Does BioAge identify accelerated aging in individuals with bipolar disorder? An exploratory study in the FACE-BD cohort.

BACKGROUND: Individuals with bipolar disorders (BD) have an estimated loss of life expectancy around 10-15 years. Several laboratory-measured biomarkers of accelerated aging exist (e.g., telomere length), however with a questionable transferability to bedside. There is a need for easily and inexpensively measurable markers of aging, usable in routine practice, such as BioAge. METHODS: We calculated BioAge that estimates biological age based on routine blood tests and a physical exam, in a sample of 2220 outpatients with BD. We investigated associations between BioAge Acceleration (BioAgeAccel), which is an indicator of accelerated aging, and sociodemographic variables, clinical variables, and current psychotropic medication use. RESULTS: Mean chronological age was 40.2 (±12.9). Mean BioAge was 39.1 (±12.4). Mean BioAgeAccel was 0.08 (±1.8). A minority of individuals (15%) had a BioAgeAccel above 2 years. Multivariable analyses suggested strong associations between a higher BioAgeAccel and younger age, male sex, overweight and sleep disturbances. Regarding current psychotropic medication use, discrepancies between univariate and multivariate analyses were observed. CONCLUSIONS: A minority of individuals with BD had an accelerated aging as measured by BioAge. We identified associations with potentially modifiable factors, such as higher body mass index and sleep disturbances, that are however nonspecific to BD. These results require replications in independent samples of individuals with BD, and comparisons with a control group matched for age and gender. Longitudinal studies are also required to test whether any change in metabolic health, or sleep might decrease BioAgeAccel.

Adherence to clinical practice guidelines for using electroconvulsive therapy in elderly depressive patients.

OBJECTIVES: Electroconvulsive therapy (ECT) is one of the most effective treatments in mood disorders, mainly in major depressive episode (MDE) in the context of either unipolar (MDD) or bipolar disorder (BD). However, ECT remains a neglected and underused treatment. Older people are at high risk patients for the development of adverse drug reactions. In this context, we sought to determine the duration of MDEs and the number of lines of treatment before the initiation of ECT in patients aged 65 years or over according to the presence or absence of first-line indications for using ECT from international guidelines. METHODS: In this multicenter, retrospective study including patients aged 65 years or over with MDEs in MDD or BD who have been treated with ECT for MDEs, data on the duration of MDEs and the number of lines of treatment received before ECT were collected. The reasons for using ECT, specifically first-line indications (suicidality, urgency, presence of catatonic and psychotic features, previous ECT response, patient preference) were recorded. Statistical comparisons between groups used standard statistical tests. RESULTS: We identified 335 patients. The mean duration of MDEs before ECT was about 9 months. It was significantly shorter in BD than in MDD- about 7 and 10 months, respectively. The co-occurrence of chronic medical disease increased the duration before ECT in the MDD group. The presence of first-line indications for using ECT from guidelines did not reduce the duration of MDEs before ECT, except where there was a previous response to ECT. The first-line indications reduced the number of lines of treatment before starting ECT. CONCLUSION: Even if ECT seems to be a key treatment in the elderly population due to its efficacity and safety for MDEs, the delay before this treatment is still too long.

Reduction of Psychosis Proneness in a Daycare Hospital Program for Patients with Severe Alcohol Use Disorder.

OBJECTIVES: Anxiety and depressive symptoms, as well as cognitive dysfunctions, improve with abstinence in individuals with alcohol use disorders (AUD), but less is known about psychotic features. The objective of this study was to evaluate the psychosis proneness in a sample of individuals with severe AUD and potential changes after alcohol withdrawal. METHOD: An observational study was conducted, assessing prospectively Peter's Delusional Inventory scale (PDI); anxiety and depression symptoms by MADRS and cognitive functioning by the MoCA at entry in daycare hospital (D0) and after 30 days (D30). Individuals with schizophrenia, chronic delusional disorder and bipolar disorder were excluded. Wilcoxon tests were used to evaluate the evolution between D0 and D30, and linear regressions were conducted to test the association between delta PDI and the variables that could be potential confounders. RESULTS: Forty individuals (72% males) with a mean age of 50 ± 9 years old and AUD evolved for 15 ± 11 years were included. After one month, PDI score decreased significantly (p = .001), and several biological and clinical parameters improved significantly with abstinence or consumption reduction: GGT (p = .003), MoCA (p < .001), MADRS (p = .047). CONCLUSION: We observed a decrease in delusional thinking along abstinence and/or consumption reduction. To our knowledge, this is the first research to study psychosis proneness evolution in patients with severe AUD. Replications are required in independent samples with larger sample size.

Associations between actigraphy estimates of sleep and circadian rhythmicity and psychotropic medications in bipolar disorders: An exploratory study.

INTRODUCTION: Disturbances in sleep and circadian rhythmicity (CR) are frequent in individuals with bipolar disorders (BD). Very few studies explored the associations between psychotropic medications and these disturbances in euthymic BD. Therefore, we aimed at exploring the associations between several classes of medications (lithium, sedative/non-sedative Atypical Antipsychotics (AAP), anticonvulsants, antidepressants, benzodiazepines) and sleep disturbances and CR dimensions in a sample of euthymic individuals with BD. METHODS: We included euthymic adults with BD type 1 or 2 assessed with 21 days of actimetry. We used a Principal Component Analysis (PCA) of sleep and CR estimates to generate dimensions to be studied in association with the current use of psychotropic medications, with adjustments for potential confounding factors. RESULTS: We included individuals with BD-1 (n = 116) or BD-2 (n = 37). The PCA led to four dimensions of sleep and CR estimates. Benzodiazepines were associated with better sleep quality (pcorrected = 0.032). Aripiprazole was associated with less robust CR (pcorrected = 0.016), but with earlier peak of activity patterns (pcorrected = 0.020). Sedative AAPs were associated with better sleep quality, which was no longer significant after correction. We found no association between lithium or anticonvulsants and CR. LIMITATIONS: The cross-sectional design and the possible non-representativeness of the sample were limitations of our study. CONCLUSIONS: In euthymic individuals with BD, benzodiazepines may have a positive effect on sleep quality, while aripiprazole may have mixed effects on CR (less robust but with earlier peak of activity patterns). No association with lithium or anticonvulsants observed. Further studies are warranted to replicate and extend these results.

Decreased telomere length in a subgroup of young individuals with bipolar disorders: replication in the FACE-BD cohort and association with the shelterin component POT1.

Bipolar disorder (BD) has been associated with premature cellular aging with shortened telomere length (TL) as compared to the general population. We recently identified a subgroup of young individuals with prematurely shortened TL. The aims of the present study were to replicate this observation in a larger sample and analyze the expression levels of genes associated with age or TL in a subsample of these individuals. TL was measured on peripheral blood DNA using quantitative polymerase chain reaction in a sample of 542 individuals with BD and clustering analyses were performed. Gene expression level of 29 genes, associated with aging or with telomere maintenance, was analyzed in RNA samples from a subsample of 129 individuals. Clustering analyses identified a group of young individuals (mean age 29.64 years), with shorter TL. None of the tested clinical variables were significantly associated with this subgroup. Gene expression level analyses showed significant downregulation of MYC, POT1, and CD27 in the prematurely aged young individuals compared to the young individuals with longer TL. After adjustment only POT1 remained significantly differentially expressed between the two groups of young individuals. This study confirms the existence of a subgroup of young individuals with BD with shortened TL. The observed decrease of POT1 expression level suggests a newly described cellular mechanism in individuals with BD, that may contribute to telomere shortening.

Mitochondrial Biomarkers and Metabolic Syndrome in Bipolar Disorder.

The object of this study is test whether mitochondrial blood-based biomarkers are associated with markers of metabolic syndrome in bipolar disorder, hypothesizing higher lactate but unchanged cell-free circulating mitochondrial DNA levels in bipolar disorder patients with metabolic syndrome. In a cohort study, primary testing from the FondaMental Advanced Centers of Expertise for bipolar disorder (FACE-BD) was conducted, including 837 stable bipolar disorder patients. The I-GIVE validation cohort consists of 237 participants: stable and acute bipolar patients, non-psychiatric controls, and acute schizophrenia patients. Multivariable regression analyses show significant lactate association with triglycerides, fasting glucose and systolic and diastolic blood pressure. Significantly higher levels of lactate were associated with presence of metabolic syndrome after adjusting for potential confounding factors. Mitochondrial-targeted metabolomics identified distinct metabolite profiles in patients with lactate presence and metabolic syndrome, differing from those without lactate changes but with metabolic syndrome. Circulating cell-free mitochondrial DNA was not associated with metabolic syndrome. This thorough analysis mitochondrial biomarkers indicate the associations with lactate and metabolic syndrome, while showing the mitochondrial metabolites can further stratify metabolic profiles in patients with BD. This study is relevant to improve the identification and stratification of bipolar patients with metabolic syndrome and provide potential personalized-therapeutic opportunities.

Diet quality and associations with lactate and metabolic syndrome in bipolar disorder.

BACKGROUND: Nutrition is largely affected in bipolar disorder (BD), however, there is a lack of understanding on the relationship between dietary categories, BD, and the prevalence of metabolic syndrome. The objective of this study is to examine dietary trends in BD and it is hypothesized that diets with increased consumption of seafood and high-fiber carbohydrates will be correlated to improved patient outcomes, and a lower frequency of metabolic syndrome. METHODS: This retrospective cohort study includes two French cohorts. The primary cohort, FACE-BD, includes 268 stable BD patients. The second cohort, I-GIVE, includes healthy controls, both stable and acute BD and schizophrenia patients. Four dietary categories were assessed: meat, seafood, low-fiber and high-fiber carbohydrates. Dietary data from two food frequency questionnaires were normalized using min-max scaling and assessed using various statistical analyses. RESULTS: In our primary cohort, the increased high-fiber carbohydrate consumption was correlated to lower prevalence of metabolic syndrome and improved mood. Low-fiber carbohydrate consumption is associated with higher BMI, while higher seafood consumption was correlated to improved mood and delayed age of onset. Results were not replicated in our secondary cohort. LIMITATIONS: Our populations were small and two different dietary questionnaires were used; thus, results were used to examine similarities in trends. CONCLUSIONS: Overall, various dietary trends were associated with metabolic syndrome, BMI, lactate, mood and age of onset. Improving our understanding of nutrition in BD can provide mechanistic insight, clinically relevant nutritional guidelines for precision medicine and ultimately improve the quality of lives for those with BD.

Lithium response in bipolar disorder is associated with focal adhesion and PI3K-Akt networks: a multi-omics replication study.

Lithium is the gold standard treatment for bipolar disorder (BD). However, its mechanism of action is incompletely understood, and prediction of treatment outcomes is limited. In our previous multi-omics study of the Pharmacogenomics of Bipolar Disorder (PGBD) sample combining transcriptomic and genomic data, we found that focal adhesion, the extracellular matrix (ECM), and PI3K-Akt signaling networks were associated with response to lithium. In this study, we replicated the results of our previous study using network propagation methods in a genome-wide association study of an independent sample of 2039 patients from the International Consortium on Lithium Genetics (ConLiGen) study. We identified functional enrichment in focal adhesion and PI3K-Akt pathways, but we did not find an association with the ECM pathway. Our results suggest that deficits in the neuronal growth cone and PI3K-Akt signaling, but not in ECM proteins, may influence response to lithium in BD.

Exploring the genetics of lithium response in bipolar disorders.

BACKGROUND: Lithium (Li) remains the treatment of choice for bipolar disorders (BP). Its mood-stabilizing effects help reduce the long-term burden of mania, depression and suicide risk in patients with BP. It also has been shown to have beneficial effects on disease-associated conditions, including sleep and cardiovascular disorders. However, the individual responses to Li treatment vary within and between diagnostic subtypes of BP (e.g. BP-I and BP-II) according to the clinical presentation. Moreover, long-term Li treatment has been linked to adverse side-effects that are a cause of concern and non-adherence, including the risk of developing chronic medical conditions such as thyroid and renal disease. In recent years, studies by the Consortium on Lithium Genetics (ConLiGen) have uncovered a number of genetic factors that contribute to the variability in Li treatment response in patients with BP. Here, we leveraged the ConLiGen cohort (N = 2064) to investigate the genetic basis of Li effects in BP. For this, we studied how Li response and linked genes associate with the psychiatric symptoms and polygenic load for medical comorbidities, placing particular emphasis on identifying differences between BP-I and BP-II. RESULTS: We found that clinical response to Li treatment, measured with the Alda scale, was associated with a diminished burden of mania, depression, substance and alcohol abuse, psychosis and suicidal ideation in patients with BP-I and, in patients with BP-II, of depression only. Our genetic analyses showed that a stronger clinical response to Li was modestly related to lower polygenic load for diabetes and hypertension in BP-I but not BP-II. Moreover, our results suggested that a number of genes that have been previously linked to Li response variability in BP differentially relate to the psychiatric symptomatology, particularly to the numbers of manic and depressive episodes, and to the polygenic load for comorbid conditions, including diabetes, hypertension and hypothyroidism. CONCLUSIONS: Taken together, our findings suggest that the effects of Li on symptomatology and comorbidity in BP are partially modulated by common genetic factors, with differential effects between BP-I and BP-II.

Factors associated with lamotrigine concentration/dose ratio in individuals with bipolar disorders.

Monitoring of lamotrigine levels is recommended in epilepsy. However, in bipolar disorders (BD), no study has described the therapeutic range in daily practice and factors being associated to it. We used retrospective data of individuals with BD, treated with lamotrigine, and included in the FondaMental Advanced Centers of Expertise for Bipolar Disorders cohort. We extracted clinical and biological data and explored associations between these variables and lamotrigine concentration/dose (C/D) ratio. The database included 675 individuals who received lamotrigine at inclusion, whose main characteristics were female sex (68.3%) and BD type 2 (52.1%). Data about lamotrigine C/D ratio were available for 205 individuals. Lamotrigine C/D ratio was significantly associated with: Body Mass Index (BMI) (r=-0.159), estimated GFR (glomerular filtration rate) (r=-0.228), total bilirubin (r = 0.241) and at a trend level, antidepressant co-prescription (U = 3169). The model obtained was: lamotrigine C/D ratio = 1.736 - 0.013*BMI + 0.095*total bilirubin (UI/L) - 0.007*eGFR (ml/min) + 0.210*AST/ALT - 0.004*GGT (UI/L) + 0.014*age (year) + 0.303*currently smoking (yes or no) - 0.588*antidepressant co-prescription (yes or no) - 0.357*gender (F = 1.899, p = 0.057, adjusted R2 = 0.11) Information about plasma lamotrigine C/D ratio were available for only 205 out of the 675 individuals in the database and has been obtained from different laboratories. The representativeness of the included sample may be questionable. This is the first study providing information on a large sample of individuals with BD regarding factors associated with lamotrigine C/D ratio. This study allows to propose a model of lamotrigine C/D ratio that would deserve further replication.

Predictors of Functional Impairment in Bipolar Disorder: Results From 13 Cohorts From Seven Countries by the Global Bipolar Cohort Collaborative.

Objectives: Persistent functional impairment is common in bipolar disorder (BD) and is influenced by a number of demographic, clinical, and cognitive features. The goal of this project was to estimate and compare the influence of key factors on community function in multiple cohorts of well-characterized samples of individuals with BD. Methods: Thirteen cohorts from 7 countries included n = 5882 individuals with BD across multiple sites. The statistical approach consisted of a systematic uniform application of analyses across sites. Each site performed a logistic regression analysis with empirically derived "higher versus lower function" as the dependent variable and selected clinical and demographic variables as predictors. Results: We found high rates of functional impairment, ranging from 41 to 75%. Lower community functioning was associated with depressive symptoms in 10 of 12 of the cohorts that included this variable in the analysis. Lower levels of education, a greater number of prior mood episodes, the presence of a comorbid substance use disorder, and a greater total number of psychotropic medications were also associated with low functioning. Conclusions: The bipolar clinical research community is poised to work together to characterize the multi-dimensional contributors to impairment and address the barriers that impede patients' complete recovery. We must also identify the core features which enable many to thrive and live successfully with BD. A large-scale, worldwide, prospective longitudinal study focused squarely on BD and its heterogeneous presentations will serve as a platform for discovery and promote major advances toward optimizing outcomes for every individual with this illness.Reprinted from Bipolar Disord 2022; 24:709-719, with permission from John Wiley and Sons. Copyright © 2022.