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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.

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.

OBJECTIVE: Duration of untreated illness represents a potentially modifiable component of any diagnosis-treatment pathway. In bipolar disorder (BD), this concept has rarely been systematically defined or not been applied to large clinically representative samples. METHOD: In a well-characterized sample of 501 patients with BD, we estimated the duration of untreated bipolar disorder (DUB: the interval between the first major mood episode and first treatment with a mood stabilizer). Associations between DUB and clinical onset and the temporal sequence of key clinical milestones were examined. RESULTS: The mean DUB was 9.6 years (SD 9.7; median 6). The median DUB for those with a hypomanic onset (14.5 years) exceeded that for depressive (13 years) and manic onset (8 years). Early onset BD cases have the longest DUB (P < 0.0001). An extended DUB was associated with more mood episodes (P < 0.0001), more suicidal behaviour (P = 0.0003) and a trend towards greater lifetime mood instability (e.g. rapid cycling, possible antidepressant-induced mania). CONCLUSION: Duration of untreated bipolar disorder (DUB) will only be significantly reduced by more aggressive case finding strategies. Reliable diagnosis (especially for BD-II) and/or instigation of recommended treatments is currently delayed by insufficient awareness of the early, polymorphous presentations of BD, lack of systematic screening and/or failure to follow established guidelines.

Background Bipolar disorders are a major public health concern. Efforts to provide optimal care by general practitioners and psychiatrists are undermined by the complexity of the disorder and difficulties in applying clinical practice guidelines and new research findings to the spectrum of cases seen in day to day practice. Method A national network of bipolar expert centres was established. Each centre has established strong links to local health services and provides support to clinicians in delivering personalized care plans derived from systematic case assessments undertaken at the centre. Results A common set of diagnostic and clinical assessment tools has been adopted at eight centres. Evaluations are undertaken by trained assessors and cross-centre reliability is monitored. A web application, e-bipolar© is used to record data in a common computerized medical file. Anonymized data is entered into a shared national database for use in multi-centre audit and research. Conclusions Instead of offering treatment advice based on clinical practice guidelines recommendations for selected sub-populations of patients (a ‘top-down’ approach), the French bipolar network offers systematic, comprehensive, longitudinal, and multi-dimensional assessments of cases representative of general bipolar populations. This ‘bottom-up’ strategy may offer a more efficient and effective way to transfer knowledge and share expertise as the referrer can appreciate the rationale underpinning suggested treatment protocols and more readily apply such principles and approaches to other cases. The network also builds an infrastructure for clinical cohort and comparative-effectiveness research on more representative patient populations.

Childhood trauma has been suggested to be involved in the susceptibility to bipolar disorder. However, case-control studies are lacking, and the preferential implication and the dose-effect of different trauma subtypes remain poorly investigated. Two hundred six bipolar patients and 94 controls completed the Childhood Trauma Questionnaire (CTQ; Bernstein et al., 1994). The CTQ total score was higher for bipolar patients than for controls. The presence of multiple trauma was significantly more frequent in bipolar patients than in controls (63% vs. 33%). Multiple logistic regression suggested that only emotional abuse was associated with bipolar disorder with a suggestive dose-effect. Clinical practice should include systematic assessment of childhood trauma among bipolar patients with a particular focus on emotional abuse.

Background Suicidal behavior is a heterogeneous entity, determined by multiple factors. This heterogeneity has major implications for clinical management of patients and identification of risk factors. Our study aims at identifying homogeneous subgroups of patients with suicidal behavior. Methods We used two validated questionnaires to assess the intent (Suicidal Intent Scale, SIS) and lethality (Risk-Rescue Rating Scale, RRRS) of the most severe suicide attempt in a sample of 608 patients recruited consecutively. We first explored the factorial structure of the two scales, using a principal component analysis, and then tested the relationship between sub-scores identified and subtypes of suicide attempts (violent, serious overdose) using a backward logistic regression. Results A four-factor structure was retained for the SIS (conception, preparation, precautions and communication). The RRRS, for which a factorial structure has not been previously published, had a three-factor structure (medical damage, implementation and rescue conditions). This structure was valid, stable and clinically relevant. Serious suicide attempts were characterized by less communication and more precautions against discovery, whereas violent attempts were associated with higher risk acts. Neither violent nor serious attempts were characterized by more planning. Limitations The SIS and RRRS were assessed retrospectively, and so could have been influenced by recall bias. Finally, censoring bias may have affected our results. Conclusions The characterization of suicidal behaviors using SIS and RRRS sub-scores constitutes a first step toward the identification of homogeneous subgroups of suicide attempters. Prospective studies are needed to test the predictive value of these sub-scores for subsequent suicidal acts.

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.

Identification of the underlying liability to develop bipolar disorders (BD) is hindered by the genetic complexity and phenotypic heterogeneity of the disease. The use of endophenotypes has been acknowledged as a promising approach that may detect the hidden manifestations of a genetic liability for an illness. One of the most commonly proposed endophenotypes in BD is neurocognitive performance. We identified and examined previously published review articles that had any data pertaining to endophenotypes in BD and combined this with an extensive review of studies of cognitive deficits in BD from 2000 onwards. Using criteria for a valid endophenotype, we identifed that the domains of executive functioning and verbal memory are the most promising candidate endophenotypes for BD. However, they do not meet the criteria for specificity as similar deficits present in schizophrenia and/or severe or psychotic major depressions. Further research is needed as the findings regarding endophenotypes show between-study heterogeneity. In the future, examination of quantitative traits may offer a more promising approach to the study of endophenotypes rather than solely focusing on diagnostic categories.

BackgroundThe clinical and dimensional features associated with suicidal behaviour in bipolar patients during euthymic states are not well characterised.MethodsIn a sample of 652 euthymic bipolar patients, we assessed clinical features with the Diagnostic Interview for Genetics Studies (DIGS) and dimensional characteristics with questionnaires measuring impulsivity/hostility and affective lability/intensity. Bipolar patients with and without suicidal behaviour were compared for these clinical and dimensional variables.ResultsOf the 652 subjects, 42.9% had experienced at least one suicide attempt. Lifetime history of suicidal behaviour was associated with being a woman, a history of head injury, tobacco misuse and indicators of severity of bipolar disorder including early age at onset, high number of depressive episodes, positive history of rapid cycling, alcohol misuse and social phobia. Indirect hostility and irritability were dimensional characteristics associated with suicidal behaviour in bipolar patients, whereas impulsivity and affective lability/intensity were not associated with suicidal behaviour.LimitationsThis study had a retrospective design with no replication sample.ConclusionsBipolar patients with earlier onset, mood instability (large number of depressive episodes, rapid cycling) and/or particular addictive and anxiety comorbid disorders might be at high risk of suicidal behaviour. In addition, hostility dimensions (indirect hostility and irritability), may be trait components associated with suicidal behaviour in euthymic bipolar patients.

International audience; BACKGROUND: The clinical presentation, course, and comorbidities of bipolar disorder type I are highly heterogeneous, and this variability remains poorly predictable. Certain onset characteristics (eg, age and polarity at onset) may delineate subgroups differing in clinical expression and outcome. METHOD: We retrospectively investigated the association between both age and polarity at onset and the clinical characteristics of bipolar I disorder (DSM-IV) in 2 independent adult samples: 480 French patients assessed in 1992-2006 (patients had been recruited from 3 university-affiliated psychiatry departments) and 714 US patients assessed in 1991-2003 (data were extracted from the Bipolar Disorder Phenome Database). RESULTS: Polarity at onset correlated with subsequent predominance (P < .001). Most patients experienced a depressive onset (57.9% in France vs 71.0% in the United States; P < .001) associated with a higher density of depressive episodes, suicidal behavior, and alcohol misuse. A manic onset was associated with a higher density of manic episodes. Early onset was frequent in both countries (42% in France vs 68% in the United States; P < .001) and was associated with suicidal behavior and cannabis and cocaine/opiate misuse. Sensitivity for the prediction of clinical characteristics was 1%-35% for age at onset and 26%-47% for polarity at onset. CONCLUSIONS: Onset characteristics are associated with subsequent predominant polarity, suicidal behavior, and substance misuse in bipolar I disorder. These findings may facilitate personalized treatment strategies based on type of onset and may also facilitate early focused strategies for preventing comorbidity. Given the relatively low sensitivity and specificity of these onset characteristics for predicting clinical variables, the relevance of age and polarity at onset as specifiers in nosographical classifications will require further studies. However, polarity at onset may be the more relevant specifier, with further investigation required for age at onset.

Objectives The current study investigated whether a single brief cognitive assessment, processing speed, could be considered as a valid endophenotype for bipolar disorder (BD). Methods Processing speed was assessed using the Digit Symbol Test (DST) in 53 euthymic BD probands (BD-P), 50 unaffected first-degree relatives (UFDR) and 60 unrelated healthy controls (HC). Results Euthymic BD-P and the UFDR were significantly more impaired on DST performance even after controlling for demography and current mood symptoms (effect sizes 0.89 and 0.52). Clinically significant performance impairment was present in about 30% BD-P and 25% UFDR. Limitations Pharmacotherapy was not controlled for. Conclusions Processing speed, as measured with the DST, is a brief reliable measure that could be used in clinical assessments of at risk populations. Our findings support the hypothesis that processing speed may be a valid endophenotype, highly specific for differentiating both euthymic BD-P and UFDR, from HC.

Findings from family, adoption and twin studies suggest that vulnerability to bipolar disorder follows a polygenic mode of inheritance with multiple genes, each of small effect, combining and contributing to the risk and the clinical expression of the disorder. The endophenotype approach has been proposed as a way to identify susceptibility genes in disorders with complex underpinnings. Endophenotypes are supposed to bridge the genotype to the clinical syndrome and to have a simpler genetic architecture than clinical diagnoses.Our first aim is to confirm if cognitive measures are good potential endophenotypes. Therefore, we will examine the reliability and frequency of cognitive impairments in individuals with bipolar disorder and their biological relatives. The study of healthy relatives avoids confounding factors and should help identify potential endophenotypes.We will also look for evidence linking particular cognitive impairments to specific genes on one hand and to the risk for bipolar disorder, on the other.A literature review of articles published in 2008-2009 suggests that the genetic architecture of cognitive endophenotypes is more complex than initially predicted. In many published studies, no genetic association was found between cognitive deficits in bipolar disorder. We will try to understand the reasons and consequences of those disappointing results by analysing some methodological limitations, in particular regarding the statistical treatment of confounding factors.We will also discuss theoretical considerations pointing out the fact that we may have been expecting too much and oversimplifying when supporting the idea that cognition is a less complex entity than bipolar disorder.

Abnormal serotonergic neurotransmission has long been demonstrated in suicidal behavior. The dorsal and median raphe nuclei housing the main serotonergic cell bodies and the prefrontal cortex (PFC), particularly the ventral part innervated by the serotonergic system, have therefore been studied extensively in suicidal behavior research. However, only a few studies have described neuropsychological function impairment in suicidal patients. We investigated PFC-related neuropsychological function in patients with suicidal behavior, separating dorsolateral PFC (DLPFC)- and orbitofrontal cortex (OFC)-related functions.We compared 30 euthymic patients with suicidal behavior aged 18-65 years with 39 control subjects, for the following neuropsychological domains: global intellectual functioning, reward sensitivity, initiation, inhibition, and working memory. Patients and controls were compared by means of univariate and multivariate analyses, adjusting for age at interview, level of education and mood state at the time of evaluation. Trait impulsivity, measured with the Barratt Impulsivity Scale version 10 (BIS-10), was also included as a covariate in a subset of analyses.Multivariate comparisons demonstrated significant executive function deficits in patients with suicidal behavior. In particular, we observed impairment in visuospatial conceptualization (p0.0001), spatial working memory (p=0.001), inhibition (Hayling B-A, p=0.04; go anticipations, p=0.01) and visual attention (or reading fluency) (p=0.002). Similar results were obtained following adjustment for motor impulsivity as a covariate, except for spatial working memory.These deficits are consistent with prefrontal dysfunction in patients with suicidal behavior. Differentiation between DLPFC- and OFC-related neuropsychological functions showed no specific dysfunction of the orbitofrontal region in patients with suicidal behavior in our sample.

© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd., Objective: An association between bipolar disorder and cognitive impairment has repeatedly been described, even for euthymic patients. Findings are inconsistent both across primary studies and previous meta-analyses. This study reanalysed 31 primary data sets as a single large sample (N = 2876) to provide a more definitive view. Method: Individual patient and control data were obtained from original authors for 11 measures from four common neuropsychological tests: California or Rey Verbal Learning Task (VLT), Trail Making Test (TMT), Digit Span and/or Wisconsin Card Sorting Task. Results: Impairments were found for all 11 test-measures in the bipolar group after controlling for age, IQ and gender (Ps 0.001, E.S. = 0.26–0.63). Residual mood symptoms confound this result but cannot account for the effect sizes found. Impairments also seem unrelated to drug treatment. Some test-measures were weakly correlated with illness severity measures suggesting that some impairments may track illness progression. Conclusion: This reanalysis supports VLT, Digit Span and TMT as robust measures of cognitive impairments in bipolar disorder patients. The heterogeneity of some test results explains previous differences in meta-analyses. Better controlling for confounds suggests deficits may be smaller than previously reported but should be tracked longitudinally across illness progression and treatment., This paper was partially supported by a Seventh Framework Programme grant from the European Union to the European Network of Bipolar Research Expert Centres (ENBREC), Grant No. Health‐F2‐2009‐223102.