Associations between residual depressive symptoms, cognition, and functioning in patients with euthymic bipolar disorder: results from the FACE-BD cohort.

BackgroundThe relationship between residual depressive symptoms, cognition and functioning in patients with euthymic bipolar disorder is a subject of debate.AimsTo assess whether cognition mediates the association between residual depressive symptoms and functioning in patients with bipolar disorder who were euthymic.MethodWe included 241 adults with euthymic bipolar disorder in a multicentre cross-sectional study. We used a battery of tests to assess six cognition domains. A path analysis was then used to perform a mediation analysis of the relationship between residual depressive symptoms, cognitive components and functioning.ResultsOnly verbal and working memory were significantly associated with better functioning. Residual depressive symptoms were associated with poorer functioning. No significant relationship was found between residual depressive symptoms and any cognitive component.ConclusionsCognition and residual depressive symptoms appear to be two independent sources of variation in the functioning of people with euthymic bipolar disorder.

Neuropsychological functioning, age, and medication adherence in bipolar disorder.

OBJECTIVES: Poor adherence to medication is frequent in bipolar disorder (BD) and has been associated with several factors. To date, the relationship between low adherence and neuropsychological functioning in BD is still unclear. As age and neuropsychological functioning might have opposing influences on adherence, our aim was to investigate this link with a particular focus on the effect of age. METHODS: In a cross-sectional study, we included 353 patients divided into two age-groups (16-46; 47-71) from a French cohort diagnosed with BD (type I, II, NOS) and strictly euthymic. All patients had a standardized clinical and neuropsychological assessment and were categorized as high (n = 186) or low (n = 167) adherent based on their score from the Medication Adherence Rating Scale. Clinical information was collected based on a standardized interview and clinical validated scales. Neuropsychological performances were evaluated with an established standardized neuropsychological battery for bipolar disorder patients. After univariate analysis, neuropsychological and clinical predictors of low adherence were included in two age-specific stepwise multiple logistic regressions. RESULTS: A smaller number of hospitalizations (OR = 0.846, p = 0.012), a shorter illness duration (OR = 0.937, p = 0.003) and higher adverse effects (OR = 1.082, p<0.001) were associated with a greater risk of low adherence in the younger patients. In the older patients, low adherence was also predicted by a smaller number of hospitalizations (OR = 0.727, p = 0.008) and higher adverse effects (OR = 1.124, p = 0.005). Interestingly poor inhibition performance was also a significant predictor of low adherence in older patients (OR = 0.924, p = 0.030). CONCLUSIONS: We found an age-specific relationship between cognitive functioning and adherence in patients with BD. Poor inhibition performances predicted low adherence in older patients only. Our results highlight the need to provide age-adapted therapeutic interventions to improve adherence in patients with BD.

Cognitive profiles in euthymic patients with bipolar disorders: results from the FACE-BD cohort.

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.

Neurocognitive performance as an endophenotype for bipolar disorder.

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.

Clinical expression of bipolar disorder type I as a function of age and polarity at onset: convergent findings in samples from France and the United States.

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.

Is processing speed a valid cognitive endophenotype for bipolar disorder?

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.

A French network of bipolar expert centres: a model to close the gap between evidence-based medicine and routine practice.

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.

Preferential association between childhood emotional abuse and bipolar disorder.

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.

Factor analyses of the Suicidal Intent Scale (SIS) and the Risk-Rescue Rating Scale (RRRS): toward the identification of homogeneous subgroups of suicidal behaviors.

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.

Prefrontal cortex dysfunction in patients with suicidal behavior.

BACKGROUND: 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. METHOD: 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. RESULTS: Multivariate comparisons demonstrated significant executive function deficits in patients with suicidal behavior. In particular, we observed impairment in visuospatial conceptualization (p<0.0001), 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. CONCLUSIONS: 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.