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.

Risk factors of suicide re-attempt: A two-year prospective study.

BACKGROUND: History of suicide attempt (SA) is the strongest predictor of a new SA and suicide. It is primordial to identify additional risk factors of suicide re-attempt. The aim of this study was to identify risk factors of suicide re-attempt in patients with recent SA followed for 2 years. METHODS: In this multicentric cohort of adult inpatients, the median of the index SA before inclusion was 10 days. Clinicians assessed a large panel of psychological dimensions using validated tools. Occurrence of a new SA or death by suicide during the follow-up was recorded. A cluster analysis was used to identify the dimensions that best characterized the population and a variable "number of personality traits" was created that included the three most representative traits: anxiety, anger, and anxious lability. Risk factors of re-attempt were assessed with adjusted Cox regression models. RESULTS: Among the 379 patients included, 100 (26.4 %) re-attempted suicide and 6 (1.6 %) died by suicide. The two major risk factors of suicide re-attempt were no history of violent SA and presenting two or three personality traits among trait anxiety, anger and anxious lability. LIMITATIONS: It was impossible to know if treatment change during follow-up occur before or after the re-attempt. DISCUSSION: One of the most important predictors of re-attempt in suicide attempters with mood disorders, was the presence of three personality traits (anger, anxiety, and anxious lability). Clinicians should provide close monitoring to patients presenting these traits and proposed treatments specifically targeting these dimensions, especially anxiety.

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.

How to target disturbed identity in borderline patients? Self-identification program: A case study.

Borderline personality disorder (BPD) is a severe and relatively prevalent psychiatric disorder, responsible for high rates of suicidal behaviors. Disturbed identity appears as at the very core of this disorder, being inter-related with all other BPD features. Notably, from a dimensional perspective on mental disorders, one should realize that it is from our usual self-representation that we live all our daily experiences. Then, if the understanding of self-concept (or identity) is impaired, all the interventions implemented to decrease the self's suffering will subsequently be impaired. The purpose of the present case study was to illustrate the nine identity diffusion categories described by Jørgensen & Bøye (2022) and how the level of identity function can be improved in a third-wave cognitive and behavioral therapy targeting progressive correct self-identification.

The impulsiveness level influences the salivary cortisol response and social stress sensitivity in suicidal patients.

INTRODUCTION: Suicide attempters (SA) are more vulnerable to social stress and show disturbed cortisol response in stressful conditions compared with psychiatric and healthy controls. Recent data suggest that this dysregulation might be related to impulsivity traits. However, little is known about the emotional consequences of social stress in SA exposed to stress. OBJECTIVES: The aim of our study was to evaluate the cortisol and emotional responses to social stress in patients with depression with and without suicide attempt, by taking into account impulsivity traits and depression severity. METHODS: 67 adult women (41 SA and 26 affective controls (AC,i.e. without suicide attempt history)) with lifetime history of major depressive episode were included. Patients performed the Trier Social Stress Test (TSST), a well-validated social stress task. Patients provided seven saliva samples, to measure the cortisol response, and filled in questionnaires to assess psychological pain, positive and negative mood, and anxiety at different time points (from 10 min before to 120 min after the TSST). Moderated regression models were used including suicide attempt history, depression severity, and impulsivity as independent variables and their interactions. RESULTS: In patients with low depression and high impulsivity, salivary cortisol response during the TSST was higher in SA than in AC (p < .001). Psychological pain, negative mood, and anxiety were increased in all patients just after the TSST, followed by a decrease at 120 min. Positive mood recovery was slower in SA, and in patients with high impulsivity and low depression level (p < .001). CONCLUSIONS: Impulsivity traits have an important role in suicidal vulnerability in stress conditions. Impulsivity traits might help to differentiate patients at risk of suicide who are highly sensitive to stress when depression level is low. Higher impulsiveness may increase the sensitivity to emotional distress that translates into inadequate physiological responses.

Sexual orientation, gender: Where is the problem? Nowhere! Correct self-identification and minority stigma.

PURPOSE: Self-concept, at the core of minority stress, is associated with negative mental health outcomes. METHODS: We aimed to assess the effectiveness of a one-shot third-wave CBT intervention targeting correct self-identification to address suffering related to minority stress. The study population included 172 participants (n = 98 heterosexuals, n=13 transgenders). The intervention consisted of a 90 minutes conference including overview of LGBT's suffering related to distal and proximal factors, a wisdom understanding of the root of suffering (mistaken self-identification) followed by a Questions & Answers session. Participants completed online self-questionnaires assessing sociodemographic data, acceptance by others (external) and oneself (internal) for sexual orientation and gender variables before the conference, immediately after the conference, and three months later. RESULTS: The conference helped to improve external acceptance of transgender for the whole sample, especially among the majority group. Those belonging to the minority (LGBT) had a positive benefit from the conference by reducing their fear of judgment. Adding a Q&A session to the conference failed to show any additional benefits. CONCLUSION: A specific wisdom-based self-identification conference appears to be an effective and low-cost intervention to target minority stigma, and therefore mental health and social integration of LGBT people.

Childhood trauma increases vulnerability to attempt suicide in adulthood through avoidant attachment.

BACKGROUND: Childhood trauma and affective disorders are known risk factors for adult suicidal behavior. Studies have shown a mediating effect of insecure attachment on the effect of childhood trauma and suicidal behavior but so far it is not clear whether this effect is related to an attachment dimension (anxiety, avoidance). AIM: The present study sought to examine the mediating effect of attachment anxiety and avoidance on suicidal behavior. METHODS: We analyzed data on childhood trauma, attachment style, depression severity, presence of prior suicide attempts and current suicide ideation from 96 patients diagnosed with an affective disorder. Two mediation analyses were conducted to assess the effect of childhood trauma on 1) prior suicide attempts and 2) current suicidal ideation through its effect on attachment. RESULTS: We found that childhood trauma had a complete mediated effect on the presence of prior suicide attempts through its effect on avoidant attachment (a1b1 = 0.0120, 95%-CI [0.0031, 0.0276]). However, only emotional abuse had a direct influence on suicidal ideation (c' = 0.0273, p < 0.01) without any indirect effect of anxious or avoidant attachment. LIMITATIONS: Variables were not assessed in a prospective way and sample size was small. CONCLUSIONS: Our findings suggest that individuals with avoidant attachment and childhood trauma are likely to present a high suicide risk. Since avoidant attachment is associated with altered perceptions and eventual rejection of social support, we recommend to screen for attachment early and to engage patients in therapeutical approaches focusing on the client-therapist alliance.

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.

Influence of childhood maltreatment on prevalence, onset, and persistence of psychiatric comorbidities and suicide attempts in bipolar disorders.

BACKGROUND: Psychiatric comorbidities and suicide attempts are highly prevalent in Bipolar Disorders (BD). We examined the associations between childhood maltreatment, psychiatric comorbidities, and suicide attempts, in terms of lifetime prevalence, sequence of onset, and current symptoms. METHODS: We assessed 3,047 individuals with BD for suicide attempts, anxiety disorders, substance use disorders, and eating disorders. Participants completed a self-report for the assessment of childhood maltreatment. Associations between childhood maltreatment and characteristics of comorbidities (lifetime prevalence, current symptoms, and age at onset) were examined using logistic regressions and network analyses. RESULTS: Psychiatric comorbidities were frequent with a mean number per individual of 1.23 (SD = 1.4). Most comorbidities occurred prior to the onset of BD. Participants who reported higher levels of childhood maltreatment had more frequent and multiple comorbidities, which were also more currently active at inclusion. Childhood maltreatment did not decrease the age of onset of comorbidities, but was associated with a faster accumulation of comorbidities prior to the onset of BD. Logistic regression and network analyses showed that emotional abuse and sexual abuse might play a prominent role in the lifetime prevalence of psychiatric comorbidities and suicide attempts. CONCLUSIONS: Childhood maltreatment was associated with suicide attempts, and with frequent, multiple, and persistent psychiatric comorbidities that accumulated more rapidly prior to the onset of BD. Hence, childhood maltreatment should be systematically assessed in individuals with BD, in particular when the course of the disorder is characterized by a high comorbid profile or by a high suicidality.

Prevalence and impact of patient suicide in psychiatrists: Results from a national French web-based survey.

BACKGROUND: Patient suicide (PS) is known to be a frequent and challenging occupational hazard for mental health professionals. No study previously explored the prevalence and impact of PS in a large sample of French psychiatrists. METHOD: A national web-based survey was performed between September and December 2019 to assess (a) the prevalence of the exposure to PS, (b) the emotional, traumatic and professional impacts of PS, and (c) the perceived support in the aftermath of PS in French psychiatrists. Participants were contacted through email to answer the online 62-item questionnaire, including a measure of traumatic impact through the Impact of Event Scale-Revised. Emotional and professional impacts and perceived support were assessed through dedicated items. RESULTS: A total of 764 psychiatrists fully completed the survey. Of them, 87.3% reported an exposure to PS and 13.7% reported PTSD symptoms afterward. Guilt, sadness and shock were the most frequent emotions. Among the exposed psychiatrists, 15.1% have temporarily considered changing their career path. The most emotionally distressing PS occurred during their ten first years of practice or during residency. A total of 37.1% of respondents felt unsupported and 50.4% reported that no team meeting had been organized in the aftermath. The feeling of responsibility for the death was strongly associated with negative impacts. CONCLUSION: Our results entail considerations to prevent negative mental health outcomes in psychiatrists after PS. Notably, our results advocate for the implementation of educational programs during psychiatric residency and postvention programs in healthcare settings to effectively help psychiatrists in dealing with PS.

The Anti-inflammatory Effect of the Tricyclic Antidepressant Clomipramine and Its High Penetration in the Brain Might Be Useful to Prevent the Psychiatric Consequences of SARS-CoV-2 Infection.

At the time of writing (December 2020), coronavirus disease 2019 (COVID-19) has already caused more than one million deaths worldwide, and therefore, it is imperative to find effective treatments. The "cytokine storm" induced by Severe Acute Respiratory Syndrome-Coronavirus type 2 (SARS-CoV-2) is a good target to prevent disease worsening, as indicated by the results obtained with tocilizumab and dexamethasone. SARS-CoV-2 can also invade the brain and cause neuro-inflammation with dramatic neurological manifestations, such as viral encephalitis. This could lead to potentially incapacitating long-term consequences, such as the development of psychiatric disorders, as previously observed with SARS-CoV. Several pathways/mechanisms could explain the link between viral infection and development of psychiatric diseases, especially neuro-inflammation induced by SARS-CoV-2. Therefore, it is important to find molecules with anti-inflammatory properties that penetrate easily into the brain. For instance, some antidepressants have anti-inflammatory action and pass easily through the blood brain barrier. Among them, clomipramine has shown very strong anti-inflammatory properties in vitro, in vivo (animal models) and human studies, especially in the brain. The aim of this review is to discuss the potential application of clomipramine to prevent post-infectious mental complications. Repositioning and testing antidepressants for COVID-19 management could help to reduce peripheral and especially central inflammation and to prevent the acute and particularly the long-term consequences of SARS-CoV-2 infection.

How Does COVID-19 Affect the Neurobiology of Suicide?

PURPOSE OF REVIEW: The aim of this review was to analyze COVID-19 effect on the biological features of suicidal vulnerability and its interaction with suicide-related biological pathways. We carried out a narrative review of international publications on the interactions of COVID-19 with the biological bases of suicide. RECENT FINDINGS: We hypothesize that SARS-CoV-2 interacts with multiple biological processes that underlie suicidal behavior, such as the renin-angiotensin system, nicotinic receptors, and central and systemic inflammation. Social distancing measures may also worsen subjective or objective social disconnection, thus increasing the risk of suicide. Interestingly, the drugs used to prevent suicide could be promising options to counteract brain damage caused by this coronavirus. SARS-CoV-2 interacts with multiple biological pathways involved in suicide and opens a new window for understanding the suicidal process. The development of suicide prevention treatments in the context of a pandemic may benefit from knowledge on these interactions.

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.