Functional connectivity of the amygdala subnuclei in various mood states of bipolar disorder.

Amygdala functional dysconnectivity lies at the heart of the pathophysiology of bipolar disorder (BD). Recent preclinical studies suggest that the amygdala is a heterogeneous group of nuclei, whose specific connectivity could drive positive or negative emotional valence. We investigated functional connectivity (FC) changes within these circuits emerging from each amygdala's subdivision in 127 patients with BD in different mood states and 131 healthy controls (HC), who underwent resting-state functional MRI. FC was evaluated between lateral and medial nuclei of amygdalae, and key subcortical regions of the emotion processing network: anterior and posterior parts of the hippocampus, and core and shell parts of the nucleus accumbens. FC was compared across groups, and subgroups of patients depending on their mood states, using linear mixed models. We also tested correlations between FC and depression (MADRS) and mania (YMRS) scores. We found no difference between the whole sample of BD patients vs. HC but a significant correlation between MADRS and right lateral amygdala /right anterior hippocampus, right lateral amygdala/right posterior hippocampus and right lateral amygdala/left anterior hippocampus FC (r = -0.44, r = -0.32, r = -0.27, respectively, all pFDR<0.05). Subgroup analysis revealed decreased right lateral amygdala/right anterior hippocampus and right lateral amygdala/right posterior hippocampus FC in depressed vs. non-depressed patients and increased left medial amygdala/shell part of the left nucleus accumbens FC in manic vs non-manic patients. These results demonstrate that acute mood states in BD concur with FC changes in individual nuclei of the amygdala implicated in distinct emotional valence processing. Overall, our data highlight the importance to consider the amygdala subnuclei separately when studying its FC patterns including patients in distinct homogeneous mood states.

Cardiovascular hospitalizations and mortality among adults aged 25-64 years in the USA.

BACKGROUND AND AIMS: Declines in cardiovascular mortality have stagnated in the USA since 2011. There is growing concern that these patterns reflect worsening cardiovascular health in younger adults. However, little is known about how the burden of acute cardiovascular hospitalizations and mortality has changed in this population. Changes in cardiovascular hospitalizations and mortality among adults aged 25-64 years were evaluated, overall and by community-level income. METHODS: Using the National Inpatient Sample, age-standardized annual hospitalization and in-hospital mortality rates for acute myocardial infarction (AMI), heart failure, and ischaemic stroke were determined among adults aged 25-64 years. Quasi-Poisson and quasi-binominal regression models were fitted to compare outcomes between individuals residing in low- and higher-income communities. RESULTS: Between 2008 and 2019, age-standardized hospitalization rates for AMI increased among younger adults from 155.0 (95% confidence interval: 154.6, 155.4) per 100 000 to 160.7 (160.3, 161.1) per 100 000 (absolute change +5.7 [5.0, 6.3], P < .001). Heart failure hospitalizations also increased (165.3 [164.8, 165.7] to 225.3 [224.8, 225.8], absolute change +60.0 (59.3, 60.6), P < .001), as ischaemic stroke hospitalizations (76.3 [76.1, 76.7] to 108.1 [107.8, 108.5], absolute change +31.7 (31.2, 32.2), P < .001). Across all conditions, hospitalizations rates were significantly higher among younger adults residing in low-income compared with higher-income communities, and disparities did not narrow between groups. In-hospital mortality decreased for all conditions over the study period. CONCLUSIONS: There was an alarming increase in cardiovascular hospitalizations among younger adults in the USA from 2008 to 2019, and disparities between those residing in low- and higher-income communities did not narrow.

Study of the different sleep disturbances during the prodromal phase of depression and mania in bipolar disorders.

BACKGROUND: One of the challenges in bipolar disorder (BD) lies in early detection of the illness and its recurrences, to improve prognosis. Sleep disturbances (SD) have been proposed as reliable predictive markers of conversion. While preliminary studies have explored the relationship between SD and the onset of mood episodes, the results remain heterogeneous and a few have specifically examined patients' perception of prodromal symptoms and their progression until the episode occurs. Identifying prodromes represents a crucial clinical challenge, as it enables early intervention, thereby reducing the severity of BD. Therefore, the objective of this study is to better characterize and evaluate the progressive nature of SD as prodromal symptoms of mood episodes, and patients' perception of it. METHODS: Patients diagnosed with BD, either hospitalized or seeking treatment for a (hypo)manic or depressive episode benefited from standardized questionnaires, structured interviews, and self-report questionnaires to evaluate SD prior to the current episode, as well as sociodemographic and clinical information. RESULTS: Out of the 41 patients included, 59% spontaneously reported SD prior to the episode, appearing 90 days before depression and 35 days before mania (pre-indexed/spontaneous reports: 51.22% insomnia complaints, 4.88% hypersomnolence complaints, 7.32% parasomnias, 2.44% sleep movements). After inquiry about specific SD, the percentage of patients reporting prodromal SD increased significantly to 83%, appearing 210 days before depression and 112.5 days before mania (post-indexed reports: 75.61% presented with insomnia complaints appearing 150 days before depression and 20 days before mania, 46.34% had hypersomnolence complaints appearing 60 days before depression, 43.9% had parasomnias appearing 210 days before depression and 22.5 days before mania, 36.59% had sleep movements appearing 120 days before depression and 150 days before mania). Of note, bruxism appeared in 35% of patients before mania, and restless legs syndrome in 20% of patients before depression. CONCLUSION: This study highlights the very high prevalence of SD prior to a mood episode in patients with BD with differences between depressive and manic episodes. The more systematic screening of sleep alterations of the prodromal phase improved the recognition and characterization of different symptoms onset by patients. This underscores the need for precise questioning regarding sleep patterns in patients, to better identify the moment of transition toward a mood episode, referred to as "Chronos syndrome". The study emphasizes the importance of educating patients about the disorder and its sleep prodromal symptoms to facilitate early intervention and prevent recurrences.

Exploring emotional regulation in insomnia with and without major depressive episode.

Previous studies have highlighted the pivotal role of emotional regulation impairment in the progression of depressive and insomnia disorders, individually. Nevertheless, to date, no study has undertaken a direct comparison of the emotional profiles in individuals experiencing insomnia with or without major depressive episode (MDE). In this study, our objective was to closely examine multiple aspects of emotional regulation among individuals experiencing insomnia, with or without concurrent depression. This descriptive observational study involved 57 participants, comprising 27 individuals with comorbid chronic insomnia and MDE, and 30 with chronic insomnia alone. All participants completed self-questionnaires assessing aspects of emotional regulation: the Affect Intensity Measure (intensity), Affective Lability Scale (lability), Temperament Evaluation of Memphis Pisa Paris and San Diego Autoquestionnaire (temperament), Cognitive Emotion Regulation Questionnaire (cognitive strategies), and Multidimensional Assessment of Thymic States (reactivity). There were statistically significant differences between the group with insomnia with MDE and insomnia without MDE in terms of anxiety/depression lability. Discrepancies also manifested in terms of activation or inhibition in motor activity and motivation. Additionally, a noteworthy variance in cognitive strategies for emotional regulation was observed, specifically in self-blame and catastrophising. From a cognitive perspective, patients with insomnia and a MDE exhibited a greater inclination towards self-blame and catastrophising, in contrast to those with insomnia only. Behaviourally, the former group demonstrated heightened inhibition of motivation and motor activity. These findings underscore the importance of larger-scale investigations to validate these insights and pave the way for clinical prospects centred around emotional regulation, ultimately fostering personalised treatments for insomnia.

CADPS functional mutations in patients with bipolar disorder increase the sensitivity to stress.

Bipolar disorder is a severe and chronic psychiatric disease resulting from a combination of genetic and environmental risk factors. Here, we identified a significant higher mutation rate in a gene encoding the calcium-dependent activator protein for secretion (CADPS) in 132 individuals with bipolar disorder, when compared to 184 unaffected controls or to 21,070 non-psychiatric and non-Finnish European subjects from the Exome Aggregation Consortium. We found that most of these variants resulted either in a lower abundance or a partial impairment in one of the basic functions of CADPS in regulating neuronal exocytosis, synaptic plasticity and vesicular transporter-dependent uptake of catecholamines. Heterozygous mutant mice for Cadps+/- revealed that a decreased level of CADPS leads to manic-like behaviours, changes in BDNF level and a hypersensitivity to stress. This was consistent with more childhood trauma reported in families with mutation in CADPS, and more specifically in mutated individuals. Furthermore, hyperactivity observed in mutant animals was rescued by the mood-stabilizing drug lithium. Overall, our results suggest that dysfunction in calcium-dependent vesicular exocytosis may increase the sensitivity to environmental stressors enhancing the risk of developing bipolar disorder.

Handedness in bipolar disorders is associated with specific neurodevelopmental features: results of the BD-FACE cohort.

OBJECTIVES: High rates of non-right-handedness (NRH) and mixed-handedness exist in neurodevelopmental disorders. Dysfunctional neurodevelopmental pathways may be implicated in the underlying pathophysiology of bipolar disorders (BD), at least in some subgroups. Yet little is known about correlates of NRH and mixed-handedness in BD. The objectives of this national study are to determine (i) the prevalence of NRH and mixed-handedness in a well-stabilized sample of BD individuals; (ii) if NRH/mixed-handedness in BD is associated with a different clinical, biological and neurocognitive profile. METHODS: We included 2174 stabilized individuals. Participants were tested with a comprehensive battery of neuropsychological tests. Handedness was assessed using a single oral question. Learning and/or language disorders and obstetrical complications were recorded using childhood records. Common environmental, clinical and biological parameters were assessed. RESULTS: The prevalence of NRH and mixed-handedness were, respectively, 11.6 and 2.4%. Learning/language disorders were found in 9.7% out of the total sample and were associated with atypical handedness (only dyslexia for mixed-handedness (p < 0.01), and dyslexia and dysphasia for NRH (p = 0.01 and p = 0.04, respectively). In multivariate analyses, NRH was associated with a younger age of BD onset (aOR 0.98 (95% CI 0.96-0.99) and lifetime substance use disorder (aOR 1.40 (95% CI 1.03-1.82) but not with any of the cognitive subtasks. Mixed-handedness was associated in univariate analyses with lifetime substance use disorder, lifetime cannabis use disorder (all p < 0.01) and less mood stabilizer prescription (p = 0.028). No association was found between NRH or mixed-handedness and the following parameters: trauma history, obstetrical complications, prior psychotic symptoms, bipolar subtype, attention deficit/hyperactivity disorder, peripheral inflammation or body mass index. CONCLUSIONS: Handedness may be associated with specific features in BD, possibly reflecting a specific subgroup with a neurodevelopmental load.

Using structural MRI to identify bipolar disorders - 13 site machine learning study in 3020 individuals from the ENIGMA Bipolar Disorders Working Group.

Bipolar disorders (BDs) are among the leading causes of morbidity and disability. Objective biological markers, such as those based on brain imaging, could aid in clinical management of BD. Machine learning (ML) brings neuroimaging analyses to individual subject level and may potentially allow for their diagnostic use. However, fair and optimal application of ML requires large, multi-site datasets. We applied ML (support vector machines) to MRI data (regional cortical thickness, surface area, subcortical volumes) from 853 BD and 2167 control participants from 13 cohorts in the ENIGMA consortium. We attempted to differentiate BD from control participants, investigated different data handling strategies and studied the neuroimaging/clinical features most important for classification. Individual site accuracies ranged from 45.23% to 81.07%. Aggregate subject-level analyses yielded the highest accuracy (65.23%, 95% CI = 63.47-67.00, ROC-AUC = 71.49%, 95% CI = 69.39-73.59), followed by leave-one-site-out cross-validation (accuracy = 58.67%, 95% CI = 56.70-60.63). Meta-analysis of individual site accuracies did not provide above chance results. There was substantial agreement between the regions that contributed to identification of BD participants in the best performing site and in the aggregate dataset (Cohen's Kappa = 0.83, 95% CI = 0.829-0.831). Treatment with anticonvulsants and age were associated with greater odds of correct classification. Although short of the 80% clinically relevant accuracy threshold, the results are promising and provide a fair and realistic estimate of classification performance, which can be achieved in a large, ecologically valid, multi-site sample of BD participants based on regional neurostructural measures. Furthermore, the significant classification in different samples was based on plausible and similar neuroanatomical features. Future multi-site studies should move towards sharing of raw/voxelwise neuroimaging data.

Non-alcoholic fatty liver disease in a sample of individuals with bipolar disorders: results from the FACE-BD cohort.

OBJECTIVE: Non-Alcoholic fatty liver disease (NAFLD) is becoming the most common liver disease in Western populations. While obesity and metabolic abnormalities are highly frequent in bipolar disorders (BD), no studies have been performed to estimate the prevalence of NALFD in individuals with BD. The aim of our study is to estimate the prevalence of NAFLD and to identify the potential associated risk factors in a large sample of BD individuals. METHODS: Between 2009 and 2019, 1969 BD individuals from the FACE-BD cohort were included. Individuals with liver diseases, Hepatitis B or C, and current alcohol use disorders were excluded from the analyses. A blood sample was drawn from participants. Screening of NAFLD was determined using fatty liver index (FLI). Individuals with FLI> 60 were considered as having NAFLD. RESULTS: The prevalence of NAFDL in this sample was estimated at 28.4%. NAFLD was observed in 40% of men and 21% of women. NAFLD was independently associated with older age, male gender, sleep disturbances, and current use of atypical antipsychotics or anxiolytics. As expected, the prevalence of NALFD was also higher in individuals with overweight and in those with metabolic syndrome. CONCLUSIONS: This study reinforces the view that individuals with BD are highly vulnerable to metabolic and cardiovascular diseases. The prevalence of NAFLD in individuals with BD was two times higher than the prevalence reported in the general population. The regular screening of the MetS in individuals with BD should be therefore complemented by the additional screening of NAFLD among these vulnerable individuals.

Association between anhedonia and suicidal events in patients with mood disorders: A 3-year prospective study.

BACKGROUND: As almost all mental disorders are associated with increased suicidal-related behavior, anhedonia might be a trans-diagnostic dimension to target for suicide prevention. METHODS: For this 3-year-long prospective study, 2,839 outpatients with mood disorders were recruited. They were divided in: (a) two groups according to the occurrence or not of suicidal ideation during the follow-up, and (b) two groups according to the occurrence or not of suicide attempts during the follow-up. Anhedonia was assessed using a composite score (the French version of the 14-item Snaith-Hamilton Pleasure Scale and item 13 of the Quick Inventory of Depressive Symptomatology scale) at inclusion and at 6, 12, 24, and 36 months after inclusion. RESULTS: Patients with mood disorders and anhedonia at least at one follow-up visit had a 1.4-fold higher risk of suicidal ideation (adjusted odds ratio = 1.35; 95% confidence interval [1.07, 1.70]), even after adjustment for confounding factors of suicide risk (i.e., bipolar or unipolar disorder, sex, age, marital status, education level, antidepressant intake, personal history of suicide attempt, at least one childhood trauma, and mean of the maximum depression score during the follow-up). Conversely, association between anhedonia and suicide attempt did not remain significant after adjustment. CONCLUSIONS: The significant association between anhedonia and suicide ideation in patients with mood disorders stresses the need of targeting hedonia in mood disorders, and of research focusing on the position to pleasure in life through eudaimonia.

Childhood maltreatment and polygenic risk in bipolar disorders.

BACKGROUND: Childhood maltreatment is a well-known risk factor for developing a more severe and complex form of bipolar disorders (BD). However, knowledge is scarce about the interactions between childhood maltreatment and underlying genetic vulnerability on the clinical expression of BD. METHOD: We assigned a BD-polygenic risk score (BD-PRS), calculated from the Psychiatric Genomics Consortium, to each individual in a sample of 402 cases with BD. The lifetime clinical expression of BD was characterized using structured interviews and patients completed the Childhood Trauma Questionnaire (CTQ) to assess the severity of childhood maltreatment. RESULTS: Cases who reported more severe childhood maltreatment had a lower BD-PRS (rho = -0.12, P = .01), especially when considering emotional abuse (rho = -0.16, P = .001). An interaction between BD-PRS and childhood maltreatment was observed for the risk of rapid cycling (P = .01). No further interactions between BD-PRS and childhood maltreatment were observed for other clinical characteristics (age at onset, suicide attempts, number of mood episodes, mixed features, substance use disorders and psychotic symptoms). CONCLUSION: Our study is the first to show that less genetic risk may be needed to develop a more unstable form of BD when exposed to childhood maltreatment. Our study supports childhood trauma as an independent risk factor for BD.

Allostatic load, emotional hyper-reactivity, and functioning in individuals with bipolar disorder.

OBJECTIVES: Diagnosis and management of bipolar disorder (BD) are limited by the absence of available biomarkers. Allostatic load (AL) represents the strain that stress, including the effects of acute phases and inter-episode chronic mood instability, exerts on interconnected biological systems. This study aimed to operationalize an AL index and explore whether it could be relevant to better characterize BD patients with and without emotional hyper-reactivity particularly those at higher risk of immune-cardiometabolic dysregulation and functional impairment. METHODS: Levels of biomarkers of chronic inflammation (hsCRP and albumin), cardiovascular (systolic/diastolic blood pressure) and metabolic functions (fasting glucose, glycosylated hemoglobin, total cholesterol, LDL, HDL, and triglycerides) were measured in 1072 adult BD outpatients. Patients were classified in two groups (with/without emotional hyper-reactivity) assessed by the Multidimensional Assessment of Thymic States scale. An Allostatic Load Index for BD (BALLI), comprising six biomarkers, was constructed using data-driven biomarker selection. RESULTS: BALLI showed 81.1% accuracy with good sensitivity (81%) and specificity (81.2%) for characterizing BD patients presenting emotional hyper-reactivity, elevated risk of inflammation (increased hsCRP, hypoalbuminemia) and cardiometabolic disturbances (hypertension, hyperglycemia, and hypertriglyceridemia). Patients classified by the BALLI as presenting emotional hyper-reactivity had significantly lower global and cognitive functioning than those without emotional hyper-reactivity (P < .0001). CONCLUSIONS: A multidimensional approach based on a simple AL score (eg, BALLI) and dimensions of behavior (eg, emotional hyper-reactivity) alongside mood is clinically relevant. AL index could be a useful tool to detect multisystemic physiological dysregulations in BD patients with/without emotional hyper-reactivity particularly those at higher risk of immune-cardiometabolic disturbances and functional impairment.

Trajectories of functioning in bipolar disorders: A longitudinal study in the FondaMental Advanced Centers of Expertise in Bipolar Disorders cohort.

OBJECTIVE: We aimed at identifying distinct trajectories of functioning and at describing their respective clinical characteristics in a cohort of individuals with bipolar disorders. METHODS: We included a sample of 2351 individuals with bipolar disorders who have been followed-up to 3 years as part as the FondaMental Advanced Centers of Expertise in Bipolar Disorders cohort. Global functioning was measured using the Functioning Assessment Short Test. We used latent class mixed models to identify distinct longitudinal trajectories of functioning over 3 years. Multivariable logistic regression models were used to identify the baseline factors that were associated with the membership to each trajectory of functioning. RESULTS: Three distinct trajectories of functioning were identified: (1) a majority of individuals (72%) had a stable trajectory of mild functional impairment, (2) 20% of individuals had a stable trajectory of severe functional impairment and (3) 8% of individuals had a trajectory of moderate functional impairment that improved over time. The membership to a trajectory of stable severe versus stable mild functional impairment was associated with unemployment, a higher number of previous hospitalizations, childhood maltreatment, a higher level of residual depressive symptoms, higher sleep disturbances, a higher body mass index and a higher number of psychotropic medications being prescribed at baseline. The model that included these seven factors led to an area under the curve of 0.85. CONCLUSION: This study enabled to stratify individuals with bipolar disorders according to three distinct trajectories of functioning. The results regarding the potential determinants of the trajectory of severe functional impairment needs to be replicated in independent samples. Nevertheless, these potential determinants may represent possible therapeutic targets to improve the prognosis of those patients at risk of persistent poor functioning.

Prevalence and determinants of cognitive impairment in the euthymic phase of bipolar disorders: results from the FACE-BD cohort.

BACKGROUND: Cognitive deficits are a well-established feature of bipolar disorders (BD), even during periods of euthymia, but risk factors associated with cognitive deficits in euthymic BD are still poorly understood. We aimed to validate classification criteria for the identification of clinically significant cognitive impairment, based on psychometric properties, to estimate the prevalence of neuropsychological deficits in euthymic BD, and identify risk factors for cognitive deficits using a multivariate approach. METHODS: We investigated neuropsychological performance in 476 euthymic patients with BD recruited via the French network of BD expert centres. We used a battery of tests, assessing five domains of cognition. Five criteria for the identification of neuropsychological impairment were tested based on their convergent and concurrent validity. Uni- and multivariate logistic regressions between cognitive impairment and several clinical and demographic variables were performed to identify risk factors for neuropsychological impairment in BD. RESULTS: One cut-off had satisfactory psychometric properties and yielded a prevalence of 12.4% for cognitive deficits in euthymic BD. Antipsychotics use were associated with the presence of a cognitive deficit. CONCLUSIONS: This is the first study to validate a criterion for clinically significant cognitive impairment in BD. We report a lower prevalence of cognitive impairment than previous studies, which may have overestimated its prevalence. Patients with euthymic BD and cognitive impairment may benefit from cognitive remediation.

Higher in vivo Cortical Intracellular Volume Fraction Associated with Lithium Therapy in Bipolar Disorder: A Multicenter NODDI Study.

BACKGROUND: MRI studies in patients with bipolar disorder have suggested that lithium is associated with grey matter increases that may underlie its therapeutic effects. However, the relationship between grey matter volume and cellular microstructural changes is not straightforward, as modifications of different cellular compartments of grey matter may be involved. OBJECTIVES: Our aim was to test the hypothesis that dendritic density is higher in patients undergoing lithium therapy than in patients without lithium, using advanced modelling of water diffusion investigated with MRI. METHOD: We included 41 patients and 40 controls matched for age and gender from two sites. All subjects underwent 3T MRI with 3 shells of diffusion. We used neurite orientation dispersion and density imaging to compare the grey matter neurite density between patients undergoing lithium therapy or not and control subjects. RESULTS: We found a significant group effect in the left prefrontal region (p = 0.001, Bonferroni corrected): patients without lithium had a lower frontal neurite density than controls (p = 0.009), while those on lithium had a higher mean neurite density than those without (p < 0.001). Patients on lithium were not different from controls (p = 0.08). CONCLUSIONS: This is the first study to report in vivo evidence of preserved neurite density of the prefrontal cortex in humans associated with lithium intake. Changes of intracellular volume fraction are thought to reflect changes of grey matter microstructural organization. This reinforces the hypothesis of lithium having a positive effect on the neuronal compartment in humans.

Revising Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, criteria for the bipolar disorders: Phase I of the AREDOC project.

OBJECTIVE: To derive new criteria sets for defining manic and hypomanic episodes (and thus for defining the bipolar I and II disorders), an international Task Force was assembled and termed AREDOC reflecting its role of Assessment, Revision and Evaluation of DSM and other Operational Criteria. This paper reports on the first phase of its deliberations and interim criteria recommendations. METHOD: The first stage of the process consisted of reviewing Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, and recent International Classification of Diseases criteria, identifying their limitations and generating modified criteria sets for further in-depth consideration. Task Force members responded to recommendations for modifying criteria and from these the most problematic issues were identified. RESULTS: Principal issues focussed on by Task Force members were how best to differentiate mania and hypomania, how to judge 'impairment' (both in and of itself and allowing that functioning may sometimes improve during hypomanic episodes) and concern that rejecting some criteria (e.g. an imposed duration period) might risk false-positive diagnoses of the bipolar disorders. CONCLUSION: This first-stage report summarises the clinical opinions of international experts in the diagnosis and management of the bipolar disorders, allowing readers to contemplate diagnostic parameters that may influence their clinical decisions. The findings meaningfully inform subsequent Task Force stages (involving a further commentary stage followed by an empirical study) that are expected to generate improved symptom criteria for diagnosing the bipolar I and II disorders with greater precision and to clarify whether they differ dimensionally or categorically.

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.

Outcomes for bipolar patients assessed in the French expert center network: A 2-year follow-up observational study (FondaMental Advanced Centers of Expertise for Bipolar Disorder [FACE-BD]).

OBJECTIVE: A new health care system for patients with bipolar disorders was established in France under the auspices of Fondation FondaMental, based on thorough clinical assessment of patients and on close collaborations between expert centers and referring practitioners. We report the results of outcomes after 2 years of observational follow-up of adult patients assessed within the network. METHOD: A total of 984 patients were included in the study. We compared several parameters (e.g., mood episodes and hospitalization) 1 year before inclusion and after 2 years of observational follow-up using the patient as his or her own control. Other outcomes were compared at baseline and during follow-up. We estimated the evolution of these parameters over a period of 2 years using mixed models for continuous parameters and a generalized estimating equation (GEE) model for categorical variables, adjusting for potential confounding factors. RESULTS: Mean age was 42.7 (±12.5) years and 58.8% were women. The number of hospitalization days decreased by 55% when comparing 1 year before inclusion vs the follow-up period. In addition, patients showed a clear functional improvement associated with a reduction of residual mood symptoms, diminished psychiatric comorbidities, improvement of sleep and a better adherence to treatment. CONCLUSIONS: This study demonstrates an overall improvement of patients followed for 2 years after an assessment in expert centers for bipolar disorders. This new organization based on a thorough clinical assessment and on personalized recommendations (drug treatments, psycho-social strategies and lifestyle measures) sent to health care professionals, and actively involving patients and families, improves the prognosis of BD patients.

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.

Clinical factors associated with lithium response in bipolar disorders.

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 <10% of good response cases. Family history of bipolar disorder I was of borderline statistical significance, being more frequent in the good response group (38%) compared with the non-response group (18%). There was a trend ( p = 0.06) for bipolar disorder II to be associated with non-response. 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.

Emotional reactivity, functioning, and C-reactive protein alterations in remitted bipolar patients: Clinical relevance of a dimensional approach.

OBJECTIVES: Inter-episode mood instability has increasingly been considered in bipolar disorder. This study aimed to investigate emotional reactivity as a major dimension for better characterizing remitted bipolar patients with subthreshold mood symptoms and functional status. This study also aimed to investigate whether high-sensitivity C-reactive protein, a marker of low-grade inflammation, could be a biological marker of emotional dysregulation in bipolar disorder (BD). METHODS: Cross-sectional study of 613 subjects who met Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition criteria for BD recruited from the FondaMental Advanced Centers of Expertise in Bipolar Disorders cohort from 2009 to 2014. All patients had been in remission for at least 3 months before assessment. Patients were classified into three groups according to levels of emotional reactivity. Emotional reactivity was assessed by using the Multidimensional Assessment of Thymic States, and functional status was assessed by the Functioning Assessment Short Test. Clinical characteristics and blood sample were collected from all patients. RESULTS: In total, 415 (68%) patients had abnormal emotional reactivity. Independent of potential confounders, including age, gender and subthreshold mood symptoms, serum levels of high-sensitivity C-reactive protein were significantly higher in patients with emotional hyper-reactivity (median = 4.0 mg/L, interquartile range = 2.7-5.6), and with emotional hypo-reactivity (median = 3.0 mg/L, interquartile range = 1-4) compared with patients with normal emotional reactivity (median = 0.95 mg/L, interquartile range = 0.4-1.9, p < 0.001). Patients with emotional hyper-reactivity showed significant cognitive functioning impairment ( p < 0.001). CONCLUSIONS: Emotional reactivity appears to be a relevant dimension for better characterizing remitted bipolar patients with subthreshold mood symptoms. Levels of high-sensitivity C-reactive protein may be an objective marker of emotional dysregulation in BD. Further studies are needed to confirm our findings.