Definition of early age at onset in bipolar disorder according to distinctive neurodevelopmental pathways: insights from the FACE-BD study.

BACKGROUND: Converging evidence suggests that a subgroup of bipolar disorder (BD) with an early age at onset (AAO) may develop from aberrant neurodevelopment. However, the definition of early AAO remains unprecise. We thus tested which age cut-off for early AAO best corresponds to distinguishable neurodevelopmental pathways. METHODS: We analyzed data from the FondaMental Advanced Center of Expertise-Bipolar Disorder cohort, a naturalistic sample of 4421 patients. First, a supervised learning framework was applied in binary classification experiments using neurodevelopmental history to predict early AAO, defined either with Gaussian mixture models (GMM) clustering or with each of the different cut-offs in the range 14 to 25 years. Second, an unsupervised learning approach was used to find clusters based on neurodevelopmental factors and to examine the overlap between such data-driven groups and definitions of early AAO used for supervised learning. RESULTS: A young cut-off, i.e. 14 up to 16 years, induced higher separability [mean nested cross-validation test AUROC = 0.7327 (± 0.0169) for ⩽16 years]. Predictive performance deteriorated increasing the cut-off or setting early AAO with GMM. Similarly, defining early AAO below 17 years was associated with a higher degree of overlap with data-driven clusters (Normalized Mutual Information = 0.41 for ⩽17 years) relatively to other definitions. CONCLUSIONS: Early AAO best captures distinctive neurodevelopmental patterns when defined as ⩽17 years. GMM-based definition of early AAO falls short of mapping to highly distinguishable neurodevelopmental pathways. These results should be used to improve patients' stratification in future studies of BD pathophysiology and biomarkers.

Physical and mental health status of former smokers and non-smokers patients with bipolar disorder.

OBJECTIVES: Up to 70% individuals with bipolar disorder (BD) are lifetime tobacco smokers, a major modifiable risk factor for morbidity. However, quitting smoking is rarely proposed to individuals with BD, mainly because of fear of unfavorable metabolic or psychiatric changes. Evaluating the physical and mental impact of tobacco cessation is primordial. The aim of this study was to characterize the psychiatric and nonpsychiatric correlates of tobacco smoking status (never- vs. current vs. former smokers) in individuals with BD. METHODS: 3860 individuals with ascertained BD recruited in the network of Fondamental expert centers for BD between 2009 and 2020 were categorized into current, former, and never tobacco smokers. We compared the sociodemographic and clinical characteristics assessed by standard instruments (e.g., BD type, current symptoms load, and non-psychiatric morbidity-including anthropometric and biological data) of the three groups using multinomial regression logistic models. Corrections for multiple testing were applied. RESULTS: Current smokers had higher depression, anxiety, and impulsivity levels than former and never-smokers, and also higher risk of comorbid substance use disorders with a gradient from never to former to current smokers-suggesting shared liability. Current smokers were at higher risk to have a metabolic syndrome than never-smokers, although this was only evidenced in cases, who were not using antipsychotics. CONCLUSIONS: Tobacco smoking was associated with high morbidity level. Strikingly, as in the general population, quitting smoking seemed associated with their return to the never-smokers' levels. Our findings strongly highlight the need to spread strategies to treat tobacco addiction in the BD population.

Association between childhood maltreatment and the clinical course of bipolar disorders: A survival analysis of mood recurrences.

OBJECTIVES: Childhood maltreatment, also referred as childhood trauma, increases the severity of bipolar disorders (BD). Childhood maltreatment has been associated with more frequent mood recurrences, however, mostly in retrospective studies. Since scarce, further prospective studies are required to identify whether childhood maltreatment may be associated with the time to recurrence in BD. METHODS: Individuals with BD (N = 2008) were assessed clinically and for childhood maltreatment at baseline, and followed up for two years. The cumulative probability of mood recurrence over time was estimated with the Turnbull's extension of the Kaplan-Meier analysis for interval-censored data, including childhood maltreatment as a whole, and then maltreatment subtypes as predictors. Analyses were adjusted for potential confounding factors. RESULTS: The median duration of follow-up was 22.3 months (IQR:12.0-24.8). Univariable analyses showed associations between childhood maltreatment, in particular all types of abuses (emotional, physical, and sexual) or emotional neglect, and a shorter time to recurrence (all p < 0.001). When including potential confounders into the multivariable models, the time to mood recurrence was associated with multiple/severe childhood maltreatment (i.e., total score above the 75th percentile) (HR = 1.32 95%CI (1.11-1.57), p = 0.002), and more specifically with moderate/severe physical abuse (HR = 1.44 95%CI(1.21-1.73), p < 0.0001). Living alone, lifetime anxiety disorders, lifetime number of mood episodes, baseline depressive and (hypo)manic symptoms, and baseline use of atypical antipsychotics were also associated with the time to recurrence. CONCLUSIONS: In addition to typical predictors of mood recurrences, an exposure to multiple/severe forms of childhood maltreatment, and more specifically to moderate to severe physical abuse, may increase the risk for a mood recurrence in BD. This leads to the recommendations of more scrutiny and denser follow-up of the individuals having been exposed to such early-life stressors.

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.

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.

Characterization of depressed bipolar patients with current suicidal ideation.

OBJECTIVE: Bipolar disorder is one of the most frequent psychiatric disorders among suicidal patients. A large part of patients with bipolar disorder (30-50%) will attempt suicide. Suicidal ideation being a major risk factor of suicidal act, it is crucial to better characterize patients with suicidal bipolar depression (i.e. depression with current suicidal ideation). The aim of this study was to characterize suicidal bipolar depressed patients in comparison with non-suicidal depressed patients in terms of clinical characteristics, evolution of depression and suicidal ideation course over time, and risk of suicide attempt during follow-up. METHODS: Among patients with bipolar disorder recruited from the network of FondaMental expert centres for bipolar disorder between 2009 and 2017, we selected patients with at least mild depression (Montgomery-Åsberg Depression Rating Scale total score >11) and without current manic symptomatology (Young Mania Rating Scale total score <7) at baseline (N = 938). Suicidal depression was defined by a baseline score ⩾2 for item 12 of the Quick Inventory of Depressive Symptomatology-Self Report (N = 271, 28.9%). Non-suicidal depression was defined by a baseline item 12 of the Quick Inventory of Depressive Symptomatology-Self Report score <2 (N = 667, 71.1%). A subsample of about 300 patients (with or without suicidal ideation at baseline) was followed up for 2 years. RESULTS: Baseline clinical features (e.g. depression severity, childhood trauma, global functioning) were more severe in patients with than without suicidal depression. Suicidal patients tended to remain more suicidal throughout the follow-up than patients without suicidal ideation at baseline (3.4-fold higher risk of persistent suicidal ideation at the 2-year visit despite an improvement in depressive symptomatology). CONCLUSIONS: Depressed bipolar disorder patients reporting suicidal ideation had more severe clinical features at baseline and were more prone to report persistent suicidal ideation during the follow-up, independently of thymic state. Clinicians should closely monitor this subgroup of patients.

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.

Crossed clinical features between eating disorders and types of bipolar disorder: Results from the FondaMental Advanced Centers of Expertise - Bipolar Disorder cohort.

BACKGROUND: Eating disorders (EDs) are liable to alter the disease course of bipolar disorder (BD). We explored the crossed clinical features between EDs and BD, particularly as a function of BD type (BD1 vs. BD2). METHODS: 2929 outpatients attending FondaMental Advanced Centers of Expertise were assessed for BD and lifetime EDs with a semi-structured interview, and their sociodemographic, dimensional and clinical data were collected according to a standardized procedure. For each ED type, bivariate analyses were used to investigate associations between these variables and the type of BD type followed by multinomial regressions with the variables associated with EDs and BDs after Bonferroni correction. RESULTS: Comorbid EDs were diagnosed in 478 (16.4 %) cases, and were more prevalent in patients with BD2 than in those with BD1 (20.6 % vs. 12.4 %, p < 0.001). Regression models showed no difference according to the subtype of bipolar disorder on the characteristics of patients with anorexia nervosa (AN), bulimia nervosa (BN) or binge eating disorder (BED). After multiple adjustments, the factors differentiating BD patients with versus without ED were primarily age, gender, body mass index, more affective lability and comorbidity with anxiety disorders. BD patients with BED also scored higher regarding childhood trauma. BD patients with AN also showed higher risk of past suicide attempts than those with BED. CONCLUSIONS: In a large sample of patients with BD, we found a high prevalence of lifetime EDs, especially for the BD2 type. EDs were associated with several severity indicators, but not with BD type-specific characteristics. This should prompt clinicians to carefully screen patients with BD for EDs, regardless of BD and ED types.

A pilot study of new approaches to exploring illness trajectories and patterns of comorbidity in major mental disorders.

AIMS: We explored lifetime comorbidities in clinical subsamples with a diagnosis of Psychosis (N = 143), bipolar (BD = 511), and unipolar disorders (UP = 861). METHODS: We analyzed trajectories and patterns of comorbidities using novel metrics, namely bubble plots and density of antecedent events per year of illness exposure per individual. RESULTS: Age at onset (AAO) of most comorbidities was similar to epidemiological studies, but cumulative rates were higher in clinical cases. There were some between group differences in patterns or burden of comorbidities, for example, Psychosis showed the earliest AAO of any mental disorder; UP showed the latest AAO of the index diagnosis. The relative risk of multimorbidity was lower in UP compared with other diagnoses, however, the goodness of fit for the illness trajectory path was lowest for BD. CONCLUSIONS: Bubble plots offer a useful representation of timing, sequence, cumulative probability and of comorbidities, the added value of reporting density measures was less obvious.

Violent suicide attempt history in elderly patients with bipolar disorder: The role of sex, abdominal obesity, and verbal memory: Results from the FACE-BD cohort (FondaMental Advanced center of Expertise for Bipolar Disorders).

BACKGROUND: Bipolar disorder (BD) is a chronic, lifelong condition, associated with increased risk of obesity, cognitive impairment, and suicidal behaviors. Abdominal obesity and a higher risk of violent suicide attempt (SA) seem to be shared correlates with older age, BD, and male sex until middle age when menopause-related female body changes occur. This study aimed at assessing the role of abdominal obesity and cognition in the violent SA burden of individuals with BD. METHODS: From the well-defined nationwide cohort FACE-BD (FondaMental Advanced center of Expertise for Bipolar Disorders), we extracted data on 619 euthymic BD patients that were 50 years or older at inclusion. Cross-sectional clinical, cognitive, and metabolic assessments were performed. SA history was based on self-report. RESULTS: Violent SA, in contrast to non-violent and no SA, was associated with higher waist circumference, abdominal obesity and poorer California Verbal Learning Test short-delay free recall (CVLT-SDFR) (ANOVA, p < .001, p = .014, and p = .006). Waist circumference and abdominal obesity were associated with violent SA history independently of sex, BD type and anxiety disorder (Exp(B) 1.02, CI 1.00-1.05, p = .018; Exp(B) 2.16, CI 1.00-4.64, p = .009, accordingly). In an exploratory model, waist circumference and CVLT-SDFR performance mediated the association between male sex and violent SA. LIMITATIONS: Cross-sectional design and retrospective reporting. CONCLUSIONS: Violent SA history was associated with abdominal obesity and poorer verbal memory in older age BD patients. These factors were interlinked and might mediate the association between male sex and violent SA.

Direct medical cost of bipolar disorder: Insights from the FACE-BD longitudinal cohort.

BACKGROUND: Bipolar disorder (BD) is a severe chronic psychiatric disorder affecting 0.5 to 1% of the population worldwide. To date, most studies have estimated the cost of BD via information sourced from insurance claims with limited information on clinical characteristics and course of BD. The aims of this study are (i) to estimate the direct healthcare cost associated with BD and to identify contributing factors and (ii) to study the evolution of cost during a two-year follow-up period. METHOD: We analyzed a sample of 1116 individuals with BD included in the Advanced Centers of Expertise in Bipolar Disorder cohort. We estimated the direct healthcare cost per year and per patient, and we identified the clinical features of patients with BD associated with higher direct healthcare costs. In a subsample of patients followed up for two years centers of expertise for BD, we studied the evolution of direct healthcare cost. RESULTS: The average cost of bipolar disorder was € 6910 per year and per patient. Clinical features of BD, sociodemographic characteristics, and associated addiction were associated with higher direct healthcare costs. In the subsample of patients followed-up for two years, direct healthcare cost dropped by more than 50%, strongly suggesting the beneficial effect of specialized care organization. LIMITATION: We did not estimate indirect healthcare and intangible costs. CONCLUSION: Our study investigates the cost of BD and its evolution in a deeply phenotyped longitudinal sample. Cost-utility and cost-effectiveness analyses are required to inform resource allocation decisions and to promote innovative healthcare organizations.

Using density of antecedent events and trajectory path analysis to investigate family-correlated patterns of onset of bipolar I disorder: a comparison of cohorts from Europe and USA.

BACKGROUND: Major contributors to the global burden of bipolar disorders (BD) are the early age at onset (AAO) and the co-occurrence of non-mood disorders before and after the onset of BD. Using data from two independent cohorts from Europe and the USA, we investigated whether the trajectories of BD-I onset and patterns of psychiatric comorbidities differed in (a) individuals with or without a family history (FH) of BD, or (b) probands and parents who both had BD-I. METHODS: First, we estimated cumulative probabilities and AAO of comorbid mental disorders in familial and non-familial cases of BD-I (Europe, n = 573), and sex-matched proband-parent pairs of BD-I cases (USA, n = 194). Then we used time to onset analyses to compare overall AAO of BD-I and AAO according to onset polarity. Next, we examined associations between AAO and polarity of onset of BD-I according to individual experiences of comorbidities. This included analysis of the density of antecedent events (defined as the number of antecedent comorbidities per year of exposure to mental illness per individual) and time trend analysis of trajectory paths plotted for the subgroups included in each cohort (using R2 goodness of fit analysis). RESULTS: Earlier AAO of BD-I was found in FH versus non-FH cases (log rank test = 7.63; p = 0.006) and in probands versus parents with BD-I (log rank test = 15.31; p = 0.001). In the European cohort, AAO of BD-I was significantly associated with factors such as: FH of BD (hazard ratio [HR]: 0.60), earlier AAO of first non-mood disorder (HR: 0.93) and greater number of comorbidities (HR: 0.74). In the USA cohort, probands with BD-I had an earlier AAO for depressive and manic episodes and AAO was also associated with e.g., number of comorbidities (HR: 0.65) and year of birth (HR: 2.44). Trajectory path analysis indicated significant differences in density of antecedents between subgroups within each cohort. However, the time trend R2 analysis was significantly different for the European cohort only. CONCLUSIONS: Estimating density of antecedent events and comparing trajectory plots for different BD subgroups are informative adjuncts to established statistical approaches and may offer additional insights that enhance understanding of the evolution of BD-I.

Clinical characteristics of bipolar disorders with postpartum depressive onset.

BACKGROUND: Postpartum period is associated with an increased risk of bipolar disorder diagnosis and relapse, mainly major depressive episode. Onset during this period might be associated with specific characteristics. AIM: To compare the socio-demographic and clinical characteristics of parous women presenting with bipolar disorder and an index depressive episode occurring during or outside the postpartum period. METHODS: Using the multicenter cohort FACE-BD (FondaMental Academic Centers of Expertise for Bipolar Disorders), we considered all women who started their BD with a major depressive episode and have at least one child. We compared two groups depending on the onset: in or outside the postpartum period. RESULTS: Among the 759 women who started BD with a major depressive episode, 93 (12.2%) had a postpartum onset, and 666 (87.8%) had not. Women who started BD in the postpartum period with a major depressive episode have a more stable family life, more children, an older age at onset, more Bipolar 2 disorder, less history of suicide attempts, less depressive episodes and more mood stabilizer treatments as compared to those who started with a major depressive episode outside the postpartum period. The multivariable logistic regression showed that women with an onset in the postpartum period had significantly more children, less lifetime depressive episodes and a lower rate of history of suicide attempts as compared to women with an onset outside the postpartum period. DISCUSSION: Our results suggest that women starting their BD with postpartum depression have a more favorable course of BD, especially less history of suicide attempt and less lifetime depressive episodes.

Childhood maltreatment and metabolic syndrome in bipolar disorders: In search of moderators.

As compared to the general population, adult individuals with bipolar disorders (BD) have higher mortality rates due to cardiovascular diseases and higher prevalence of Metabolic Syndrome (MetS). Recent evidence suggests that childhood maltreatment may contribute to the cardiovascular burden in individuals with BD. However, studies are scarce, with limited sample sizes and inconsistent results. We explored the associations between a self-reported history of childhood maltreatment and MetS (and its subcomponents) in a large sample of 2390 individuals with BD. Childhood maltreatment was assessed using the Childhood Trauma Questionnaire and MetS was defined according to the revised criteria of the ATEP III. We suggested associations between childhood maltreatment and the presence of MetS in men and in younger individuals. The association between childhood maltreatment and the presence of MetS in the early onset subgroup was not significant after adjustment for site of recruitment and level of education. Hence, some links between childhood maltreatment and MetS might exist only in specific subgroups of individuals with BD, but confirmation is required in independent and large samples, while taking into account potential confounders. This would help defining how psychosocial interventions that target childhood maltreatment and its consequences may be beneficial for physical health.

The course of bipolar disorder as a function of the presence and sequence of onset of comorbid alcohol use disorders in outpatients attending the Fondamental Advanced Centres of Expertise.

OBJECTIVES: The comorbidity of alcohol use disorder (AUD) and bipolar disorder (BD) has been repeatedly associated with poorer clinical outcomes than BD without AUD. We aimed to extend these findings by focusing on the characteristics associated with the sequence of onset of BD and AUD. METHODS: 3,027 outpatients from the Fondamental Advanced Centres of Expertise were ascertained for BD-1, BD-2 and AUD diagnoses, including their respective ages at onset (AAOs, N =2,804). We selected the variables associated with both the presence and sequence of onset of comorbid AUD using bivariate analyses corrected for multiple testing to enter a binary regression model with the sequence of onset of BD and AUD as the dependent variable (AUD first - which also included 88 same-year onsets, vs. BD first). RESULTS: BD patients with comorbid AUD showed more severe clinical profile than those without. Compared to BD-AUD (N =269), AUD-BD (N =276) was independently associated with a higher AAO of BD (OR =1.1, p <0.001), increased prevalence of comorbid cannabis use disorder (OR =2.8, p <0.001) a higher number of (hypo)manic/mixed BD episodes per year of bipolar illness (OR =3, p <0.01). LIMITATIONS: The transversal design prevents from drawing causal conclusions. CONCLUSION: Increased severity of BD with AUD compared to BD alone did not differ according to the sequence of onset. A few differences, though, could be used to better monitor the trajectory of patients showing either one of these disorders.

Metabolic and psychiatric effects of acyl coenzyme A binding protein (ACBP)/diazepam binding inhibitor (DBI).

Acyl coenzyme A binding protein (ACBP), also known as diazepam binding inhibitor (DBI) is a multifunctional protein with an intracellular action (as ACBP), as well as with an extracellular role (as DBI). The plasma levels of soluble ACBP/DBI are elevated in human obesity and reduced in anorexia nervosa. Accumulating evidence indicates that genetic or antibody-mediated neutralization of ACBP/DBI has anorexigenic effects, thus inhibiting food intake and inducing lipo-catabolic reactions in mice. A number of anorexiants have been withdrawn from clinical development because of their side effects including an increase in depression and suicide. For this reason, we investigated the psychiatric impact of ACBP/DBI in mouse models and patient cohorts. Intravenously (i.v.) injected ACBP/DBI protein conserved its orexigenic function when the protein was mutated to abolish acyl coenzyme A binding, but lost its appetite-stimulatory effect in mice bearing a mutation in the γ2 subunit of the γ-aminobutyric acid (GABA) A receptor (GABAAR). ACBP/DBI neutralization by intraperitoneal (i.p.) injection of a specific mAb blunted excessive food intake in starved and leptin-deficient mice, but not in ghrelin-treated animals. Neither i.v. nor i.p. injected anti-ACBP/DBI antibody affected the behavior of mice in the dark-light box and open-field test. In contrast, ACBP/DBI increased immobility in the forced swim test, while anti-ACBP/DBI antibody counteracted this sign of depression. In patients diagnosed with therapy-resistant bipolar disorder or schizophrenia, ACBP/DBI similarly correlated with body mass index (BMI), not with the psychiatric diagnosis. Patients with high levels of ACBP/DBI were at risk of dyslipidemia and this effect was independent from BMI, as indicated by multivariate analysis. In summary, it appears that ACBP/DBI neutralization has no negative impact on mood and that human depression is not associated with alterations in ACBP/DBI concentrations.

Sleep quality, chronotype and metabolic syndrome components in bipolar disorders during the remission period: Results from the FACE-BD cohort.

Data on sleep or circadian abnormalities and metabolic disturbances in euthymic bipolar disorders are scarce and based on small sample sizes. The aim of this study was to explore the associations between sleep disturbances, chronotype and metabolic components in a large sample of euthymic patients with bipolar disorders (BD). From 2009 to 2015, 752 individuals with bipolar disorders from the FACE-BD cohort were included and assessed for sleep quality, chronotype and metabolic components. The Structured Clinical Interview for DSM-IV Axis I Disorders (SCID) was used to confirm the diagnosis of BD. Subjective sleep quality was measured with the Pittsburgh Sleep Quality Index and chronotype with the Composite Scale of Morningness. Sociodemographic and clinical characteristics, psychotropic treatment, psychiatric comorbidities and blood samples were collected. In our sample, 22.4% of individuals with BD presented with a metabolic syndrome, 53.7% had sleep disturbances, 25.4% were considered as having an evening chronotype and 12.6% as having a morning chronotype. Independently of potential confounders, euthymic patients with sleep disturbances had a higher abdominal circumference, and patients with evening chronotype had a significantly higher level of triglycerides. There was an association between evening chronotype and an increased atherogenic index of plasma (OR = 4.8, 95%CI = 1.6-14.7). Our findings contribute the scant literature on the relationship between sleep quality, chronotype and cardiometabolic components in euthymic individuals with BD and highlight the need to improve quality of sleep and patient education about healthier sleep-hygiene practices.

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.