Hôpital-Camfrout, France
Hôpital-Camfrout, France

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Bellivier F.,French Institute of Health and Medical Research | Bellivier F.,University Paris Est Creteil | Bellivier F.,Foundation FondaMental | Yon L.,French Institute of Health and Medical Research | And 9 more authors.
Bipolar Disorders | Year: 2011

Objectives: To compare patients with and without a history of suicidal attempts in a large cohort of patients with bipolar disorder and to identify variables that are associated with suicidal behavior. Methods: European Mania in Bipolar Longitudinal Evaluation of Medication (EMBLEM) is a two-year, prospective, observational study that enrolled 3,684 adult patients with bipolar disorder and initiated or changed oral treatment for an acute manic/mixed episode. Of those, 2,416 patients were eligible for the two-year follow-up. Only baseline characteristics were studied in the present study, included sociodemographic data, psychiatric history and comorbidities, history of suicide attempts, history of substance use problems, compliance with treatment, inpatient admissions, and functional status. Symptom severity was assessed using the Clinical Global Impression-Bipolar Disorder (CGI-BP) scale, the Young Mania Rating Scale (YMRS), and the 5-item Hamilton Depression Rating Scale (HAMD-5). A logistic regression model identified baseline variables independently associated with a history of suicidal behavior. Results: Of the 2,219 patients who provided data on their lifetime history of suicide attempts, 663 (29.9%) had a history of suicidal behavior (at least one attempt). Baseline factors associated with a history of suicidal behavior included female gender, a history of alcohol abuse, a history of substance abuse, young age at first treatment for a mood episode, longer disease duration, greater depressive symptom severity (HAMD-5 total score), current benzodiazepine use, higher overall symptom severity (CGI-BP: mania and overall score), and poor compliance. Conclusions: These factors may be considered as potential characteristics to identify subjects at risk for suicidal behavior throughout the course of bipolar disorder. © 2011 John Wiley and Sons A/S.


Pagan C.,Institute Pasteur Paris | Pagan C.,University of Paris Descartes | Botros H.G.,Institute Pasteur Paris | Poirier K.,University of Paris Descartes | And 31 more authors.
BMC Medical Genetics | Year: 2011

Background: Intellectual disability (ID) is frequently associated with sleep disorders. Treatment with melatonin demonstrated efficacy, suggesting that, at least in a subgroup of patients, the endogenous melatonin level may not be sufficient to adequately set the sleep-wake cycles. Mutations in ASMT gene, coding the last enzyme of the melatonin pathway have been reported as a risk factor for autism spectrum disorders (ASD), which are often comorbid with ID. Thus the aim of the study was to ascertain the genetic variability of ASMT in a large cohort of patients with ID and controls.Methods: Here, we sequenced all exons of ASMT in a sample of 361 patients with ID and 440 controls. We then measured the ASMT activity in B lymphoblastoid cell lines (BLCL) of patients with ID carrying an ASMT variant and compared it to controls.Results: We could identify eleven variations modifying the protein sequence of ASMT (ID only: N13H, N17K, V171M, E288D; controls only: E61Q, D210G, K219R, P243L, C273S, R291Q; ID and controls: L298F) and two deleterious splice site mutations (IVS5+2T>C and IVS7+1G>T) only observed in patients with ID. We then ascertained ASMT activity in B lymphoblastoid cell lines from patients carrying the mutations and showed significantly lower enzyme activity in patients carrying mutations compared to controls (p = 0.004).Conclusions: We could identify patients with deleterious ASMT mutations as well as decreased ASMT activity. However, this study does not support ASMT as a causative gene for ID since we observed no significant enrichment in the frequency of ASMT variants in ID compared to controls. Nevertheless, given the impact of sleep difficulties in patients with ID, melatonin supplementation might be of great benefit for a subgroup of patients with low melatonin synthesis. © 2011 Pagan et al; licensee BioMed Central Ltd.


Golmard J.-L.,University Paris 6 et | Scott J.,Northumbria University | Scott J.,Institute of Psychiatry | Etain B.,French Institute of Health and Medical Research | And 17 more authors.
Acta Psychiatrica Scandinavica | Year: 2016

Objective: It is suggested that age at onset (AAO) of bipolar I disorder (BP-I) is decreasing. We tested for a birth-cohort effect on AAO using admixture analysis. Method: A clinical sample of 3896 BP-I cases was analysed using two approaches: (i) in a subsample with untruncated AAO × birth year distribution (n = 1865), we compared the best-fitting model for the observed AAO in patients born ≤1960 and >1960, (ii) to control for potential confounders, two separate subsamples born ≤1960 and >1960 were matched for age at interview (n = 250), and a further admixture analysis was undertaken. Results: The two approaches indicated that the proportion of cases in the early AAO category was significantly greater in cases born >1960; manic onsets were also more frequent in the early onset BP-I cases born >1960. Conclusion: The decrease in AAO of BP-I in recent birth-cohorts appears to be associated with an increase in the proportion of cases in the early onset subgroup; not with a decrease in the mean AAO in each putative subgroup. This could indicate temporal changes in exposure to risk factors for mania. © 2016 John Wiley & Sons A/S, Published by John Wiley & Sons Ltd.


Chaste P.,Institute Pasteur Paris | Clement N.,University of Paris Descartes | Clement N.,French Institute of Health and Medical Research | Mercati O.,Institute Pasteur Paris | And 25 more authors.
PLoS ONE | Year: 2010

Melatonin is a powerful antioxidant and a synchronizer of many physiological processes. Alteration of the melatonin pathway has been reported in circadian disorders, diabetes and autism spectrum disorders (ASD). However, very little is known about the genetic variability of melatonin receptors in humans. Here, we sequenced the melatonin receptor MTNR1A and MTNRW, genes coding for MT1 and MT2 receptors, respectively, in a large panel of 941 individuals including 295 patients with ASD, 362 controls and 284 individuals from different ethnic backgrounds. We also sequenced GPR50, coding for the orphan melatonin-related receptor GPR50 in patients and controls. We identified six non-synonymous mutations for MTNR1A and ten for MTNRW. The majority of these variations altered receptor function. Particularly interesting mutants are MT1-I49N, which is devoid of any melatonin binding and cell surface expression, and MT1-G166E and MT1-I212T, which showed severely impaired cell surface expression. Of note, several mutants possessed pathway-selective signaling properties, some preferentially inhibiting the adenylyl cyclase pathway, others preferentially activating the MAPK pathway. The prevalence of these deleterious mutations in cases and controls indicates that they do not represent major risk factor for ASD (MTNR1A case 3.6% vs controls 4.4%;MTNR7S case 4.7% vs 3% controls). Concerning GPR50, we detected a significant association between ASD and two variations, Δ502-505 and T532A, in affected males, but it did not hold up after Bonferonni correction for multiple testing. Our results represent the first functional ascertainment of melatonin receptors in humans and constitute a basis for future structure-function studies and for interpreting genetic data on the melatonin pathway in patients. © 2010 Chaste et al.


PubMed | AP HM, University of Lausanne, Foundation Fondamental, Northumbria University and 3 more.
Type: Journal Article | Journal: Acta psychiatrica Scandinavica | Year: 2016

It is suggested that age at onset (AAO) of bipolar I disorder (BP-I) is decreasing. We tested for a birth-cohort effect on AAO using admixture analysis.A clinical sample of 3896 BP-I cases was analysed using two approaches: (i) in a subsample with untruncated AAO birth year distribution (n = 1865), we compared the best-fitting model for the observed AAO in patients born 1960 and >1960, (ii) to control for potential confounders, two separate subsamples born 1960 and >1960 were matched for age at interview (n = 250), and a further admixture analysis was undertaken.The two approaches indicated that the proportion of cases in the early AAO category was significantly greater in cases born >1960; manic onsets were also more frequent in the early onset BP-I cases born >1960.The decrease in AAO of BP-I in recent birth-cohorts appears to be associated with an increase in the proportion of cases in the early onset subgroup; not with a decrease in the mean AAO in each putative subgroup. This could indicate temporal changes in exposure to risk factors for mania.

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