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International audience; Aims: Actigraphy studies of individuals with bipolar disorders (BD) suggest that illness progression may be associated with a range of progressive disruptions in 24-hour rest-activity rhythms (RAR). However, those longitudinal studies were undertaken in older adults with extended histories or illness and treatment rather than young people with emerging BD. To our knowledge, this is the first study to use network modelling to examine the statistical associations between clinical phenotypes of BD and different subsets of RAR markers.Methods: This study of adolescents and young adults (mean age 22 years; 69% female) uses network modelling to examine which self-rated or actigraphic markers of RAR are more strongly associated with full threshold BD (referred to as Stage 2; N = 15) compared with BD-at risk syndromes (subthreshold presentations referred to as Stage 1; N = 25).Results: Network analysis demonstrated that some RAR are associated with both stage of BD and a family history of BD (such as longer sleep duration and higher levels of daytime impairment). Markers of circadian rhythmicity indicated that regulation of this system is weaker in Stage 2 compared with Stage 1 of BD.Limitations: The small subgroup samples may have undermined the ability to detect some associations between phenotypes and RAR.Conclusions: Network modelling may offer a useful strategy for visualizing and analysing patterns of association between RAR and clinical phenotypes defined by stage of illness, familial loading or symptom profile. This could prove useful in understanding the underlying pathophysiology of sleep-wake cycle and circadian rhythm disturbances in BD.

International audience; Objectives Clinical practice guidelines (CPGs) for the treatment of bipolar disorder (BD) provide guidance to health care professionals and patients about the management of core aspects of BD. This study evaluated the overall quality of CPGs and examined the quantity, specificity, clarity and utility of recommendations about four key contemporary themes: sleep, circadian rhythms, activity and energy, and healthy lifestyles. Methods English language editions of CPGs for the treatment of BD were identified by a systematic search of the literature from 2007 onwards (i.e. 15 years). Blind independent ratings were combined to give consensus scores for the quality of each CPGs (using the 14-item International Center for Allied Health Evidence guideline checklist). Composite ratings of the quantity, specificity, clarity and utility of recommendations about the key themes were undertaken using a 0-3 scale. Results Twenty-five CPGs were eligible for review. Overall quality was high (median checklist score=10), but only 11 (44%) CPGs included even basic information about circadian rhythm disturbances. Combined scores for composite ratings about sleep and circadian rhythms were significantly correlated with overall quality of the CPG (sleep, r = 0.43; circadian rhythms, r = 0.42) but not with year of publication. Limitations No reliable scale exists for generating composite ratings of the four themes we examined. Conclusions Circadian rhythms and chronobiology represent neglected domains in CPGs. Incorporating this important theme into future editions of CPGs would aid health care professionals to identify, prevent, or intervene with these problems and improve outcomes for a significant proportion of individuals with BD.

The 10–15-years decrease in life expectancy observed in individuals with bipolar disorder (BD) has been linked to the concept of accelerated cellular aging. Telomere length (TL) and mitochondrial DNA copy number (mtDNAcn) have been proposed as markers of cellular aging and comparisons between individuals with BD and healthy controls (HC) sometimes led to conflicting results. Previous studies had moderate sample sizes and studies combining these two markers into a single analysis are scarce. Using quantitative polymerase chain reaction, we measured both TL and mtDNAcn in DNA (peripheral blood) in a sample of 130 individuals with BD and 78 HC. Regression analyses, receiver operating characteristic (ROC), and clustering analyses were performed. We observed significantly lower TL and mtDNAcn in individuals with BD as compared to HC (respective decrease of 26.5 and 35.8%). ROC analyses showed that TL and mtDNAcn highly discriminated groups (AUC = 0.904 for TL and AUC = 0.931 for mtDNAcn). In the whole population, clustering analyses identified a group of young individuals (age around 36 years), with accelerated cellular aging (both shorter TL and lower mtDNAcn), which consisted mostly of individuals with BD (85.5%). The subgroup of patients with young age but accelerated aging was not characterized by specific clinical variables related to the course of BD or childhood maltreatment. However, patients in this subgroup were more frequently treated with anticonvulsants. Further characterization of this subgroup is required to better understand the molecular mechanisms and the risk factors of accelerated cellular aging in BD.

International audience; Based on the observed circadian rhythms disruptions and sleep abnormalities in bipolar disorders (BD), a chronobiological model has been proposed suggesting that core clock genes play a central role in the vulnerability to the disorder. In this context, the analysis of circadian genes expression levels is particularly relevant, however studies focused on the whole set of core clock genes are scarce. We compared the levels of expression of 19 circadian genes (including the recently described circadian repressor (CIART)) in 37 euthymic individuals with BD and 20 healthy controls (HC), using data obtained by RNA sequencing of lymphoblastoid cell lines and validated the results using RT-qPCR. RNA sequencing data showed that CIART gene expression was correlated with those of ARNTL, ARNTL2, DBP, PER2 and TIMELESS. Data from RNA sequencing showed that the level of expression of four circadian genes (ARNTL, ARNTL2, BHLHE41 and CIART) discriminated individuals with BD from HC. We replicated this result using RT-qPCR for ARNTL and CIART. This study suggests that an imbalance between activation/repression of the transcription within the circadian system in individuals with BD as compared to HC and as such opens avenues for further research in larger independent samples combining both expression and epigenetic analyses.

International audience; Aims: We explored lifetime comorbidities in clinical subsamples with a diagnosis of Psychosis (N = 143), bipolar (BD = 511), and unipolar disorders (UP = 861).Methods: We analyzed trajectories and patterns of comorbidities using novel metrics, namely bubble plots and density of antecedent events per year of illness exposure per individual.Results: Age at onset (AAO) of most comorbidities was similar to epidemiological studies, but cumulative rates were higher in clinical cases. There were some between group differences in patterns or burden of comorbidities, for example, Psychosis showed the earliest AAO of any mental disorder; UP showed the latest AAO of the index diagnosis. The relative risk of multimorbidity was lower in UP compared with other diagnoses, however, the goodness of fit for the illness trajectory path was lowest for BD.Conclusions: Bubble plots offer a useful representation of timing, sequence, cumulative probability and of comorbidities, the added value of reporting density measures was less obvious.

International audience; Sleep disturbances are typical symptoms of acute episodes of bipolar disorder (BD) and differentiate euthymic BD cases from healthy controls (HC). Researchers often employ objective recordings to evaluate sleep patterns, such as actigraphy, whilst clinicians often use subjective ratings, such as the Pittsburgh Sleep Quality Index (PSQI). As evidence suggests the measures may disagree, we decided to compare subjective (PSQI) and objective (3 weeks of actigraphy) sleep profiles in BD cases and HC (n = 154). We examined whether a dimensional approach helps to illustrate different patterns of sleep disturbances and whether the concordance between subjective and objective recordings varies according to clinical status (BD versus HC). Principal component analysis (PCA) extracted two factors from the PSQI, and separate PCAs of actigraphy recordings extracted two factors for mean values of sleep parameters and one factor for intra-individual variability. Correlational and linear regression analyses of PCA-derived dimensions demonstrated that, in both BD and HC, a PSQI "Sleep duration-efficiency" factor was significantly correlated with an actigraphy "Sleep initiation-duration" factor. Furthermore, in BD cases only, the PSQI total score and a PSQI "Sleep Impairments" factor were each significantly correlated with an actigraphy "Sleep Variability" factor. Overall, we found that subjective experiences of sleep may be modulated by different components of objectively recorded sleep in BD compared with HC. Also, the use of PCA enabled us to consider the multi-dimensional nature of subjective sleep, whilst the inclusion of intra-individual sleep variability afforded a more subtle evaluation of objective sleep.

International audience; Background: Bipolar disorder (BD) is a severe chronic psychiatric disorder affecting 0.5 to 1% of the population worldwide. To date, most studies have estimated the cost of BD via information sourced from insurance claims with limited information on clinical characteristics and course of BD. The aims of this study are (i) to estimate the direct healthcare cost associated with BD and to identify contributing factors and (ii) to study the evolution of cost during a two-year follow-up period.Method: We analyzed a sample of 1116 individuals with BD included in the Advanced Centers of Expertise in Bipolar Disorder cohort. We estimated the direct healthcare cost per year and per patient, and we identified the clinical features of patients with BD associated with higher direct healthcare costs. In a subsample of patients followed up for two years centers of expertise for BD, we studied the evolution of direct healthcare cost.Results: The average cost of bipolar disorder was € 6910 per year and per patient. Clinical features of BD, sociodemographic characteristics, and associated addiction were associated with higher direct healthcare costs. In the subsample of patients followed-up for two years, direct healthcare cost dropped by more than 50%, strongly suggesting the beneficial effect of specialized care organization.Limitation: We did not estimate indirect healthcare and intangible costs.Conclusion: Our study investigates the cost of BD and its evolution in a deeply phenotyped longitudinal sample. Cost-utility and cost-effectiveness analyses are required to inform resource allocation decisions and to promote innovative healthcare organizations.

International audience; Objective: Chronobiological models postulate that abnormalities in circadian rest/activity rhythms (CRAR) are core phenomena of bipolar disorders (BDs). We undertook a meta-analysis of published studies to determine whether self- or observer ratings of CRAR differentiate BD cases from comparators (typically healthy controls [HCs]).Method: We undertook systematic searches of four databases to identify studies for inclusion in random effects meta-analyses and meta-regression analyses. Effect sizes (ES) for pooled analyses of self- and observer ratings were expressed as standardized mean differences with 95% confidence intervals (CIs).Results: The 30 studies meeting eligibility criteria included 2840 cases and 3573 controls. Compared with HC, BD cases showed greater eveningness (ES: 0.33; 95% CI: 0.12-0.54), lower flexibility of rhythms (ES: 0.36; 95% CI: 0.06-0.67), lower amplitude of rhythms (ES: 0.55; 95% CI: 0.39-0.70) and more disturbances across a range of CRAR (ES of 0.78-1.12 for general and social activities, sleep and eating patterns). Between study heterogeneity was high (I2 > 70%) and evidence indicated a potential publication bias for studies using the Biological Rhythms Interview of Assessment in Neuropsychiatry. Meta-regression analyses suggested significantly larger ES were observed in studies using observer ratings or including BD cases with higher levels of depressive symptoms.Conclusion: This meta-analysis demonstrates that BD is associated with higher levels of self- or observer-rated CRAR disturbances compared with controls. However, further studies should examine the respective performance of individual instruments when used alone or in combination, to clarify their applicability and utility in clinical practice.

Background Olfactory deficits (OD) are reported as markers for a large spectrum of neuro-psychiatric disorders. Alterations can concern perception, identification, discrimination and assignment of odour's valence of olfaction process. We propose a comprehensive review to summarize which kind of OD were reported in bipolar disorders (BD) and in which phase of the disease, to know if they could be a marker of state or trait. Methods A Systematic Literature Review was conducted using PRISMA guidelines to include all studies assessing olfaction with objective measures in BD. Results 9 studies were identified. All of them have assessed odour identification and 3 reported deficits mainly in patients with psychotic features or elements of illness severity in comparison to healthy subjects. There is no difference in threshold of perception between BD patients and controls and it is no possible to conclude for discrimination because only one study has assessed this dimension in comparison to control. We cannot conclude for hedonic value of odours regarding these studies. Limitations These studies are very incomplete because only one has evaluated all the processes involved in olfaction process. Conclusions In light of this review, evidence is still missing to unveil potential disturbances of olfactory process as a marker of BD. These new avenues of research could help to clarify the links between OD and BD and provide information on the pathophysiology of the disorder according to the impaired dimension.

Bipolar disorder (BD) might be associated with higher infection rates of coronavirus disease (COVID-19) which in turn could result in worsening the clinical course and outcome. This may be due to a high prevalence of somatic comorbidities and an increased risk of delays in and poorer treatment of somatic disease in patients with severe mental illness in general. Vaccination is the most important public health intervention to tackle the ongoing pandemic. We undertook a systematic review regarding the data on vaccinations in individuals with BD. Proportion of prevalence rates, efficacy and specific side effects of vaccinations and in individuals with BD were searched. Results show that only five studies have investigated vaccinations in individuals with BD, which substantially limits the interpretation of overall findings. Studies on antibody production after vaccinations in BD are very limited and results are inconsistent. Also, the evidence-based science on side effects of vaccinations in individuals with BD so far is poor. (c) 2021 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/ )

International audience; Because quantitative reverse transcription PCR (RT-qPCR) gene expression data are compositional, amounts of quantified RNAs must be normalized using reference genes. However, the two most used methods to select reference genes (NormFinder and geNorm) ignore the compositional nature of RT-qPCR data, and often lead to different results making reliable reference genes selection difficult. We propose a method, based on all pairwise equivalence tests on ratio of gene expressions, to select genes that are stable enough to be used as reference genes among a set a candidate genes. This statistical procedure controls the error of selecting an inappropriate gene. Application to 30 candidate reference genes commonly used in human studies, assessed by RT-qPCR in RNA samples from lymphoblastoid cell lines of 14 control subjects and 26 patients with bipolar disorder, allowed to select 7 reference genes. This selection was consistent with geNorm's ranking, less with NormFinder's ranking. Our results provide an important fundamental basis for reference genes identification using sound statistics taking into account the compositional nature of RT-qPCR data. The method, implemented in the SARP.compo package for R (available on the CRAN), can be used more generally to prove that a set of genes shares a common expression pattern.

Kleine-Levin syndrome (KLS) is a rare disorder characterized by severe episodic hypersomnia, with cognitive impairment accompanied by apathy or disinhibition. Pathophysiology is unknown, although imaging studies indicate decreased activity in hypothalamic/thalamic areas during episodes. Familial occurrence is increased, and risk is associated with reports of a difficult birth. We conducted a worldwide case.control genome-wide association study in 673 KLS cases collected over 14 y, and ethnically matched 15,341 control individuals. We found a strong genome-wide significant association (rs71947865, Odds Ratio [OR] = 1.48, P = 8.6 × 10-9) within the 3'region of TRANK1 gene locus, previously associated with bipolar disorder and schizophrenia. Strikingly, KLS cases with rs71947865 variant had significantly increased reports of a difficult birth. As perinatal outcomes have dramatically improved over the last 40 y, we further stratified our sample by birth years and found that recent cases had a significantly reduced rs71947865 association. While the rs71947865 association did not replicate in the entire follow-up sample of 171 KLS cases, rs71947865 was significantly associated with KLS in the subset follow-up sample of 59 KLS cases who reported birth difficulties (OR = 1.54, P = 0.01). Genetic liability of KLS as explained by polygenic risk scores was increased (pseudo R2= 0.15; P < 2.0 ∼ 10-22at P = 0.5 threshold) in the follow-up sample. Pathway analysis of genetic associations identified enrichment of circadian regulation pathway genes in KLS cases. Our results suggest links between KLS, circadian regulation, and bipolar disorder, and indicate that the TRANK1 polymorphisms in conjunction with reported birth difficulties may predispose to KLS.

International audience; Introduction: Although clinical practice guidelines (CPG) identify first, second- and third-line mood stabilizer (MS) treatments, they rarely define clinical response to prophylaxis or the core issues to be considered. This project aimed to develop a template for describing how clinical response may be classified and a framework to assist decision-making and monitoring of response in day-to-day practice.Method: A scoping exercise was undertaken followed by narrative synthesis of (a) qualitative and quantitative definitions of MS response applied in clinical and research practice and (b) potential confounders (eg, non-adherence; tolerability issues) of relevance to routine practice, for example, the concepts are applicable to individuals with bipolar disorder for whom sustained remission is a less realistic goal. Expert consensus was employed to develop a taxonomy of response and key concepts that inform clinical judgements about MS response.Results: Five core constructs can be used to systematize clinical judgements regarding MS response and its monitoring: (a) quantitative, qualitative and/or patient-reported outcome measures (PROMS), (b) personalized assessment of the acceptable benefit-to-harm ratio of a proposed treatment, (c) adequacy of treatment exposure (dose, duration, therapeutic monitoring and adherence), (d) illness activity pre- and post-MS initiation, and (e) other potential confounders (co-prescription of MS; polypharmacy) or protective factors (eg, psychosocial factors).Conclusions: This heuristic framework might be used as a teaching aid or by clinicians who wish to take a more systematic approach to developing shared criteria for judging MS response that better match patient expectations and preferences. Heuristic approaches also allow seamless introduction of new evidence.

BackgroundStudying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools.AimsTo examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics.MethodGenome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts.ResultsEarlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = −0.34 years, s.e. = 0.08), major depression (β = −0.34 years, s.e. = 0.08), schizophrenia (β = −0.39 years, s.e. = 0.08), and educational attainment (β = −0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO.ConclusionsAAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.

International audience; Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.

International audience; Sleep and circadian rhythms disturbances (SCRD) in young people at high risk or with early onset of bipolar disorders (BD) are poorly understood. We systematically searched for studies of self, observer or objective estimates of SCRD in asymptomatic or symptomatic offspring of parents with BD (OSBD), individuals with presentations meeting recognised BD-at-risk criteria (BAR) and youth with recent onset of full-threshold BD (FT-BD). Of 76 studies eligible for systematic review, 35 (46%) were included in random effects meta-analyses. Pooled analyses of self-ratings related to circadian rhythms demonstrated greater preference for eveningness and more dysregulation of social rhythms in BAR and FT-BD groups; analyses of actigraphy provided some support for these findings. Meta-analysis of prospective studies showed that pre-existing SCRD were associated with a 40% increased risk of onset of BD, but heterogeneity in assessments was a significant concern. Overall, we identified longer total sleep time (Hedges g: 0.34; 95% confidence intervals:.1, .57), especially in OSBD and FT-BD and meta-regression analysis indicated the effect sizes was moderated by the proportion of any sample manifesting psychopathology or receiving psychotropic medications. This evolving field of research would benefit from greater attention to circadian rhythm as well as sleep quality measures.

International audience; Patients with bipolar disorder (BD) frequently have cognitive deficits even when euthymic. These deficits are considered one of the main drivers of functional disability in BD. This study investigated whether computerized working memory training using the COGMED® program in patients with BD can improve global functioning, therapeutic compliance, and subjective quality of life. Methods: For this naturalistic prospective study, 40 patients with BD and cognitive complaints were recruited. Sociodemographic, clinical, neurocognitive and functional data were collected before starting the remediation intervention (baseline). At home, patients used the web-based working memory training program COGMED® that included a battery of interactive games (daily sessions, five days per week for five weeks), supported by weekly phone-based feedback. The clinical, neurocognitive and functional assessment was repeated four weeks after the intervention end and compared with the baseline data.Results: Thirty-two patients completed the study. Compared with baseline, general functioning was improved after the working memory training program, as indicated by a mean reduction of 6.78 (SD 4.65) points in the Functioning Assessment Short Test (p

Background Although psychoeducation programmes are the gold-standard intervention in bipolar disorder (BD), more innovative tools are needed to broaden and consolidate their effects, especially on treatment adherence. Serious games could be an option. Methods We carried out a two-arm open randomized controlled trial to compare the add-on use of the serious game BIPOLIFE® for one month (n = 20) vs. treatment as usual (TAU; n = 21) following the completion of a psychoeducation programme in euthymic adults with BD. The primary outcome was the percentage of adherent patients (i.e., patients with a Medication Adherence Rating Scale, MARS, total score >7) at 4 months after the end of the psychoeducation programme. We also measured the changes in therapeutic adherence and beliefs on pharmacological treatments (Drug Attitude Inventory, DAI) between study inclusion and the 1-month (end of BIPOLIFE® use) and 4-month visits, healthcare use during the study period, and BIPOLIFE® acceptability. Results The percentage of adherent patients was lower in the BIPOLIFE® group than in the TAU group at inclusion (p = 0.02). Conversely, the absolute variation of the MARS and DAI scores was higher in the BIPOLIFE® than in the TAU group at the 1-month visit (p = 0.03 and p = 0.002, respectively) but not at the 4-month visit (p = 0.22 and p = 0.07, respectively). Limitations Small sample size, and low frequency of connexion to BIPOLIFE® declared by the patients. Conclusion BIPOLIFE® may help patients with BD to increase their confidence in medications, if used regularly.

Background: Unipolar mania is a putative subtype of bipolar disorder (BD) in which individuals experience recurrent manic but not major depressive episodes. Few studies of unipolar mania have been conducted in developed countries and none in the UK. This study aimed to identify and characterise people with unipolar mania in the UK and France. \ud \ud Methods: People with unipolar mania were ascertained using a South London UK electronic case register and a French BD case series. Each unipolar mania group was compared to a matched group of people with BD who have experienced depressive episodes. \ud \ud Results: 17 people with unipolar mania were identified in South London and 13 in France. The frequency of unipolar mania as a percentage of the BD clinical population was 1.2% for the South London cohort and 3.3% for the French cohort. In both cohorts, people with unipolar mania experienced more manic episodes than people with BD, and in the French cohort were more likely to experience a psychotic illness onset and more psychiatric admissions. Treatment characteristics of people with unipolar mania were similar to people with BD except that the unipolar mania group was less likely to be treated with antidepressants. \ud \ud Limitations: The relatively small number of people with unipolar mania identified by this study limits its power to detect differences in clinical variables. \ud \ud Conclusions: People with unipolar mania can be identified in France and the UK, and they may experience a higher frequency of manic episodes but have similar treatment characteristics to people with BD.

ObjectivesSleep complaints are very common in bipolar disorders (BD) both during acute phases (manic and depressive episodes) and remission (about 80 % of patients with remitted BD have poor sleep quality). Sleep complaints during remission are of particular importance since they are associated with more mood relapses and worse outcomes. In this context, this review discusses the characterization and treatment of sleep complaints in BD.MethodsWe examined the international scientific literature in June 2016 and performed a literature search with PubMed electronic database using the following headings: “bipolar disorder” and (“sleep” or “insomnia” or “hypersomnia” or “circadian” or “apnoea” or “apnea” or “restless legs”).ResultsPatients with BD suffer from sleep and circadian rhythm abnormalities during major depressive episodes (insomnia or hypersomnia, nightmares, nocturnal and/or early awakenings, non-restorative sleep) and manic episodes (insomnia, decreased need for sleep without fatigue), but also some of these abnormalities may persist during remission. These remission phases are characterized by a reduced quality and quantity of sleep, with a longer sleep duration, increased sleep latency, a lengthening of the wake time after sleep onset (WASO), a decrease of sleep efficiency, and greater variability in sleep/wake rhythms. Patients also present frequent sleep comorbidities: chronic insomnia, sleepiness, sleep phase delay syndrome, obstructive sleep apnea/hypopnea syndrome (OSAHS), and restless legs syndrome (RLS). These disorders are insufficiently diagnosed and treated whereas they are associated with mood relapses, treatment resistance, affect cognitive global functioning, reduce the quality of life, and contribute to weight gain or metabolic syndrome. Sleep and circadian rhythm abnormalities have been also associated with suicidal behaviors. Therefore, a clinical exploration with characterization of these abnormalities and disorders is essential. This exploration should be helped by questionnaires and documented on sleep diaries or even actimetric objective measures. Explorations such as ventilatory polygraphy, polysomnography or a more comprehensive assessment in a sleep laboratory may be required to complete the diagnostic assessment. Treatments obviously depend on the cause identified through assessment procedures. Treatment of chronic insomnia is primarily based on non-drug techniques (by restructuring behavior and sleep patterns), on psychotherapy (cognitive behavioral therapy for insomnia [CBT-I]; relaxation; interpersonal and social rhythm therapy [IPSRT]; etc.), and if necessary with hypnotics during less than four weeks. Specific treatments are needed in phase delay syndrome, OSAHS, or other more rare sleep disorders.ConclusionsBD are defined by several sleep and circadian rhythm abnormalities during all phases of the disorder. These abnormalities and disorders, especially during remitted phases, should be characterized and diagnosed to reduce mood relapses, treatment resistance and improve BD outcomes., ObjectifsCette revue propose une synthèse sur la caractérisation et le traitement des plaintes de sommeil dans les troubles bipolaires (TB).MéthodesUne recherche de la littérature scientifique a été effectuée en juin 2016 sur PubMed à l’aide d’une équation de recherche suivante : « bipolar disorder » and (« sleep » or « insomnia » or « hypersomnia » or « circadian » or « apnea » or « restless legs »).RésultatsLes TB présentent des perturbations du sommeil et des rythmes circadiens durant les épisodes aigus mais également au cours des phases de rémission marquées par des anomalies de la qualité et de la quantité du sommeil, et une plus grande variabilité des rythmes veille/sommeil. Ces patients souffrent très fréquemment de troubles du sommeil comorbides : insomnie chronique, hypersomnolence, retard de phase, syndrome d’apnées-hypopnées obstructives du sommeil (SAHOS), et syndrome des jambes sans repos. Ces troubles favorisent les rechutes thymiques, altèrent le fonctionnement cognitif, diminuent la qualité de vie, favorisent une prise de poids et l’apparition d’un syndrome métabolique. Une exploration clinique avec caractérisation de ces troubles est donc indispensable, aidée par des questionnaires, et documentée sur des agendas du sommeil voire des mesures objectives actimétriques. Un bilan plus complet en laboratoire du sommeil peut être nécessaire. Les traitements associés dépendent de la cause. Le traitement de l’insomnie chronique s’appuie sur des techniques non médicamenteuses (restructuration des comportements et rythmes du sommeil), la psychothérapie, et si besoin sur les hypnotiques. Des traitements spécifiques seront proposés dans le syndrome de retard de phase, le SAHOS, ou les autres troubles du sommeil plus rares.

BackgroundMany studies have shown associations between a history of childhood trauma and more severe or complex clinical features of bipolar disorders (BD), including suicide attempts and earlier illness onset. However, the psychopathological mechanisms underlying these associations are still unknown. Here, we investigated whether affective lability mediates the relationship between childhood trauma and the severe clinical features of BD.MethodA total of 342 participants with BD were recruited from France and Norway. Diagnosis and clinical characteristics were assessed using the Diagnostic Interview for Genetic Studies (DIGS) or the Structured Clinical Interview for DSM-IV Axis I disorders (SCID-I). Affective lability was measured using the short form of the Affective Lability Scale (ALS-SF). A history of childhood trauma was assessed using the Childhood Trauma Questionnaire (CTQ). Mediation analyses were performed using the SPSSprocessmacro.ResultsUsing the mediation model and covariation for the lifetime number of major mood episodes, affective lability was found to statistically mediate the relationship between childhood trauma experiences and several clinical variables, including suicide attempts, mixed episodes and anxiety disorders. No significant mediation effects were found for rapid cycling or age at onset.ConclusionsOur data suggest that affective lability may represent a psychological dimension that mediates the association between childhood traumatic experiences and the risk of a more severe or complex clinical expression of BD.

International audience; High mobility group box 1 (HMGB1) is a pro-inflammatory cytokine that emerges as a promising peripheral marker of inflammation. HMGB1 and C-reactive protein levels were assessed in plasma of control subjects and remitted patients with bipolar disorder (BD). HMGB1 levels were significantly higher in patients with BD as compared to control subjects whereas C-reactive protein levels did not differ between the two groups. No significant effect of potential covariates was identified. The results of this pilot study suggest that HMGB1 might be a specific peripheral marker of inflammation in BD.

Introduction : les patients psychiatriques sont à risque de nombreuses comorbidités somatiques. La plupart de ces comorbidités sont liées à des facteurs de risque modifiables. Il existe des recommandations récentes sur le sujet. L’objectif de cette étude est d’évaluer le suivi somatique réalisé, pour ces patients, par les médecins généralistes des 7ème, 8ème et 17ème arrondissements de Paris. Méthode : il s’agit d’une étude épidémiologique transversale déclarative. La liste et l’adresse des médecins sélectionnés ont été élaborées à partir des pages jaunes numériques. Le questionnaire a évalué les différents éléments nécessaires d’un suivi de qualité selon les recommandations en vigueur, et comprends deux questions ouvertes sur les défis et pistes d’amélioration pour la prise en charge de ces patients. Résultats : le taux de réponse au questionnaire est de 18%. Les patients psychiatriques sont fréquemment vus, les différents paramètres de santé clinique sont régulièrement relevés hormis le poids et l’IMC, un bilan biologique est régulièrement prescrit, un ECG est rarement pratiqué pour ces patients, l’orientation vers les spécialistes somatiques n’est pas systématique, la correspondance avec les psychiatres est plutôt pauvre. Concernant les défis et les pistes d’amélioration, apparaît en prédominance la nécessité de mieux correspondre avec les psychiatres. Conclusion : nombre de pratiques sont en accord avec les recommandations. Cependant une sensibilisation sur la nécessité d’une surveillance pondérale et ECG plus fréquente, le recours plus systématique aux spécialistes somatiques, et une meilleure correspondance avec les psychiatres est souhaitable.

Genome-wide analysis (GWA) is an effective strategy to discover extreme effects surpassing genome-wide significant levels in studying complex disorders; however, when sample size is limited, the true effects may fail to achieve genome-wide significance. In such case, there may be authentic results among the pools of nominal candidates, and an alternative approach is to consider nominal candidates but are replicable across different samples. Here, we found that mRNA expression of the choline dehydrogenase gene (CHDH) was uniformly upregulated in the brains of bipolar disorder (BPD) patients compared with healthy controls across different studies. Follow-up genetic analyses of CHDH variants in multiple independent clinical datasets (including 11,564 cases and 17,686 controls) identified a risk SNP rs9836592 showing consistent associations with BPD (Pmeta = 5.72 × 10−4), and the risk allele indicated an increased CHDH expression in multiple neuronal tissues (lowest P = 6.70 × 10−16). These converging results may identify a nominal but true BPD susceptibility gene CHDH. Further exploratory analysis revealed suggestive associations of rs9836592 with childhood intelligence (P = 0.044) and educational attainment (P = 0.0039), a “proxy phenotype” of general cognitive abilities. Intriguingly, the CHDH gene is located at chromosome 3p21.1, a risk region implicated in previous BPD genome-wide association studies (GWAS), but CHDH is lying outside of the core GWAS linkage disequilibrium (LD) region, and our studied SNP rs9836592 is ∼1.2 Mb 3′ downstream of the previous GWAS loci (e.g., rs2251219) with no LD between them; thus, the association observed here is unlikely a reflection of previous GWAS signals. In summary, our results imply that CHDH may play a previously unknown role in the etiology of BPD and also highlight the informative value of integrating gene expression and genetic code in advancing our understanding of its biological basis.

International audience

International audience; BACKGROUND:Immune dysfunction could play a significant role in the pathogenesis of bipolar disorder (BD) and schizophrenia (SZ), conditions with an underlying pro-inflammatory state. Studies on humoral immune responses (which reflects antibody mediated fight against pathogens) in schizophrenia and bipolar disorder are sparse and often providing contradictory results. The aim of this study was to assess humoral immunity in a group of stable bipolar disorder and schizophrenia patients compared to controls by determining total Immunoglobulins and IgG subclasses and to assess their association with latent Toxoplasma gondii and/or CMV infection.METHODS:334 subjects (124 BD, 75 SZ and 135 Healthy Controls [HC]) were included and tested for humoral immunity by determining the total immunoglobulins (IgG,A and M) and IgG subclasses (IgG1, IgG2, IgG3, IgG4) and their relationship with latent Toxoplasma gondii infection, an established risk factor for BD and SZ.RESULTS:Although lower levels of IgG, IgG1, IgG2, IgG4 and IgA were found among BD as compared to HC and/or SZ, after adjustment for confounding variables, only low levels of IgG and IgG1 in BD remai- ned significant. Strikingly highest levels of antibodies to T. gondii (but not CMV) infection in BD and SZ were associated with lowest levels of IgG3 and IgG4 levels as compared to controls.CONCLUSIONS:Schizophrenia and bipolar disorder patients with latent T. gondii specific infection may be more vulnerable to changes in immuno-inflammatory processes than controls with similar latent infectious state. Simultaneous sequential immunological monitoring both in steady state and active disease phases in the same BD and SZ patients are warranted to understand the role of Toxoplasma gondii latency in these disorders.

International audience; Importance: Lithium is a first-line mood stabilizer for the treatment of bipolar affective disorder (BPAD). However, the efficacy of lithium varies widely, with a nonresponse rate of up to 30%. Biological response markers are lacking. Genetic factors are thought to mediate treatment response to lithium, and there is a previously reported genetic overlap between BPAD and schizophrenia (SCZ).Objectives: To test whether a polygenic score for SCZ is associated with treatment response to lithium in BPAD and to explore the potential molecular underpinnings of this association.Design, setting, and participants: A total of 2586 patients with BPAD who had undergone lithium treatment were genotyped and assessed for long-term response to treatment between 2008 and 2013. Weighted SCZ polygenic scores were computed at different P value thresholds using summary statistics from an international multicenter genome-wide association study (GWAS) of 36 989 individuals with SCZ and genotype data from patients with BPAD from the Consortium on Lithium Genetics. For functional exploration, a cross-trait meta-GWAS and pathway analysis was performed, combining GWAS summary statistics on SCZ and response to treatment with lithium. Data analysis was performed from September 2016 to February 2017.Main outcomes and measures: Treatment response to lithium was defined on both the categorical and continuous scales using the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder score. The effect measures include odds ratios and the proportion of variance explained.Results: Of the 2586 patients in the study (mean [SD] age, 47.2 [13.9] years), 1478 were women and 1108 were men. The polygenic score for SCZ was inversely associated with lithium treatment response in the categorical outcome, at a threshold P < 5 × 10-2. Patients with BPAD who had a low polygenic load for SCZ responded better to lithium, with odds ratios for lithium response ranging from 3.46 (95% CI, 1.42-8.41) at the first decile to 2.03 (95% CI, 0.86-4.81) at the ninth decile, compared with the patients in the 10th decile of SCZ risk. In the cross-trait meta-GWAS, 15 genetic loci that may have overlapping effects on lithium treatment response and susceptibility to SCZ were identified. Functional pathway and network analysis of these loci point to the HLA antigen complex and inflammatory cytokines.Conclusions and relevance: This study provides evidence for a negative association between high genetic loading for SCZ and poor response to lithium in patients with BPAD. These results suggest the potential for translational research aimed at personalized prescribing of lithium.Trial registration: ClinicalTrials.gov NCT00001174.

Introduction: the management of pregnant women with chronic depression or bipolar disorder is an important challenge. The aim is to maintain an euthymic status while taking into account the fetal and neonatal risks of exposure to treatment. Some studies also suggest an increased rate of obstetric complications including prematurity and low birth weights, but this is controversial and possibly related to methodological issues. Objective: to evaluate obstetric and neonatal impact in patients with bipolar disorder or depressive syndrome preexisting in pregnancy and treated with an antidepressant or a mood stabilizer. Material and method: a retrospective observational retrospective study of exposed-non-exposed type with matching cases. The study period was from January 15, 2012 to May 4, 2016. Our primary outcome was a composite outcome: preterm delivery

International audience; Comment on : Enrichment of deleterious variants of mitochondrial DNA polymerase gene (POLG1) in bipolar disorder. [Psychiatry Clin Neurosci. 2017]

Objectives To examine (i) the frequency of different sleep complaints (early wake-up, trouble falling asleep, hypersomnia) and their co-occurrence and (ii) the sociodemographic characteristics and psychiatric comorbidity associated with each type of sleep profiles. Methods Data were drawn from the Wave 2 National Epidemiologic Survey on Alcohol and Related Conditions, a nationally representative survey of the US adult population (wave 1, 2001–2002; wave 2, 2004–2005). The primary analyses were limited to 3573 participants who had a DSM-IV-TR diagnosis of major depressive episode (MDE) between the two waves. We used a multiple regression model to estimate the strength of independent associations between self-reported sleep complaints, sociodemographic characteristics and lifetime psychiatric comorbidity. Results Most of participants with MDE (92%) reported significant sleep complaints, from whom 85.2% had insomnia and 47.5% hypersomnia symptoms. The prevalence rates were for insomnia “only” of 48.5%, hypersomnia “only” of 13.7%, and their co-occurrence of 30.2%. We found that several sociodemographic characteristics (gender, age, education, individual and familial income, marital status) and psychiatric disorders (bipolar disorders, post-traumatic disorders and panic disorder) were significantly and independently associated with different sleep profiles. The co-occurrence of insomnia (especially early wake-up) and hypersomnia presented with a two-/three- fold increase risk of bipolar disorders. Limitations Definitions of sleep complaints were qualitative and subjective. Conclusion Sleep complaints are prevalent and heterogeneous in expression during MDE. Sleep disturbance profiles are associated with specific patterns of comorbidity. Our findings highlight the importance of continued research on sleep complaints during MDE while taking into account psychiatric comorbidity.

IntroductionAntibiomania is characterized by the emergence of a manic episode in reaction to antibiotics. Although relatively uncommon, this kind of side effect is observed in a growing number of cases and mostly occurs in patients who do not have a history of bipolar disorder. Several dozen cases have been reported showing the onset of manic symptoms after taking antibiotics. The antibiotic most frequently involved is clarithromycin.Clinical caseWe report the case of a 61-year-old patient who presented a manic episode after taking an antibiotic combination to treat Helicobacter pylori. Five days after the start of highly active antiretroviral therapy (HAART), behavioral problems appeared (aggressiveness, irritability, talkativeness, insomnia). At the time of hospitalization, she had an acute delusional symptomatology, with a theme of persecution, associated with intuitive, interpretive and imaginative mechanisms. Manic symptoms were obvious: psychomotor excitement, aggressiveness and irritability, flight of ideas, verbal disinhibition and a denial of problems. There was no toxic cause. Brain magnetic resonance imaging (MRI) was normal. Her condition improved very quickly and delusions disappeared in four days. Mrs. H. could critic her delirium and recovered a euthymic state. During hospitalization, treatment divalproate sodium was introduced (250 mg, 3 times a day), was maintained following hospital discharge for 2 years for prevention, and then decreased to the stop. There are currently no further behavioral problems or sleep disorders two years after this episode.DiscussionFacing this clinical case, several questions arise: Which drug therapy is the most suitable for this type of mental disorder? Are there predictors of antibiomania? Is there a risk of recurrence of mood episodes following an antibiomania that occurs spontaneously? What are the pathophysiological mechanisms that could explain this reaction? In all cases identified, stopping the antibiotics was decisive. However, the introduction of a psychotropic and the duration of this treatment remain unclear. First, longitudinal follow-up would assess this variable. Second, it is unclear whether the presence of personal psychiatric history is a predictor of antibiomania. Finally, there are several hypotheses to explain antibiomania: the competitive effect of GABAergic inhibitory receptors, seizure-like phenomena that mimic psychiatric symptoms, and disruption of the intestinal microbiota by antibiotics leading to a modification of the functioning of the central nervous system. The explanatory model of antibiomania is not yet known and requires further research., L’antibiomania se définit par l’apparition d’un épisode maniaque en réaction à la prise d’antibiotiques. Ce phénomène, bien qu’assez rare, n’est pas négligeable étant donné le nombre croissant de cas observé. Il se manifeste en général chez des sujets n’ayant pas d’antécédent de trouble bipolaire. Nous décrivons le cas d’une patiente de 61 ans qui a présenté un épisode maniaque suite à la prise d’une trithérapie antibiotique reçue pour l’éradication d’Helicobacter pylori dans le cadre d’un ulcère gastroduodénal. À l’arrêt du traitement antibiotique, les symptômes maniaques ont régressé en quelques jours. Plusieurs questions se posent notamment sur l’attitude thérapeutique à adopter et les causes expliquant l’antibiomania. Celles-ci sont encore floues. Nous abordons par ailleurs plusieurs hypothèses étiologiques : l’effet compétitif inhibiteur au niveau des récepteurs gabaergiques, l’effet épileptogène mimant un tableau psychiatrique, et la perturbation du microbiote intestinal par les antibiotiques, modifiant de façon indirecte le fonctionnement du système nerveux central.

Introduction: sleep and circadian rhythms abnormalities are frequently observed in bipolar disorders (BD), and have an important impact on patient’s health. On the other hand, the prevalence of metabolic syndrome in BD is higher than in the general population, and multiple factors are involved. Our hypothesis in this thesis is that there might be a link between sleep and circadian abnormalities, and the components of the metabolic syndrome in BD. Such associations have already been shown, but studies in this field are rare. This links have been studied in the general population, and hormonal and inflammation mechanisms may be involved. Aim of the study: to study the association between sleep efficiency (SE) and M10 onset and the components of the metabolic syndrome and BMI in a population of 67 bipolar inpatients in remission. Then we also explore associations with fragmentation index of sleep (IF) and amplitude of the circadian rhythm. Results: we showed that there was a significant association between SE and triglycerides levels, and between M10 onset and systolic blood pressure (PAS). Furthermore, we found a significant association between FI and PAS. The impact of some potential confounding factors such as obstructive sleep apnea or treatments might not explained the associations we observed. Conclusion: this exploratory results should be further investigated in larger studies, because it might shed some light on the physiopathology of the metabolic syndrome in this vulnerable population and lead to new ways to treat BP comorbidities.; Introduction : les patients atteints de troubles bipolaires (TB) en rémission présentent des troubles du sommeil et des anomalies des rythmes circadiens, qui ont des répercussions importantes sur leur santé. D’autre part, la prévalence du syndrome métabolique chez ces patients est plus élevée que dans la population générale, et les facteurs qui y contribuent sont encore mal déterminés. L’hypothèse de cette thèse est qu’il existe un lien entre ces troubles du sommeil et des rythmes et les composantes du syndrome métabolique dans les TB. De telles associations ont déjà été retrouvées dans la littérature. Cependant les études dans ce domaine sont rares, et aucune ne se penche sur le syndrome métabolique dans son ensemble. Dans la population générale ces liens ont pourtant été étudiés, et les hypothèses physiopathologiques qui les soutiennent comprennent des phénomènes hormonaux et inflammatoires. Objectif : étudier, dans une population de 67 patients bipolaires en rémission, l’association entre l’efficacité du sommeil (EF) et le M10 onset mesurés par actigraphie, avec les composantes du syndrome métabolique et l’IMC. Les critères de jugement secondaires étaient l’indice de fragmentation du sommeil (IF) et l’amplitude de l’activité. Résultats : nous retrouvions une association significative entre l’EF et le taux de triglycérides, et entre le M10 onset et la pression artérielle systolique (PAS). De plus, nous trouvions une association significative entre l’IF et la PAS. Ces liens ne semblent pas dépendant de facteurs confondants tels que le risque d’OSA, le tabagisme actuel, la prescription d’APA. Conclusion : ces résultats exploratoires méritent d’être explorés dans des études plus larges, car ils permettent une meilleure compréhension de la physiopathologie du syndrome métabolique dans une population particulièrement vulnérable et peuvent ouvrir la voie à de nouvelles thérapeutiques dans les TB.

International audience; Objective: To explore the prevalence and clinical profile of males and females who develop antidepressant treatment-emergent mania (ATEM).Method: From an original sample of 754 patients with BD, we identified ATEM+ cases (n = 75) and ATEM- controls (n = 135) that met stringent criteria. We specifically examined the combinations of clinical factors that best classified males and females as ATEM+ cases.Results: Seventy-five individuals were classified as ATEM+; 87% of ATEM events occurred during antidepressant monotherapy. Regression analyses demonstrated that the presence of an alcohol and/or substance use disorder [Odds Ratio (OR) 6.37], a history of one or more suicide attempts (OR 4.19) and higher number of depressive episodes per year of illness (OR 1.71) correctly classified 73% of males. In contrast, 84% of females were correctly classified on the basis of a positive history of thyroid disorder (OR 3.23), a positive family history of BD I (OR 2.68) and depressive onset polarity (OR 2.01).Conclusion: Using stringent definitions of ATEM status to reduce the probability of inclusion of false-positive cases and false-negative controls, we identified for the first time that the risk profiles for the development of an ATEM differ significantly according to gender.

Background It is increasingly recognised that reliable and valid assessments of lithium response are needed in order to target more efficiently the use of this medication in bipolar disorders (BD) and to identify genotypes, endophenotypes and biomarkers of response. Methods In a large, multi-centre, clinically representative sample of 300 cases of BD, we assess external clinical validators of lithium response phenotypes as defined using three different recommended approaches to scoring the Alda lithium response scale. The scale comprises an A scale (rating lithium response) and a B scale (assessing confounders). Results Analysis of the two continuous scoring methods (A scale score minus the B scale score, or A scale score in those with a low B scale score) demonstrated that 21–23% of the explained variance in lithium response was accounted for by a positive family history of BD I and the early introduction of lithium. Categorical definitions of response suggest poor response is also associated with a positive history of alcohol and/or substance use comorbidities. High B scale scores were significantly associated with longer duration of illness prior to receiving lithium and the presence of psychotic symptoms. Limitations The original sample was not recruited specifically to study lithium response. The Alda scale is designed to assess response retrospectively. Conclusions This cross-validation study identifies different clinical phenotypes of lithium response when defined by continuous or categorical measures. Future clinical, genetic and biomarker studies should report both the findings and the method employed to assess lithium response according to the Alda scale.

International audience; Objectives: Although cognitive deficits are a well-established feature of bipolar disorders (BD), even during periods of euthymia, little is known about cognitive phenotype heterogeneity among patients with BD.Methods: We investigated neuropsychological performance in 258 euthymic patients with BD recruited via the French network of expert centers for BD. We used a test battery assessing six domains of cognition. Hierarchical cluster analysis of the cross-sectional data was used to determine the optimal number of subgroups and to assign each patient to a specific cognitive cluster. Subsequently, subjects from each cluster were compared on demographic, clinical functioning, and pharmacological variables.Results: A four-cluster solution was identified. The global cognitive performance was above normal in one cluster and below normal in another. The other two clusters had a near-normal cognitive performance, with above and below average verbal memory, respectively. Among the four clusters, significant differences were observed in estimated intelligence quotient and social functioning, which were lower for the low cognitive performers compared to the high cognitive performers.Conclusions: These results confirm the existence of several distinct cognitive profiles in BD. Identification of these profiles may help to develop profile-specific cognitive remediation programs, which might improve functioning in BD.Keywords: attention; bipolar disorders; cluster analysis; cognition; euthymia; executive functions; social functioning; speed processing; verbal memory; working memory.

Borderline personality disorder (BOR) is determined by environmental and genetic factors, and characterized by affective instability and impulsivity, diagnostic symptoms also observed in manic phases of bipolar disorder (BIP). Up to 20% of BIP patients show comorbidity with BOR. This report describes the first case–control genome-wide association study (GWAS) of BOR, performed in one of the largest BOR patient samples worldwide. The focus of our analysis was (i) to detect genes and gene sets involved in BOR and (ii) to investigate the genetic overlap with BIP. As there is considerable genetic overlap between BIP, major depression (MDD) and schizophrenia (SCZ) and a high comorbidity of BOR and MDD, we also analyzed the genetic overlap of BOR with SCZ and MDD. GWAS, gene-based tests and gene-set analyses were performed in 998 BOR patients and 1545 controls. Linkage disequilibrium score regression was used to detect the genetic overlap between BOR and these disorders. Single marker analysis revealed no significant association after correction for multiple testing. Gene-based analysis yielded two significant genes: DPYD (P=4.42 × 10−7) and PKP4 (P=8.67 × 10−7); and gene-set analysis yielded a significant finding for exocytosis (GO:0006887, PFDR=0.019; FDR, false discovery rate). Prior studies have implicated DPYD, PKP4 and exocytosis in BIP and SCZ. The most notable finding of the present study was the genetic overlap of BOR with BIP (rg=0.28 [P=2.99 × 10−3]), SCZ (rg=0.34 [P=4.37 × 10−5]) and MDD (rg=0.57 [P=1.04 × 10−3]). We believe our study is the first to demonstrate that BOR overlaps with BIP, MDD and SCZ on the genetic level. Whether this is confined to transdiagnostic clinical symptoms should be examined in future studies.

International audience; Objectives: Reliable predictors of response to lithium are still lacking in bipolar disorders (BDs). However, childhood trauma has been hypothesized to be associated with poor response to lithium.Methods: We included 148 patients with BD, euthymic when retrospectively and clinically assessed for response to lithium and childhood trauma using reliable scales.Results: According to the 'Alda scale', the sample consisted in 20.3% of excellent responders, 49.3% of partial responders and 30.4% of non-responders to lithium. A higher level of physical abuse significantly correlated with a lower level of response to lithium (P = 0.009). As compared to patients not exposed to any abuse, patients with at least two trauma abuses (emotional, physical or sexual) were more at risk of belonging to the non-responders group (OR = 4.91 95% CI (1.01-27.02)). Among investigated clinical variables, lifetime presence of mixed episodes and alcohol misuse were associated with non-response to lithium. Multivariate analyses demonstrated that physical abuse and mixed episodes were independently associated with poor response to lithium (P = 0.005 and P = 0.013 respectively).Conclusions: Childhood physical abuse might be involved in a poor future response to lithium prophylaxis, this effect being independent of the association between clinical expression of BD and poor response to lithium.

International audience; Bipolar disorder (BD) is associated with an increased risk of tobacco dependence, the leading addictive substance worldwide. Toll-like receptor 4, a sensor of pathogens and of products of cellular stress and damage, is a major innate immune molecule and logical candidate gene for tobacco dependence in BD because (i) the involvement of TLR4 molecules in several substance use disorders has been suggested, (ii) and the association between the TLR4 gene and BD. We analysed herein the potential association between six TLR4 polymorphisms and lifetime tobacco smoking in 514 BD patients. Significant association between tobacco smoking and rs10759932 was found (genotype, Cochrane Armitage trend test, p=0.008, pcorrected=0.040 and alleles, p=0.008; pcorrected=0.040), where the C minor allele is associated with a protective effect, even after adjusting for confounding factors (OR=1.54 [1.04-2.30], p=0.03). Our results suggest that TLR4 gene polymorphism may act as an intermediate factor for the association between tobacco smoking addiction and BD.

International audience; Preliminary studies suggest that lithium (Li) response might be associated with some circadian gene polymorphisms, we therefore performed a pharmacogenetic study on the core clock genes in two independent samples suffering from bipolar disorder (BD) and thoroughly characterized for their Li response. Two independent Caucasian samples (165 and 58 bipolar patients) treated with Li were selected from samples recruited in a French multicenter study and assessed for their Li response using the Alda scale. The two samples were genotyped using the Human660 (H660) and OmniExpress (OE) BeadChips and gene-based association analyses of 22 core clock genes were conducted. In the first sample (H660 chip), the RAR-related orphan receptor-a gene (RORA) and the Peroxisome Proliferator-Activated Receptor Gamma, Coactivator 1 Alpha gene (PPARGC1A or PGC-1α) were significantly associated with the Li response (empirical P-value = 0.0015 and 0.04, respectively), and remained significant only for RORA after Bonferroni correction. In the second sample (OE chip), PPARGC1A was significantly associated with the Li response (empirical P-value = 0.04), and did not remain significant after Bonferroni correction. PPARGC1A is a master regulator of mitochondrial function and a key component of the endogenous clock that stimulates the expression of Bmal1 and Rev-erb-alpha through coactivation of RORA. Although the observed associations deserve further replication and investigation, our results suggest genetic associations between Li response and these two close biological partners: PPARGC1A and RORA involved in circadian rhythms and bioenergetics processes in Li response.

Background: Bipolar disorder is a common chronic illness characterized by high levels of morbidity and all-cause mortality. Lithium is one of the gold standard mood stabilizer treatments, but the identification of good, partial and non-responders in clinical settings is inconsistent. Methods: We used an established rating scale (the Alda scale) to classify the degree of lithium response (good response, partial response, non-response) in a large, multicentre clinically representative sample of well-characterized cases of bipolar disorders I and II. Next, we examined previously reported clinical predictors of response to determine which factors significantly differentiated between the three response groups. Results: Of 754 cases, 300 received lithium, for at least 6 months, as a treatment for bipolar disorder (40%). Of these cases, 17% were classified as good response, 52% as partial response and 31% as non-response. Lifetime history of mixed episodes ( p = 0.017) and alcohol use disorders ( p = 0.015) both occurred in >20% of partial response and non-response groups but Conclusions: Only three factors previously identified as predictors of lithium response significantly differentiated the response groups identified in our sample. Interestingly, these factors have all been found to co-occur more often than expected by chance, and it can be hypothesized that they may represent a shared underlying factor or dimension. Further prospective studies of predictors and the performance of the Alda scale are recommended.

Background Childhood trauma has been associated with a more severe clinical expression of bipolar disorder (BD). However, the results that specifically associated traumatic events and psychotic features in BD have been inconsistent, possibly due to the low resolution of the phenotypes being used. Methods 270 normothymic patients with BD completed the Childhood Trauma Questionnaire (CTQ) and the Peters Delusion Inventory (PDI) that assessed 21 delusional beliefs. Patients were characterized for the lifetime presence of psychotic features during episodes and cannabis misuse in accordance with DSM-IV. We performed a series of path analyses to investigate the links from three types of childhood abuse (physical, sexual and emotional) directly to delusional beliefs and psychotic features, and indirectly through cannabis misuse. Results A first path analysis showed no link between any of the childhood abuse types and psychotic features when only a categorical definition of psychosis was used. When incorporating the quasi-dimensional measure of delusional beliefs in a second path analysis, we found that emotional and physical abuse and cannabis misuse were each directly associated with PDI score. PDI score and psychotic features were strongly correlated. Childhood abuse did not operate through cannabis misuse to increase delusional beliefs. Including type of BD in the model did not alter the results. Conclusion Emotional and physical abuse, but also cannabis misuse, increased delusional beliefs in patients with BD. Using a quasi-dimensional measure of psychotic symptoms in BD provided higher resolution of the psychosis phenotype and helped reconcile ambiguous findings from previous studies.

Background: Clinical features of attention deficit hyperactivity disorder can be frequently observed in cases with bipolar disorders and associated with greater severity of bipolar disorders. Although designed as a screening tool for attention deficit hyperactivity disorder, the Wender Utah Rating Scale could, given its factorial structure, be useful in investigating the early history of impulsive, inattentive or mood-related symptoms among patients with bipolar disorders. Methods: We rated the Wender Utah Rating Scale in 276 adult bipolar disorder cases and 228 healthy controls and tested its factorial structure and any associations with bipolar disorder phenomenology. Results: We confirmed a three-factor structure for the Wender Utah Rating Scale (‘ impulsivity/temper’, ‘ inattentiveness’ and ‘ mood/self-esteem’). Cases and controls differed significantly on Wender Utah Rating Scale total score and sub-scale scores ( p-values −5). About 23% of bipolar disorder cases versus 5% of controls were classified as ‘ WURS positive’ (odds ratio = 5.21 [2.73–9.95]). In bipolar disorders, higher Wender Utah Rating Scale score was associated with earlier age at onset, severity of suicidal behaviors and polysubstance misuse; multivariate analyses, controlling for age and gender, confirmed the associations with age at onset ( p = 0.001) and alcohol and substance misuse ( p = 0.001). Conclusion: Adults with bipolar disorders who reported higher levels of childhood symptoms on the Wender Utah Rating Scale presented a more severe expression of bipolar disorders in terms of age at onset and comorbidity. The Wender Utah Rating Scale could be employed to screen for attention deficit hyperactivity disorder but also for ‘ at-risk behaviors’ in adult bipolar disorder cases and possibly for prodromal signs of early onset in high-risk subjects.

The ElectroConvulsive Therapy (ECT) is a major treatment, as a first or second line, for mood disorders, especially when talking about major depressive disorders. This is nowadays commonly accepted and is therefore included in the current psychiatric guidelines.However, this therapy causes significant sides effects at a cognitive level and in terms of memory losses. Many studies describe them as well as ongoing studies to find a way to minimize these side effects. A less well understood, though described since ECT have started, is the mood switch during the therapy, mainly ECT-induced mania.Mood switches can be spontaneous or triggered, many factors could in that case be involved. ECT and other brain stimulation technics are now spotted as triggering factors for developing mania. Nevertheless, there are no guidelines for supporting patients in such a case. DSM V is though describing the ECT-induced mania as a bipolar disorder criteria.This academic work is illustrated through 4 case reports which show major differences in the way of handling the ECT-induced mania. This enhances the need for guidelines.; L’ÉlectroConvulsivoThérapie (ECT) est un traitement de choix en première ou deuxième intention dans les troubles de l’humeur, en particulier les épisodes dépressifs majeurs d’intensité sévère. Ceci est validé au niveau international et apparaît dans les différentes recommandations actuelles.Cependant, cette technique provoque des effets secondaires non négligeables au niveau cognitif et mnésique. Il existe de nombreuses études les décrivant ainsi que des recherches en cours pour les réduire. Un phénomène moins bien identifié mais pourtant décrit depuis le début de l’utilisation de l’ECT est le virage de l’humeur lors d’une cure, principalement dans le sens dépression – manie.Les virages de l’humeur peuvent être spontanés ou déclenchés, de nombreux facteurs peuvent alors être mis en cause. L’ECT et les autres techniques de stimulation cérébrales sont maintenant identifiées comme des facteurs susceptibles de favoriser un virage de l’humeur. Or, il n’existe pas de recommandation pour la prise en charge d’un tel évènement chez le patient. Le DSM V qualifie pourtant le virage de l’humeur sous ECT comme un critère de bipolarité de type I. Quatre cas cliniques illustrant des différences majeurs de pratiques sont rapportés dans ce travail venant confirmer la nécessité d’établir une recommandation.

Obesity has a direct adverse effect on both the somatic and the psychiatric course of bipolar disorder, likely through the low grade inflammation associated to obesity. Since weight loss improves significantly the inflammatory profile, treating the bipolar obese subject goes hand in hand with an appropriate care of the excess weight. Bipolar patients seem to achieve a weight loss comparable to others after bariatric surgery without an increased risk of a psychiatric decompensation, and yet, many are denied surgery as psychiatrists choose the road to precautionary management. Our objective is to assess the benefit/risk ratio of the laparoscopic sleeve gastrectomy in bipolar obese subjects through our case studies and an extensive literature review. In the case studies, follow-up data at 1 year showed, on average, a 32.8% total body weight loss among bipolar obese patients who underwent sleeve gastrectomy, a result comparable to the general bariatric population. Somatic outcome was favorable, no psychiatric hospitalization was reported, and quality of life and depression scores were improved. As our results match the recent literature review, a favorable benefit/risk ratio of a sleeve gastrectomy in this group of patients is expected. Those preliminary encouraging results could make psychiatrists less wary of sleeve gastrectomy and promote future studies with larger samples to confirm these findings. A recommendation algorithm as well as a study protocol to address a number of unanswered questions are suggested at the end of the thesis.; L’obésité assombrit l’évolution du trouble bipolaire sur le plan somatique et psychiatrique, par le biais probable de l’inflammation de bas grade associée à l’obésité. L’amélioration du profil inflammatoire passe essentiellement par la perte de poids, par conséquent le traitement de la maladie bipolaire chez l’obèse est indissociable de la prise en charge de son excès pondéral. La chirurgie bariatrique permettrait une perte de poids chez le bipolaire similaire aux autres et sans risque majoré de décompensation, pourtant de nombreux patients se voient refuser la chirurgie par principe de précaution. Notre objectif est d’évaluer le rapport bénéfice/risque de la sleeve gastrectomie (SG) chez le patient bipolaire obèse à travers des études de cas ainsi qu’une revue exhaustive de la littérature récente. Dans notre étude, les patients bipolaires obèses stables ayant bénéfice d’une SG ont perdu en moyenne 32,8% de leur poids initial après plus d’un an de suivi, un succès équivalant à celui de la population bariatrique générale. On observe une amélioration des troubles somatiques, aucune décompensation psychiatrique ayant nécessité une hospitalisation n’a été déplorée et les scores de qualité de vie et de dépression se sont améliorés. Nos résultats étant concordants avec la littérature récente, un rapport bénéfice/risque en faveur du bipolaire obèse après SG est attendu. Ces résultats préliminaires encourageants pourraient rendre les psychiatres moins méfiants vis-à-vis de la SG et promouvoir des études à grande échelle pour confirmer ces bénéfices. Des recommandations pour la pris en charge du bipolaire obèse ainsi qu’un protocole d’étude ont été élaborés à la fin de la thèse.

International audience; IntroductionAntibiomania is characterized by the emergence of a manic episode in reaction to antibiotics. Although relatively uncommon, this kind of side effect is observed in a growing number of cases and mostly occurs in patients who do not have a history of bipolar disorder. Several dozen cases have been reported showing the onset of manic symptoms after taking antibiotics. The antibiotic most frequently involved is clarithromycin.Clinical caseWe report the case of a 61-year-old patient who presented a manic episode after taking an antibiotic combination to treat Helicobacter pylori. Five days after the start of highly active antiretroviral therapy (HAART), behavioral problems appeared (aggressiveness, irritability, talkativeness, insomnia). At the time of hospitalization, she had an acute delusional symptomatology, with a theme of persecution, associated with intuitive, interpretive and imaginative mechanisms. Manic symptoms were obvious: psychomotor excitement, aggressiveness and irritability, flight of ideas, verbal disinhibition and a denial of problems. There was no toxic cause. Brain magnetic resonance imaging (MRI) was normal. Her condition improved very quickly and delusions disappeared in four days. Mrs. H. could critic her delirium and recovered a euthymic state. During hospitalization, treatment divalproate sodium was introduced (250 mg, 3 times a day), was maintained following hospital discharge for 2 years for prevention, and then decreased to the stop. There are currently no further behavioral problems or sleep disorders two years after this episode.DiscussionFacing this clinical case, several questions arise: Which drug therapy is the most suitable for this type of mental disorder? Are there predictors of antibiomania? Is there a risk of recurrence of mood episodes following an antibiomania that occurs spontaneously? What are the pathophysiological mechanisms that could explain this reaction? In all cases identified, stopping the antibiotics was decisive. However, the introduction of a psychotropic and the duration of this treatment remain unclear. First, longitudinal follow-up would assess this variable. Second, it is unclear whether the presence of personal psychiatric history is a predictor of antibiomania. Finally, there are several hypotheses to explain antibiomania: the competitive effect of GABAergic inhibitory receptors, seizure-like phenomena that mimic psychiatric symptoms, and disruption of the intestinal microbiota by antibiotics leading to a modification of the functioning of the central nervous system. The explanatory model of antibiomania is not yet known and requires further research.; L’antibiomania se définit par l’apparition d’un épisode maniaque en réaction à la prise d’antibiotiques. Ce phénomène, bien qu’assez rare, n’est pas négligeable étant donné le nombre croissant de cas observé. Il se manifeste en général chez des sujets n’ayant pas d’antécédent de trouble bipolaire. Nous décrivons le cas d’une patiente de 61 ans qui a présenté un épisode maniaque suite à la prise d’une trithérapie antibiotique reçue pour l’éradication d’Helicobacter pylori dans le cadre d’un ulcère gastroduodénal. À l’arrêt du traitement antibiotique, les symptômes maniaques ont régressé en quelques jours. Plusieurs questions se posent notamment sur l’attitude thérapeutique à adopter et les causes expliquant l’antibiomania. Celles-ci sont encore floues. Nous abordons par ailleurs plusieurs hypothèses étiologiques : l’effet compétitif inhibiteur au niveau des récepteurs gabaergiques, l’effet épileptogène mimant un tableau psychiatrique, et la perturbation du microbiote intestinal par les antibiotiques, modifiant de façon indirecte le fonctionnement du système nerveux central.

Preliminary studies suggested that age at onset (AAO) may help to define homogeneous bipolar affective disorder (BPAD) subtypes. This candidate symptom approach might be useful to identify vulnerability genes. Thus, the probability of detecting major disease-causing genes might be increased by focusing on families with early-onset BPAD type I probands. This study was conducted as part of the European Collaborative Study of Early Onset BPAD (France, Germany, Ireland, Scotland, Switzerland, England, Slovenia). We performed a genome-wide search with 384 microsatellite markers using non parametric linkage analysis in 87 sib-pairs ascertained through an early-onset BPAD type I proband (age at onset of 21 years or below). Non parametric multi-point analysis suggested eight regions of linkage with p-values

International audience; Bipolar disorder continues to be underrecognized, despite being known for 2000 years. Mania, the fullest expression of the disease affects approximately 1% of the population; the less-than-manic forms of the disease dominated by depressive episodes have recently been found to be more common, affecting 4-5% of the population. In reviewing the international literature on this broadened bipolar spectrum, this paper pays particular tribute to the French EPIDEP and EPIMAN studies and Italo-American collaboration which have generated the largest set of systematic data on the new clinical portrait of bipolar disorders. Early detection is crucial, because untreated bipolar disorder has a high mortality rate. A review of the diagnostic criteria for the various subtypes of bipolar disorder has identified several factors that interfere with making an accurate diagnosis. These include age at onset, ethnic differences, co-morbidity (particularly substance abuse and alcoholism), and the broad range of clinical presentations. Moreover, symptoms frequently overlap with those of other psychiatric disorders including schizophrenia, attention-deficit disorder and personality disorders. Misdiagnosis is a major factor leading to a poor outcome for patients. Accurate identification and diagnosis of the different forms of mania can lead to specific treatment choices that may improve prognosis. Particularly important are recent data indicating reduced mortality with a variety of psychopharmacologic agents including, but not limited to, lithium and valproate.

International audience

International audience; Bipolar disorder (BD) has a multifactorial etiology with heterogeneous clinical presentations. Around 25% of BD patients may present with a depressive seasonal pattern (SP). However, there are limited scientific data on the prevalence of SP, its clinical manifestations, and any gender influence. Four hundred and fifty-two BD I and II cases (62% female), recruited from three French university-affiliated psychiatric departments, were assessed for SP. Clinical, treatment, and sociodemographic variables were obtained from structured interviews. One hundred and two (23%) cases met DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) criteria for SP, with similar frequency according to gender. Multivariate analysis showed a significant association between SP and BD II (odds ratio [OR] = 1.99, p = 0.01), lifetime history of rapid cycling (OR = 2.05, p = 0.02), eating disorders (OR = 2.94, p = 0.003), and total number of depressive episodes (OR = 1.13, p = 0.002). Seventy-one percent of cases were correctly classified by this analysis. However, when stratifying the analyses by gender, SP was associated with BD II subtype (OR = 2.89, p = 0.017) and total number of depressive episodes (OR = 1.21, p = 0.0018) in males but with rapid cycling (OR = 3.02, p = 0.0027) and eating disorders (OR = 2.60, p = 0.016) in females. This is the first study to identify different associations between SP and clinical characteristics of BD according to gender. The authors suggest that SP represents a potentially important specifier of BD. These findings indicate that seasonality may reflect increased severity or complexity of disorder.

International audience; Bipolar disorder (BD) has a multifactorial etiology with heterogeneous clinical presentations. Around 25% of BD patients may present with a depressive seasonal pattern (SP). However, there are limited scientific data on the prevalence of SP, its clinical manifestations, and any gender influence. Four hundred and fifty-two BD I and II cases (62% female), recruited from three French university-affiliated psychiatric departments, were assessed for SP. Clinical, treatment, and sociodemographic variables were obtained from structured interviews. One hundred and two (23%) cases met DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) criteria for SP, with similar frequency according to gender. Multivariate analysis showed a significant association between SP and BD II (odds ratio [OR] = 1.99, p = 0.01), lifetime history of rapid cycling (OR = 2.05, p = 0.02), eating disorders (OR = 2.94, p = 0.003), and total number of depressive episodes (OR = 1.13, p = 0.002). Seventy-one percent of cases were correctly classified by this analysis. However, when stratifying the analyses by gender, SP was associated with BD II subtype (OR = 2.89, p = 0.017) and total number of depressive episodes (OR = 1.21, p = 0.0018) in males but with rapid cycling (OR = 3.02, p = 0.0027) and eating disorders (OR = 2.60, p = 0.016) in females. This is the first study to identify different associations between SP and clinical characteristics of BD according to gender. The authors suggest that SP represents a potentially important specifier of BD. These findings indicate that seasonality may reflect increased severity or complexity of disorder.