorphisms (SNP) in GRIK2 and one in GRIK3, we found no evidence for association in case-control or family-based analyses. Only the GRIK2 SNP I867, recently associated with autism, was less transmitted than expected (p < 0.03), supporting a functional role for this variant. These findings suggest the need for further investigation of the role of GRIK2 in OCD.

Adolescent↗

PubMed2004

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.

Adult↗

PubMed2004

Platelet serotonergic predictors of clinical improvement in obsessive compulsive disorder.

OBJECTIVE: Serotonin reuptake inhibitors (SRIs) are the most efficient pharmacological treatment of obsessive-compulsive disorders (OCD). Previous studies have suggested that some peripheral serotonergic parameters can be used to predict the clinical outcome of the treatment of OCD patients with SRIs. We tried to identify further peripheral serotonergic parameters that could help predict the clinical outcome of SRI treatment in a sample of patients with OCD. METHODS: We compared 19 OCD patients before and after 8 weeks of SRI treatment with 19 sex-matched and age-matched controls. We assessed clinical improvement and whole-blood serotonin (5-HT) concentration, platelet 5-HT transporter (5-HTT) and 5-HT2A receptor binding characteristics and platelet IP3 content. RESULTS: Before treatment, OCD patients had higher platelet IP3 content and fewer 5-HTT binding sites than the controls. Treatment with SRIs further lowered the number of 5-HTT binding sites, normalized platelet IP3 contents, and lowered the number of platelet 5-HT2A binding sites and whole-blood 5-HT concentrations below control values. The patients who improved most following SRI treatment had higher whole-blood 5-HT concentrations before treatment. CONCLUSION: Our results confirm that whole-blood 5-HT concentration is a predictor for clinical improvement and indicate that abnormal intracellular mechanisms may be involved in OCD patients, in particular, the overstimulation of the phosphoinositide signaling system.

Adolescent↗

PubMed2004

Bipolar patients with suicidal behavior: toward the identification of a clinical subgroup.

BACKGROUND: Suicide is the most severe and frequent complication of bipolar disorder, but little is known about the clinical characteristics of bipolar patients at risk of suicide. The purpose of this study was to identify those characteristics. METHOD: We studied 307 prospectively recruited DSM-IV-diagnosed bipolar I or II patients from November 1994 through October 2001. Semi-structured diagnostic interviews (the Diagnostic Interview for Genetic Studies and the Family Interview for Genetic Studies) were used to determine the diagnosis of bipolar disorder and its lifetime description, lifetime comorbid Axis I disorder diagnoses, familial history of psychiatric disorders and demographic characteristics. RESULTS: One hundred twenty-nine bipolar patients (42%) had made at least 1 suicide attempt in their life. Lifetime history of suicidal behavior was associated with history of suicidal behavior in first-degree relatives but not with a familial history of mood disorder. Early age at onset of mood disorder, total number of previous depressive episodes, alcohol and tobacco use, social phobia, antidepressant-induced mania, and personal history of head injury were associated with suicidal behavior. No association was observed with gender or diagnosis of bipolar I or II disorder. Social phobias, tobacco use, and personal history of head injury were no longer associated with suicidal behavior in the multivariate analysis. CONCLUSION: Bipolar patients with early age at bipolar disorder onset, high number of depressive episodes, personal history of antidepressant-induced mania, comorbid alcohol abuse, and suicidal behavior constitute a clinical subgroup at risk of suicidal behavior. This information, as well as familial history of suicide behavior, should improve suicide risk assessment in bipolar patients.

Adult↗

PubMed2003

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.

Adolescent↗

PubMed2003

Analysis of transmission of novel polymorphisms in the somatostatin receptor 5 (SSTR5) gene in patients with autism.

Infantile autism is a pervasive developmental disorder with a strong genetic component. The mode of inheritance appears to be complex and no specific susceptibility genes have yet been identified. Chromosome 16p13.3 may contain a susceptibility gene based on findings from genome scans and reports of chromosome abnormalities in individuals with autism. The somatostatin receptor 5 (SSTR5) gene is located on chromosome 16p13.3 and is thus a positional candidate gene for autism. SSTR5 may also be a functional candidate gene for autism because somatostatin inhibits growth hormone secretion, and increased growth hormone response has been reported in some individuals with autism. Moreover, the somatostatinergic system interacts with the dopaminergic system, which has been hypothesized to be involved in the etiology of autism; in particular, somatostatin secretion is regulated by dopamine, and the dopamine D2 receptor and the SSTR5 receptor interact to form a receptor complex with enhanced functional activity. In the present study, we tested whether the alleles of twelve new single nucleotide polymorphisms (SNPs) in the SSTR5 gene were preferentially transmitted, using the transmission disequilibrium test (TDT) in a sample of 79 trios with autism (18 from Denmark and 61 from France). Furthermore, we combined four missense SNPs into haplotypes and searched for preferential transmission using the program TRANSMIT. No significant preferential transmission of the alleles and haplotypes of the twelve SNPs was found. Our results do not suggest the SSTR5 gene as a susceptibility gene for autism.

Autistic Disorder↗

PubMed2003

Apolipoprotein E in schizophrenia: a French association study and meta-analysis.

Schizophrenic disorders are complex genetic disorders that may involve multiple genes of small effect. Apolipoprotein E (ApoE) gene variants are associated with alterations in brain function and an increased risk of Alzheimer's disease (AD). However, conflicting results have been reported in schizophrenia. We compared the ApoE genotypes of 114 French Caucasian schizophrenic patients and 91 normal controls. No differences in ApoE allele or genotype frequencies were observed between the two groups. However, we observed a possible association between male schizophrenic patients and the ApoE epsilon 2 epsilon 3 genotype. In addition, a meta-analysis of all published case-control studies on ApoE and schizophrenia did not support a major role for ApoE gene variants in schizophrenia as a whole. However, ApoE may be associated with particular forms of schizophrenia.

Alleles↗

PubMed2003

Anhedonia in schizophrenia: a distinct familial subtype?

Failures to replicate results in psychiatric genetics might be due to our inability to define the heritable phenotype. Instead of relying entirely on classical nosographical approaches, the use of a candidate symptom approach to identify more homogeneous forms of diseases among affected subjects and subclinical traits among first-degree relatives may increase genetic validity. Anhedonia may be a marker for subjects at risk of schizophrenia or schizophrenia spectrum disorders. We compared the familiality of anhedonia characterized by a high level of physical anhedonia (score above 23) in a sample of schizophrenic probands (N=80) and their relatives (N=78), with that in bipolar patients (N=109), their relatives (N=33) and normal controls (N=94). We identified a subform of schizophrenia characterized by highly anhedonic schizophrenic probands with a three-fold higher familial risk of schizophrenia and schizophrenic spectrum disorders. We also found that their first-degree relatives had a high level of anhedonia. An intrafamilial correlation analysis confirmed the familial nature of anhedonia. Our data suggest that anhedonia is a candidate symptom for schizophrenia. Refining phenotype definition by studying subgroups of anhedonic and non-anhedonic probands with relevant candidate genes might be fruitful.

Adult↗