Methylomic biomarkers of lithium response in bipolar disorder: a clinical utility study.

BACKGROUND: Response to lithium (Li) is highly variable in bipolar disorders (BD). Despite decades of research, no clinical predictor(s) of response to Li prophylaxis have been consistently identified. Recently, we developed epigenetic Methylation Specific High-Resolution Melting (MS-HRM) assays able to discriminate good responders (GR) from non-responders (NR) to Li in individuals with BD type 1 (BD-I). This study examined whether a combination of clinical and epigenetic markers can distinguish NR from other types of Li responders. METHODS: We recorded clinical variables that are potentially associated with Li response in 64 individuals with BD-I. MS-HRM assays were performed on DNA isolated from peripheral blood. We used backward stepwise logistic regression analyses, followed by receiver operating characteristic (ROC) curve analysis to estimate the performance of the clinical variables, alone then in combination with the epigenetic biomarkers, to identify GR and partial responders (PaR) vs NR. RESULTS: Polarity at onset, psychotic symptoms at onset and family history of BD classified correctly 70% of individuals according to their Li response (PaR + GR = 86%; NR = 35%). When combined with the epigenetic biomarkers, these three clinical variables plus alcohol misuse (and one DMR: Differentially Methylated Region) correctly classified 86% of individuals, improving the prediction of PaR + GR (93%) and of NR (70%). The ROC analysis demonstrated an improvement in the area under the curve from 0.75 (clinical variables alone) to 0.87 (combination of clinical and epigenetic markers). CONCLUSIONS: Combining clinical predictors and DNA methylation markers of Li response may have greater utility in clinical practice than relying on clinical characteristics alone.

Evolution and characteristics of the use of valproate in women of childbearing age with bipolar disorder: Results from the FACE-BD cohort.

BACKGROUND: Valproate is associated with teratogenic and neurodevelopmental effects. Several agencies have restricted the conditions of its prescription in bipolar disorders (BD). We aimed to assess the evolution of valproate prescription and the clinical profile of BD women of childbearing age receiving valproate. METHODS: Based on a large national cohort, we included all BD women 16-50 years old. Sociodemographic, clinical and pharmacological data were recorded. Logistic regression analyses were used to describe variables associated with valproate prescription. RESULTS: Of the 1018 included women 16-50 years old, 26.9% were treated with valproate with a mean daily dosage of 968 mg. The prevalence of BD women using valproate was 32.6% before May 2015 and 17.3% after May 2015 (p<0.001), the date of French regulatory publication of restriction of valproate prescription. The multivariate analysis revealed that the inclusion period after May 2015 (OR=0.54, CI 95% 0.37-0.78, p=0.001), the age lower than 40 years (OR=0.65, CI 95% 0.43-0.98, p=0.040) and the number of lifetime mood episodes (OR=0.98, CI 95% 0.95-0.99, p=0.040) were the variables negatively associated with the use of valproate. LIMITATIONS: Study could be underpowered to determine a clinical profile associated with valproate prescription. CONCLUSIONS: The regulatory change in BD women of childbearing age had a significant impact on valproate prescription, even if the prescription rate remains high. Important efforts are needed to help clinicians and patients to improve quality of care in BD women of childbearing age.

Psychiatric comorbidities in bipolar disorders: An examination of the prevalence and chronology of onset according to sex and bipolar subtype.

OBJECTIVES: Bipolar Disorder (BD) is frequently comorbid with other psychiatric disorders. However, few studies systematically examine which disorders are more likely to occur pre- or post-BD onset. We examine the prevalence and Age At Onset (AAO) of psychiatric conditions in adults with BD. METHODS: A structured clinical interview was used to assess lifetime history and AAO of alcohol and cannabis misuse, suicide attempts, anxiety and eating disorders in a French sample of euthymic patients with BD (n = 739). Regression analyses were used to test for statistically significant associations between rates and AAO of comorbidities in BD groups stratified by sex or subtype. RESULTS: Prevalence of alcohol and cannabis misuse was associated with male sex and BD-I subtype; whilst most anxiety and eating disorders were associated with female sex. The AAO of most comorbid conditions preceded that of BD, except for panic disorder, agoraphobia and alcohol misuse. Few variations were observed in AAO of comorbidities according to groups. LIMITATIONS: All assessments were retrospective, so estimates of prevalence rates and especially exact AAO of some comorbidities are at risk of recall bias. CONCLUSIONS: Sex and BD subtype are associated with different rates of comorbid disorders. However, there were minimal between group differences in median AAO of comorbidities. By describing the chronological sequence of comorbidities in BD we were able to demonstrate that a minority of comorbidities typically occurred post-onset of BD. This is noteworthy as these disorders might be amenable to interventions aimed at early secondary prevention.

[Exploring Early Maladaptative Schema (EMS) in adults with bipolar disorder: A systematic review of the scientific literature]. / L'exploration des Schémas Précoces Inadaptés (SPI) chez les personnes adultes atteintes de troubles bipolaires: une revue systématique de la littérature scientifique.

OBJECTIVES: Clinical heterogeneity during euthymic states is a crucial issue in bipolar disorders. Indeed, actual data are not sufficient to understand why some patients are unharmed by subthreshold symptoms and have functional impairments whereas others have a functional remission but have subthreshold symptoms. Based on the Ball model, cognitive and schematic vulnerability interact with genetic vulnerability and trigger affective symptoms with the intervention of stressful life events. Furthermore, according to this model, adjustment and adaptation to illness assessed by functional outcome and illness experience are associated with this cognitive and schematic vulnerability. So, theoretical arguments support that childhood adversity and temperamental deregulation characterize patients with bipolar disorders. Thus, the aim of this study is to systematically review studies of Early Maladaptive Schemas in bipolar disorder, to determine whether Early Maladaptive Schemas have specificity in bipolar disorder in comparison with other populations, and to identify which Early Maladaptive Schemas could be activated. The challenge of this review is to identify if the taking of early maladaptive schemas into account could allow us to better identify, understand and manage bipolar disorders. METHODS: This systematic review was led according to the Preferred Reporting Items for Systematic review and Meta-Analysis statement on the electronic databases Cochrane, PsycArticles, Psychology and Behavioral Sciences Collection, PsycInfo, PubMed, ScienceDirect and Scopus with « early maladaptive schemas ¼ AND « bipolar disorder ¼ as keywords. Only studies meeting eligibility criteria concerning publication status, language, population and outcomes were included after several screenings on basis of title, abstract and full-text. Then, we carried out data extraction in accordance with criteria defined in principle (about characteristics of participants, objectives, materiel and methods, principle results and bias). RESULTS: Among 39 records identified, a total of 10 studies met eligibility criteria for inclusion in this review. Synthesizing findings across the studies revealed three important topics. First, early maladaptive schemas appear as potential cognitive characteristics that clinicians have to investigate in clinical practice. Indeed, patients with bipolar disorders present greater activation of the early maladaptive schemas in comparison with people who have no disorder. This point supports the first part of Ball's theoretical model that considers schemas as a vulnerability to bipolarity. Secondly, early maladaptive schemas are relevant to distinguish bipolar disorders from unipolar depression and borderline personality disorder. A greater and a lower activation are respectively identified among bipolar disorders. Thirdly, supporting the second part of Ball's model, early maladaptive schemas play a key role in recovery regarding their impact on the course of bipolarity, in particular on suicidality and functional impairment. Finally, these dysfunctional schemas allow us to understand the clinical heterogeneity of bipolar disorder, and among others, about the type of bipolarity. These results have several implications, but there are some limits in this systematic review. First, no French study has been done. Then, reduced sample sizes in these studies increased the risk to conclude wrongly to an activation difference between groups. Furthermore, probably due to the variety of methods and populations, we could not identify an homogeneous pattern of early activated maladaptive schemas. Overall, scientific approaches used in these studies are based on statistical models using mean and standard deviation. These types of statistical analyses are the main limit because they cannot represent the heterogeneity of early maladaptive schemas profiles. CONCLUSIONS: Schema theory proves to be a relevant approach in bipolar disorders, and early maladaptive schemas appear to be important to take into account in clinical practice. Nevertheless, in order to propose schemas therapy appropriately, it is necessary to specify if early maladaptive schemas are activated and to specify therapeutic indications because of clinical heterogeneity. Moreover, data do not yet allow us to understand the disparity of profiles during the inter-episode period. Indeed, a French research perspective is being considered that will prefer a person-oriented approach.

[Therapeutic education: A lever to change perceptions of bipolar disorder in family caregivers]. / L'éducation thérapeutique : un levier pour modifier les perceptions du trouble bipolaire chez les aidants familiaux.

OBJECTIVES: The patient with bipolar disorder and his family are caught in a reciprocal interaction: on one hand, the pathology leads to family sufferings and on the other hand, family behavior affects the disease of the patient and its development. Therefore, it seems of core importance that the psychologist should work with the family on their perception of bipolar disorder, that is to say, on their knowledge and psychological representations of the pathology. The aim of our study is to assess whether the initial perception of bipolar disorder evolves after a therapeutic education program. METHOD: Our research was conducted at the Bipolar Expertise Centre in Bordeaux/Centre Expert Bipolaire in Bordeaux on a sample of 145 participants (78patients and 67 family caregivers). They were all interviewed before and after the therapeutic education program (12 sessions in 6months). The Brief Illness Perception Questionnaire Revised (Moss-Morris, 2002) measures the perception of bipolar disorder and the BP Quizz (Fondation Fondamental) assesses the degree of knowledge of the disorder. RESULTS: Results show that therapeutic education helps families to level up their knowledge about bipolar disorder. Furthermore, representations on bipolar disorder have globally changed so that on average, bipolar disorder is viewed as less threatening by families after 12 sessions of therapeutic education. More precisely, after the program, families have a better understanding and a better insight of the disorder, which is then perceived as being less severe. On the emotional level, anxiety and stress have decreased. So there are an increase of knowledge and a change in perception. CONCLUSION: Our study shows that the therapeutic education program enables families to change their perception of the disease, that is to say, their knowledge but also their representations of the disease, which is a fundamental element according to the models of therapeutic education. Our results point out one of the active processes of therapeutic education at work in the sessions: in the perception of the disease, which is composed of both knowledge and representations of the disease, just a change in representations constitutes a lever for therapeutic education. Therefore, working on representations should be a therapeutic target. As a conclusion, we can say that therapeutic education of families cannot be reduced to an educational dimension which would only consist of gaining knowledge. Then, the right posture of the psychologist is to hold each participant's own development and changing process of representations.

Sleep quality and emotional reactivity cluster in bipolar disorders and impact on functioning.

OBJECTIVE: Bipolar disorders (BD) are characterized by sleep disturbances and emotional dysregulation both during acute episodes and remission periods. We hypothesized that sleep quality (SQ) and emotional reactivity (ER) defined clusters of patients with no or abnormal SQ and ER and we studied the association with functioning. METHOD: We performed a bi-dimensional cluster analysis using SQ and ER measures in a sample of 533 outpatients patients with BD (in remission or with subsyndromal mood symptoms). Clusters were compared for mood symptoms, sleep profile and functioning. RESULTS: We identified three clusters of patients: C1 (normal ER and SQ, 54%), C2 (hypo-ER and low SQ, 22%) and C3 (hyper-ER and low SQ, 24%). C1 was characterized by minimal mood symptoms, better sleep profile and higher functioning than other clusters. Although highly different for ER, C2 and C3 had similar levels of subsyndromal mood symptoms as assessed using classical mood scales. When exploring sleep domains, C2 showed poor sleep efficiency and a trend for longer sleep latency as compared to C3. Interestingly, alterations in functioning were similar in C2 and C3, with no difference in any of the sub-domains. CONCLUSION: Abnormalities in ER and SQ delineated three clusters of patients with BD and significantly impacted on functioning.

Childhood trauma, dimensions of psychopathology and the clinical expression of bipolar disorders: A pathway analysis.

BACKGROUND: This study aims at testing for paths from childhood abuse to clinical indicators of complexity in bipolar disorder (BD), through dimensions of affective dysregulation, impulsivity and hostility. METHOD: 485 euthymic patients with BD from the FACE-BD cohort were included from 2009 to 2014. We collect clinical indicators of complexity/severity: age and polarity at onset, suicide attempt, rapid cycling and substance misuse. Patients completed questionnaires to assess childhood emotional, sexual and physical abuses, affective lability, affect intensity, impulsivity, motor and attitudinal hostility. RESULTS: The path-analysis demonstrated significant associations between emotional abuse and all the affective/impulsive dimensions (p < 0.001). Sexual abuse was moderately associated with emotion-related dimensions but not with impulsivity nor motor hostility. In turn, affect intensity and attitudinal hostility were associated with high risk for lifetime presence of suicide attempts (p < 0.001), whereas impulsivity was associated with a higher risk of lifetime presence of substance misuse (p < 0.001). No major additional paths were identified when including Emotional and Physical Neglect in the model. CONCLUSIONS: This study provides refinement of the links between early adversity, dimensions of psychopathology and the complexity/severity of BD. Mainly, dimensions of affective dysregulation, impulsivity/hostility partially mediate the links between childhood emotional to suicide attempts and substance misuse in BD.

Affect lability predicts occurrence of suicidal ideation in bipolar patients: a two-year prospective study.

OBJECTIVE: The aim of our study was to investigate, in bipolar patients, whether affect lability was associated with suicidal ideation incidence during 2-year follow-up, and which subtype of affect lability was associated with suicidal ideation. METHOD: A total of 319 euthymic or mildly depressed bipolar outpatients recruited in the French FondaMental Advanced Centres of Expertise for Bipolar Disorder were divided into two subgroups according to the occurrence of suicidal ideation during a 2-year follow-up. Affect lability was assessed by the French version of the Affect Lability Scale. RESULTS: Bipolar patients with high affect lability were more likely to report suicidal ideation during follow-up, even after adjustment for age, study level, rapid cycling, current depression level, anxiety disorder, and lifetime history SA (OR = 2.47; 95% CI [1.15-5.30], P = 0.01). The risk of suicidal ideation increased with the level of affect lability. More specifically, the propensity to switch from neutral to elation affect, from anxious to depressive affect (or inversely), and from neutral to anger affect predicted suicidal ideation. CONCLUSION: Reducing affective lability could become a new therapeutic target of suicidal prevention in bipolar disorder.

Childhood trauma and mixed episodes are associated with poor response to lithium in bipolar disorders.

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.

Affective lability mediates the association between childhood trauma and suicide attempts, mixed episodes and co-morbid anxiety disorders in bipolar disorders.

BACKGROUND: Many 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. METHOD: A 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 SPSS process macro. RESULTS: Using 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. CONCLUSIONS: Our 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.

Physical and mental health burden in cases of bipolar disorder classified as current, former, or non-tobacco smokers.

BACKGROUND: Tobacco smoking increases the global burden of bipolar disorder (BD). We examined markers of physical and mental health that are associated with tobacco smoking, controlling for confounders that have not always been considered in previous studies of BD. METHODS: Over 600 individuals with BD I or II referred to the French Network for bipolar disorder (FACE-BD) who completed standardized assessments, and could be reliably classified as current (CS) or former smokers (FS), were compared with those who were never smokers (NS) on: BD symptom load and psychiatric comorbidities; prevalence of alcohol and substance use disorders (ASUD); medication usage; functioning and physical health parameters. The bivariate and multivariate analyses took into account age and gender. RESULTS: 300 cases (49%) were CS, 78 (13%) FS and 238 (39%) had never smoked. Rates were similar across genders regardless of BD subtype. Compared with NS, CS were more likely to have an ASUD (Odds Ratio (OR) 5.18), BD I (OR 2.09), and lower abdominal obesity (OR 0.97), and FS were more likely to have an ASUD (OR 6.32) and higher abdominal obesity (OR 1.03). LIMITATIONS: The sample comprised of white Europeans; the FS subgroup was relatively small and we did not apply any statistical correction for the bivariate analyses. CONCLUSIONS: The increased risk of physical and mental health burden in CS and FS compared to NS represents avoidable morbidity in BD. This study offers support to the argument that individuals with BD should be routinely offered support to prevent or stop tobacco smoking.

Association between childhood dimensions of attention deficit hyperactivity disorder and adulthood clinical severity of bipolar disorders.

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 < 10-5). 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.

Effect of early trauma on the sleep quality of euthymic bipolar patients.

OBJECTIVE: Poor quality of sleep is frequent in euthymic bipolar patients and conveys worse clinical outcomes. We investigated the features of euthymic bipolar patients associated with poor sleep quality, with a focus on the effect of childhood trauma. METHOD: 493 euthymic patients with DSM-IV-defined bipolar disorders were recruited in FondaMental Advanced Centers of Expertize for Bipolar Disorders (FACE-BD) between 2009 and 2014. Clinical variables were recorded. Subjective sleep quality and history of childhood trauma were respectively measured by the Pittsburgh Sleep Quality Index (PSQI) and the Childhood Trauma Questionnaire (CTQ). RESULTS: Poor sleepers were older, less professionally active, had significantly higher anxiety levels, took more anxiolytic drugs and did endorse more suicide attempts and suicidal ideas than good sleepers after adjusting for anxiety levels and age. Emotional abuse was associated with poor sleep quality after adjustment for BMI, age, professional activity, and bipolar disorders (BD) type (OR=1.83; 95% CI [1.30; 3.10]; p=0.02). However, this association was lost after adjustment for anxiety levels, anxiolytic treatment and suicide ideation/attempts. LIMITATIONS: The main limitation was the type of sleep assessment, which only measured the subjective part of sleep complaints. CONCLUSION: A history of emotional abuse might underlie sleep problems in many bipolar patients but anxiety seems to act as a confounding factor in this relationship. New studies are needed to elucidate the role of childhood maltreatment on poor sleep among bipolar patients.

Interaction between SLC6A4 promoter variants and childhood trauma on the age at onset of bipolar disorders.

Age at onset (AAO) of bipolar disorders (BD) could be influenced both by a repeat length polymorphism (5HTTLPR) in the promoter region of the serotonin transporter gene (SLC6A4) and exposure to childhood trauma. We assessed 308 euthymic patients with BD for the AAO of their first mood episode and childhood trauma. Patients were genotyped for the 5HTTLPR (long/short variant) and the rs25531. Genotypes were classified on functional significance (LL, LS, SS). A sample of 126 Brazilian euthymic patients with BD was used for replication. In the French sample, the correlation between AAO and trauma score was observed only among 'SS' homozygotes (p = 0.002) but not among 'L' allele carriers. A history of at least one trauma decreased the AAO only in 'SS' homozygotes (p = 0.001). These results remained significant after correction using FDR. Regression models suggested an interaction between emotional neglect and 'SS' genotype on the AAO (p = 0.009) and no further interaction with other trauma subtypes. Partial replication was obtained in the Brazilian sample, showing an interaction between emotional abuse and 'LS' genotype on the AAO (p = 0.02). In conclusion, an effect of childhood trauma on AAO of BD was observed only in patients who carry a specific stress responsiveness-related SLC6A4 promoter genotype.

[Femoroacetabular impingement: rehabilitation and return to sport]. / Rééducation des conflits fémoro-acétabulaires et retour au sport.

Femoroacetabular impingements (FAI) are quite frequent among young athletes. An early detection is essential in order to prevent more labral and cartilage damage. Conservative treatment should not focus on forcing the full range of motion but on restoring a good muscle balance around the joint and a better lower limb dynamic stability and control. The patient should be educated to master the end of hip range of motion during his activities. If the outcome is not satisfactory, a surgical treatment is offered. The post-operative treatment protocol is tailored to the type of repair, following several stages, from neuromuscular control to strengthening up to the return to sport. FAI prevention should be more studied in order to protect the hip of the growing athlete.

Increased risk of suicide attempt in bipolar patients with severe tobacco dependence.

BACKGROUND: The aim of our study was to investigate, in bipolar patients, the association between tobacco status (use and dependence) and history of suicide attempt, and to assess the possible role of inflammation as a missing link in the association between smoking status and history of suicide attempt. METHODS: A total of 453 adult bipolar out-patients recruited in the French FondaMental Advanced Centres of Expertise for Bipolar Disorder were divided into two subgroups: 274 patients without past history of suicide attempt (non-SA), and 179 patients with a past history of suicide attempt (SA). Tobacco use and dependence, psychiatric and somatic comorbidities, history of childhood abuse, family history of suicide were assessed. Fasting blood tests yielded samples collected for the measurement of high sensitivity (hs-)CRP. RESULTS: The risk of suicide attempt increased with smoking dependence. Notably, bipolar patients with a history of suicide attempt were three times more likely to have severe tobacco dependence, independently of confounding factors. However, we failed to find arguments promoting the hypothesis of inflammatory markers (through hs-CRP measure) in the link between tobacco dependence and suicidal behavior. CONCLUSIONS: We found a significant association between severe tobacco dependence and history of suicide attempt, but not with level of CRP, independently of confusing factors. Longitudinal studies taken into account all these potential confusing factors are needed to confirm our results.

Clinical and neuropsychological characteristics of euthymic bipolar patients having a history of severe suicide attempt.

OBJECTIVE: Identifying bipolar patients at high-suicide risk is a major health issue. To improve their identification, we compared dimensional and neuropsychological profile of bipolar patients with or without history of suicide attempt, taking into account suicidal severity (i.e. admission to intensive ward). METHOD: A total of 343 adult euthymic bipolar out-patients recruited in the French FondaMental Advanced Centres of Expertise for Bipolar Disorder were divided into three subgroups: 214 patients without history of suicide attempt, 88 patients with past history of non-severe suicide attempt and 41 patients with past history of severe suicide attempt. General intellectual functioning, speed of information processing, verbal learning and memory, verbal fluency and executive functioning were assessed. RESULTS: Severe suicide attempters had lower affective intensity and lability than non-severe attempters. Severe suicide attempters outperformed non-severe attempters for verbal learning and non-attempters for Stroop word reading part after adjustment for study centre, age, gender, educational level, antipsychotics use, depression score, anxious and addictive comorbidities. CONCLUSION: Neuropsychological tasks commonly used to assess bipolar patients do not seem accurate to identify suicide attempters in euthymic patients. In the future, decision-making and emotional recognition tasks should be assessed. Moreover, clinical and neuropsychological profiles should be considered together to better define suicidal risk.

Association between circadian genes, bipolar disorders and chronotypes.

Abnormalities in circadian rhythms play an important role in the pathogenesis of bipolar disorders (BD). Previous genetic studies have reported discrepant results regarding associations between circadian genes and susceptibility to BD. Furthermore, plausible behavioral consequences of at-risk variants remain unclear since there is a paucity of correlates with phenotypic biomarkers such as chronotypes. Here, we combined association studies with a genotype/phenotype correlation in order to determine which circadian genes variants may be associated with the circadian phenotypes observed in patients with BD. First, we compared the allele frequencies of 353 single nucleotide polymorphisms spanning 21 circadian genes in two independent samples of patients with BD and controls. The meta-analysis combining both samples showed a significant association between rs774045 in TIMELESS (OR = 1.49 95%CI[1.18-1.88]; p = 0.0008) and rs782931 in RORA (OR = 1.31 95%CI[1.12-1.54]; p = 0.0006) and BD. Then we used a "reverse phenotyping approach" to look for association between these two polymorphisms and circadian phenotypes in a subsample of patients and controls. We found that rs774045 was associated with eveningness (p = 0.04) and languid circadian type (p = 0.01), whereas rs782931 was associated with rigid circadian type (p = 0.01). Altogether, these findings suggest that these variants in the TIMELESS and RORA genes may confer susceptibility to BD and impact on circadian phenotypes in carriers who thus had lower ability to properly adapt to external cues.

Affect intensity measure in bipolar disorders: a multidimensional approach.

BACKGROUND: Emotional dysregulation, characterized by high levels of both arousal and intensity of emotional responses, is a core feature of bipolar disorders (BDs). In non-clinical populations, the 40-item Affect Intensity Measure (AIM) can be used to assess the different dimensions of emotional reactivity. METHODS: We analyzed the factor structure of the AIM in a sample of 310 euthymic patients with BD using Principal Component Analysis and examined associations between AIM sub-scale scores and demographic and illness characteristics. RESULTS: The French translation of the AIM demonstrated good reliability. A four-factor solution similar to that reported in non-clinical samples (Positive Affectivity, Unpeacefulness [lack of Serenity], Negative Reactivity, Negative Intensity), explained 47% of the total variance. Age and gender were associated with Unpeacefulness and Negative reactivity respectively. 'Unpeacefulness' was also positively associated with psychotic symptoms at onset (p=0.0006), but negatively associated with co-morbid substance misuse (p=0.008). Negative Intensity was positively associated with social phobia (p=0.0005). LIMITATIONS: We cannot definitively exclude a lack of statistical power to classify all AIM items. Euthymia was carefully defined, but a degree of 'contamination' of the self-reported levels of emotion reactivity may occur because of subsyndromal BD symptoms. It was not feasible to control for the possible impact of on-going treatments. CONCLUSIONS: The AIM scale appears to be a useful measure of emotional reactivity and intensity in a clinical sample of patients with BD, suggesting it can be used in addition to other markers of BD characteristics and sub-types.