Functioning and neurocognition in very early and early-life onset bipolar disorders: the moderating role of bipolar disorder type.

Defining homogeneous subgroups of bipolar disorder (BD) is a major goal in personalized psychiatry and research. According to the neurodevelopmental theory, age at onset may be a key variable. As potential trait markers of neurodevelopment, cognitive and functional impairment should be greater in the early form of the disease, particularly type 1 BD (BD I). The age at onset was assessed in a multicenter, observational sample of 4190 outpatients with BD. We used a battery of neuropsychological tests to assess six domains of cognition. Functioning was measured using the Functioning Assessment Short Test (FAST). We studied the potential moderation of the type of BD on the associations between the age at onset and cognitive and functioning in a subsample of 2072 euthymic participants, controlling for potential clinical and socio-demographic covariates. Multivariable analyses showed cognition to not be impaired in individuals with early (21-30 years) and very early-life (before 14 years) onset of BD. Functioning was equivalent between individuals with early and midlife-onset of BD II and NOS but better for individuals with early onset of BD I. In contrast, functioning was not worse in individuals with very early-onset BD I but worse in those with very early-onset BD II and NOS. Early-life onset BDs were not characterized by poorer cognition and functioning. Our results do not support the neurodevelopmental view that a worse cognitive prognosis characterizes early-life onset BD. This study suggests that functional remediation may be prioritized for individuals with midlife-onset BD I and very early life onset BD 2 and NOS.

Incidence and predictors of metabolic syndrome onset in individuals with bipolar disorders: A longitudinal study from the FACE-BD cohort.

INTRODUCTION: Metabolic syndrome (MetS) is a cluster of components including abdominal obesity, hyperglycemia, hypertension, and dyslipidemia. MetS is highly prevalent in individuals with bipolar disorders (BD) with an estimated global rate of 32.6%. Longitudinal data on incident MetS in BD are scarce and based on small sample size. The objectives of this study were to estimate the incidence of MetS in a large longitudinal cohort of 1521 individuals with BD and to identify clinical and biological predictors of incident MetS. METHODS: Participants were recruited from the FondaMental Advanced Center of Expertise for Bipolar Disorder (FACE-BD) cohort and followed-up for 3 years. MetS was defined according to the International Diabetes Federation criteria. Individuals without MetS at baseline but with MetS during follow-up were considered as having incident MetS. A logistic regression model was performed to estimate the adjusted odds ratio and its corresponding 95% confidence interval (CI) for an association between each factor and incident MetS during follow-up. We applied inverse probability-of-censoring weighting method to minimize selection bias due to loss during follow-up. RESULTS: Among individuals without MetS at baseline (n = 1521), 19.3% developed MetS during follow-up. Multivariable analyses showed that incident MetS during follow-up was significantly associated with male sex (OR = 2.2, 95% CI = 1.7-3.0, p < 0.0001), older age (OR = 2.14, 95% CI = 1.40-3.25, p = 0.0004), presence of a mood recurrence during follow-up (OR = 1.91, 95% CI = 1.22-3.00, p = 0.0049), prolonged exposure to second-generation antipsychotics (OR = 1.56, 95% CI = 0.99, 2.45, p = 0.0534), smoking status at baseline (OR = 1.30, 95% CI = 1.00-1.68), lifetime alcohol use disorders (OR = 1.33, 95% CI = 0.98-1.79), and baseline sleep disturbances (OR = 1.04, 95% CI = 1.00-1.08), independently of the associations observed for baseline MetS components. CONCLUSION: We observed a high incidence of MetS during a 3 years follow-up (19.3%) in individuals with BD. Identification of predictive factors should help the development of early interventions to prevent or treat early MetS.

Comparative analysis of anticholinergic burden scales to explain iatrogenic cognitive impairment and self-reported side effects in the euthymic phase of bipolar disorders: Results from the FACE-BD cohort.

Bipolar disorders (BD) are characterized by cognitive impairment during the euthymic phase, to which treatments can contribute. The anticholinergic properties of medications, i.e., the ability of a treatment to inhibit cholinergic receptors, are associated with cognitive impairment in elderly patients and people with schizophrenia but this association has not been well characterized in individuals with remitted BD. Moreover, the validity of only one anticholinergic burden scale designed to assess the anticholinergic load of medications has been tested in BD. In a literature review, we identified 31 existing scales. We first measured the associations between 27 out of the 31 scales and objective cognitive impairment in bivariable regressions. We then adjusted the bivariable models with covariates: the scales significantly associated with cognitive impairment in bivariable and multiple logistic regressions were defined as having good concurrent validity to assess cognitive impairment. In a sample of 2,031 individuals with euthymic BD evaluated with a neuropsychological battery, two scales had good concurrent validity to assess cognitive impairment, whereas chlorpromazine equivalents, lorazepam equivalents, the number of antipsychotics, or the number of treatments had not. Finally, similar analyses with subjective anticholinergic side-effects as outcome variables reported 14 scales with good concurrent validity to assess self-reported peripheral anticholinergic side-effects and 13 to assess self-reported central anticholinergic side-effects. Thus, we identified valid scales to monitor the anticholinergic burden in BD, which may be useful in estimating iatrogenic cognitive impairment in studies investigating cognition in BD.

Key findings on bipolar disorders from the longitudinal FondaMental Advanced Center of Expertise-Bipolar Disorder (FACE-BD) cohort.

BACKGROUND: The FACE-BD cohort is an observational cohort of individuals with bipolar disorders (BD) who benefited from a systematic evaluation with evidence-based treatment recommendations and who were followed-up every year for 3 years in France. The objectives were to describe the lifetime course of BD, associated psychiatric and somatic comorbidities, and cognition profile. This cohort aims to identify clinical/biological signatures of outcomes, trajectories of functioning and transition between clinical stages. This article summarizes 10 years of findings of the FACE-BD cohort. METHOD & RESULTS: We included 4422 individuals, all having a baseline assessment, among which 61.2% had at least one follow-up visit at either one, two or three years. A subsample of 1200 individuals had at least one biological sample (serum, plasma, DNA). Assessments include family history of psychiatric disorders, psychiatric diagnosis, current mood symptoms, functioning, hospitalizations, suicidal attempts, physical health, routine blood tests, treatment history, psychological dimensions, medico-economic data and a cognitive assessment. Studies from this cohort illustrate that individuals with BD display multiple coexistent psychiatric associated conditions including sleep disturbances, anxiety disorders, substance use disorders and suicide attempts as well as a high prevalence of metabolic syndrome. During follow-up, we observed a 55% reduction of the number of days of hospitalization and a significant improvement in functioning. CONCLUSIONS: The FACE-BD cohort provides a strong research infrastructure for clinical research in BD and has a unique position among international cohorts because of its comprehensive clinical assessment and sustainable funding from the French Ministry of Health.

Clinical predictors of recurrences in bipolar disorders type 1 and 2: A FACE-BD longitudinal study.

OBJECTIVE: To examine which characteristics predict the time to a first mood recurrence at three years in Bipolar Disorder type I (BD-I) and type II (BD-II). METHODS: Individuals with BD were followed up to 3 years. Turbull's extension of the Kaplan-Meier analysis for interval-censored data was used to estimate the cumulative probability of recurrence over time. Separate models were performed according to BD subtype to determine which baseline factors were predictive of recurrences and were adjusted for age, gender and educational level. RESULTS: We included 630 individuals with BD-I and 505 with BD-II. The first recurrence of any polarity occurred earlier in BD-II (p = 0.03). The first depressive recurrence occurred earlier in BD-II (p < 0.0001), whereas the first (hypo)manic recurrence occurred earlier in BD-I (p = 0.0003). In BD-I, the clinical variables that were associated to the time to a first mood recurrence were depressive symptoms, lifetime rapid cycling, global activation and the number of psychotropic medications at baseline. In BD-II, the time to a first recurrence was associated with a younger age at onset of BD and a higher number of lifetime mood episodes. The Areas Under the Curve for both models were moderate. CONCLUSION: Predictors of recurrences showed few specificities to BD-I or BD-II. The ability to predict recurrences in BD based on socio-demographic and clinical variables remained too moderate for a transfer in daily practice. This study highlights the need for further studies that would include other types of predictors, such as molecular, cognitive or neuro-imaging ones, to achieve an accurate level of prediction of recurrences in BD.

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.

Minimum clinically important differences for the Functioning Assessment Short Test and a battery of neuropsychological tests in bipolar disorders: results from the FACE-BD cohort.

AIMS: Establishing the minimum clinically important difference (MCID) in functioning and cognition is essential to the interpretation of the research and clinical work conducted in bipolar disorders (BD). The present study aimed to estimate the MCID for the Functioning Assessment Short Test (FAST) and a battery of neuropsychological tests in BD. METHODS: Anchor-based and distributive methods were used to estimate the MCID for the FAST and cognition using data from a large, multicentre, observational cohort of individuals with BD. The FAST and cognition were linked with the Clinical Global Impressions Scale-Severity (CGI-S) and Global Assessment of Functioning (GAF) using an equipercentile method. The magnitude of the standard error measurement (s.e.m.) provided another estimate of the MCID. RESULTS: In total, 570 participants were followed for 2 years. Cross-sectional CGI-S and GAF scores were linked to a threshold ⩽7 on the FAST for functional remission. The MCID for the FAST equalled 8- or 9-points change from baseline using the CGI-S and GAF. One s.e.m. on the FAST corresponded to 7.6-points change from baseline. Cognitive variables insufficiently correlated with anchor variables (all ρ <0.3). One s.e.m. for cognitive variables corresponded to a range of 0.45 to 0.93-s.d. change from baseline. CONCLUSIONS: These findings support the value of the estimated MCID for the FAST and cognition and may be a useful tool to evaluate cognitive and functional remediation effects and improve patient functional outcomes in BD. The CGI-S and GAF were inappropriate anchors for cognition. Further studies may use performance-based measures of functioning instead.

Emotional hyper-reactivity and cardiometabolic risk in remitted bipolar patients: a machine learning approach.

OBJECTIVE: Remitted bipolar disorder (BD) patients frequently present with chronic mood instability and emotional hyper-reactivity, associated with poor psychosocial functioning and low-grade inflammation. We investigated emotional hyper-reactivity as a dimension for characterization of remitted BD patients, and clinical and biological factors for identifying those with and without emotional hyper-reactivity. METHOD: A total of 635 adult remitted BD patients, evaluated in the French Network of Bipolar Expert Centers from 2010-2015, were assessed for emotional reactivity using the Multidimensional Assessment of Thymic States. Machine learning algorithms were used on clinical and biological variables to enhance characterization of patients. RESULTS: After adjustment, patients with emotional hyper-reactivity (n = 306) had significantly higher levels of systolic and diastolic blood pressure (P < 1.0 × 10-8 ), high-sensitivity C-reactive protein (P < 1.0 × 10-8 ), fasting glucose (P < 2.23 × 10-6 ), glycated hemoglobin (P = 0.0008) and suicide attempts (P = 1.4 × 10-8 ). Using models of combined clinical and biological factors for distinguishing BD patients with and without emotional hyper-reactivity, the strongest predictors were: systolic and diastolic blood pressure, fasting glucose, C-reactive protein and number of suicide attempts. This predictive model identified patients with emotional hyper-reactivity with 84.9% accuracy. CONCLUSION: The assessment of emotional hyper-reactivity in remitted BD patients is clinically relevant, particularly for identifying those at higher risk of cardiometabolic dysfunction, chronic inflammation, and suicide.

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.

Chronotypes of bipolar patients in remission: validation of the French version of the circadian type inventory in the FACE-BD sample.

Circadian rhythm disturbances have been associated with bipolar disorder (BD) during both the mood episodes and the periods of remission. Circadian phase preferences for the evening have been reported for remitted patients, whereas the amplitude and stability of their rhythms have never been assessed using questionnaires. The primary aim of our study was the validation of a French version of the Circadian Type Inventory (CTI), whereas its secondary aim was the comparison between remitted patients with BD and healthy controls for rhythm stability and amplitude and for phase preference. For this purpose, we used the CTI and the Composite Scale of Morningness (CSM) that assesses phase preference ("morning" or "evening" type). First, we report here on the validation of the French version of the 11-item Circadian Type Inventory in a sample of 140 remitted patients with BD and 156 healthy controls. Principal components analysis revealed a two-factor structure (FR: flexibility/rigidity scale corresponding to rhythm stability; LV: languid/vigorous scale corresponding to rhythm amplitude) explaining 52% of the variance in the control group and 47% in the bipolar group. Cronbach's alpha was 0.75 for FR and 0.73 for LV. The test-retest reliability was 0.74 for FR and 0.86 for LV (3 wks) and 0.62 for FR and 0.72 for LV (6 mos). LV and FR scores correlated with the Composite Scale of Morningness score (p < 0.00001 and p = 0.0002, respectively). Second, as compared with controls, patients with BD were more languid (p < 0.00001) and showed an evening preference (p = 0.0003), but they did not differ from the controls with regard to flexibility/rigidity. The French version of the CTI appeared to have satisfactory psychometrics characteristics. Bipolar patients exhibited not only abnormalities in phase preference but also in amplitude as measured by languidity. Since circadian rhythm dysfunction has been shown to predict poor functioning and mood relapses in interepisodic patients with BD, this tool would appear to be a promising, easy-to-use, measure of the amplitude and flexibility of circadian rhythms that could enrich the arsenal of assessments used in clinical settings.

[Comparative study of paroxetine and mianserin in depression in elderly patients: efficacy, tolerance, serotonin dependence]. / Etude comparative de la paroxétine et de la miansérine dans la dépression du sujet âgé: efficacité, tolérance, sérotoninodépendance.

The primary objective of this multicentre, randomized, double-blind study carried out in France was to compare the efficacy and safety of a 6-week treatment with paroxetine (20 mg/day) or mianserine (30 mg/day) in geriatric hospitalized or ambulatory patients (> or = 60 years) treated for a major depressive disorder (according to DSM III-R). A secondary objective was to discriminate those items predicting the response to an agent according to its serotoninergic or noradrenergic pharmacologic profile. The tool used for this latter purpose was the Aubin-Jouvent-Rating-Scale (AJRS) which was designed to assess the deficit of serotonin: this is a scale with 10 items, some of them regrouped into a "general" factor (irritability, sudden mood change, impatience, aggressivity) or a "depression" factor (pain, anxiety, suicidal ideas) with additional items related to sleep disorders, abnormalities in eating behavior and inability to tolerate isolation. In the perspective of this assessment, paroxetine was chosen due to its potential to inhibit serotonin re-uptake, as compared to mianserin which blocks presynaptic alpha-adrenergic receptors with negligible action on serotonin. This was a multicenter study carried out in France in 50 hospital or private practice psychiatrists. The assessment criteria included the MADRS, the AJRS, the COVI's anxiety scale, the Folstein's Mini-mental state (MMS) as well as a global assessment by the investigator at the end of the study. Safety was measured with a nondirective questionnaire, routine laboratory tests as well as a global assessment by the investigator. The primary efficacy criteria was the change in the MADRS global score. Statistical analysis included chi-square or Fisher's test as well as Student's and Wilcoxon tests for comparability at baseline, and analysis of variance for the changes in scores as during the study. A total of 116 patients was randomised (paroxetine: 54; mianserine: 62), of whom 96 completed the study (paroxetine: 43; mianserine: 53). With the exception of MADRS moderately higher in the paroxetine group, both groups were comparable at baseline. After 6 weeks of treatment, a marked improvement was recorded in both groups for all criteria except MMS; there was a consistent tendency favouring paroxetine which reached statistical significance for the COVI' scale (p = 0.001). For a given criterion, the difference paroxetine versus mianserine appeared related to the score at baseline; it was also more marked in those patients with a AJRS baseline score > or = 20 with a difference for MADRS reduction of marginal significance in favor of paroxetine (p = 0.061). As regards safety, at least one adverse event was reported in 31.5% of the patients receiving paroxetine versus 41.9% in those receiving mianserin (NS); premature withdrawal related to an adverse event was reported in 11.1% of the patients in the paroxetine group versus 12.9% in the mianserin group. No abnormality of clinical significance was reported in either group concerning laboratory tests. In conclusion, this study confirmed the therapeutic value and good safety of paroxetine as an antidepressant in geriatric populations, especially when exist a concomitant anxiety or symptoms likely to reflect a deficit of serotonine (irritability, emotional lability, restlessness, aggressivity) and to predict a good response to an agent such as this one.

A single photon emission computed tomography study of cerebral regional perfusion changes induced by a learning task in subjects with mild memory impairment.

Fifteen nondemented subjects with memory complaints underwent serial single photon emission computed tomography (SPECT) studies with technetium-99m-d, l-hexamethyl-propylene amine oxime (HMPAO) as tracer. Scans were carried out under a baseline conditions and during the learning phase of the Memory Efficiency Profile (MEP), a combined visual perception and memory task developed by Rey. Results indicate a positive correlation between activation, as indexed by HMPAO uptake, and neuropsychological assessment. Right temporal activation was correlated with MEP immediate recall. The right cerebellum was correlated with both MEP immediate and delayed recall. This study suggests that SPECT can show cortical activation during cognitive performance in subjects with mild memory impairment.

[Hypothetical model of serotonin deficit in the aged subject. Development and validation of a clinical scale]. / Modélisation hypothétique du déficit sérotoninergique chez le sujet âgé. Construction et validation d'une échelle clinique.

Few works exist about specific abnormalities of neurotransmission, therefore noticeable and with important clinical consequences in elderly patients. Specially serotonin, which neurotransmission is lower, seems to have a wide influence. The symptomatology of the serotonin shortage is well known in the young adult (Asberg and Van Praag). The aim of this study is to apply those hypothesis and to look for a particular clinical expression of symptoms usually related to a low level of serotonin in an older population, and this in a transnosographic way. We built up a clinical scale gathering different symptoms supposed to be related to a defect in the serotonin transmission in elderly subjects. From a first factor analysis, a dimensional scale of ten items as been settled and validated in 75 inpatients over 60 years old; each patient has also been assessed by a series of tests (MMS of Folstein, Hamilton Depression Rating Scale, Jouvent mood scale, Widlöcher Retardation Scale). Factor analysis results show an homogeneous factorial structure and highly selective items and had a three factors dispatching (a "main" factor, a "depression" factor, and "sleep" factor). Those subgroups of symptoms have a clinical meaning and fit the litterature. We also find a good specificity: the factor analysis on added items of depressive semiology (Hamilton scale) and serotonin related semiology shows the splitting of the Hamilton items, whenever the 5-HT- Scale items keep a steady factorial repartition. Those preliminary results deserve further studies; and external validation of the scale remains to be done. Nevertheless, the structure of this scale shows a beginning of internal validation and seems to be interesting in the elderly clinical evaluation.