Plasma and Platelet Brain-Derived Neurotrophic Factor (BDNF) Levels in Bipolar Disorder Patients with Post-Traumatic Stress Disorder (PTSD) or in a Major Depressive Episode Compared to Healthy Controls.

Post-traumatic stress disorder (PTSD) is a highly disabling mental disorder arising after traumatism exposure, often revealing critical and complex courses when comorbidity with bipolar disorder (BD) occurs. To search for PTSD or depression biomarkers that would help clinicians define BD presentations, this study aimed at preliminarily evaluating circulating brain-derived-neurotrophic factor (BDNF) levels in BD subjects with PTSD or experiencing a major depressive episode versus controls. Two bloodstream BDNF components were specifically investigated, the storage (intraplatelet) and the released (plasma) ones, both as adaptogenic/repair signals during neuroendocrine stress response dynamics. Bipolar patients with PTSD (n = 20) or in a major depressive episode (n = 20) were rigorously recruited together with unrelated healthy controls (n = 24) and subsequently examined by psychiatric questionnaires and blood samplings. Platelet-poor plasma (PPP) and intraplatelet (PLT) BDNF were measured by ELISA assays. The results showed markedly higher intraplatelet vs. plasma BDNF, confirming platelets' role in neurotrophin transport/storage. No between-group PPP-BDNF difference was reported, whereas PLT-BDNF was significantly reduced in depressed BD patients. PLT-BDNF negatively correlated with mood scores but not with PTSD items like PPP-BDNF, which instead displayed opposite correlation trends with depression and manic severity. Present findings highlight PLT-BDNF as more reliable at detecting depression than PTSD in BD, encouraging further study into BDNF variability contextually with immune-inflammatory parameters in wider cohorts of differentially symptomatic bipolar patients.

Cognitive Remediation in Bipolar (CRiB2): study protocol for a randomised controlled trial assessing efficacy and mechanisms of cognitive remediation therapy compared to treatment as usual.

BACKGROUND: A substantial proportion of people with bipolar disorder (BD) experience persistent cognitive difficulties associated with impairments in psychosocial functioning and a poorer disorder course. Emerging evidence suggests that cognitive remediation (CR), a psychological intervention with established efficacy in people with schizophrenia, can also benefit people with BD. Following a proof-of-concept trial showing that CR is feasible and potentially beneficial for people with BD, we are conducting an adequately powered trial in euthymic people with BD to 1) determine whether an individual, therapist-supported, computerised CR can reduce cognitive difficulties and improve functional outcomes; and 2) explore how CR exerts its effects. METHODS: CRiB2 is a two-arm, assessor-blind, multi-site, randomised controlled trial (RCT) comparing CR to treatment-as-usual (TAU). Participants are people with a diagnosis of BD, aged between 18 and 65, with no neurological or current substance use disorder, and currently euthymic. 250 participants will be recruited through primary, secondary, tertiary care, and the community. Participants will be block-randomised (1:1 ratio, stratified by site) to continue with their usual care (TAU) or receive a 12-week course of therapy and usual care (CR + TAU). The intervention comprises one-on-one CR sessions with a therapist supplemented with independent cognitive training for 30-40 h in total. Outcomes will be assessed at 13- and 25-weeks post-randomisation. Efficacy will be examined by intention-to-treat analyses estimating between-group differences in primary (i.e., psychosocial functioning at week 25 measured with the Functional Assessment Short Test) and secondary outcomes (i.e., measures of cognition, mood, patient-defined goals, and quality of life). Global cognition, metacognitive skills, affect fluctuation, and salivary cortisol levels will be evaluated as putative mechanisms of CR through mediation models. DISCUSSION: This study will provide a robust evaluation of efficacy of CR in people with BD and examine the putative mechanisms by which this therapy works. The findings will contribute to determining the clinical utility of CR and potential mechanisms of action. TRIAL REGISTRATION: Cognitive Remediation in Bipolar 2 (CRiB2): ISRCTN registry: https://www.isrctn.com/ISRCTN10362331 . Registered 04 May 2022. Overall trial status: Ongoing; Recruitment status: Recruiting.

ER-mitochondria communication is involved in NLRP3 inflammasome activation under stress conditions in the innate immune system.

Endoplasmic reticulum (ER) stress and mitochondrial dysfunction, which are key events in the initiation and/or progression of several diseases, are correlated with alterations at ER-mitochondria contact sites, the so-called "Mitochondria-Associated Membranes" (MAMs). These intracellular structures are also implicated in NLRP3 inflammasome activation which is an important driver of sterile inflammation, however, the underlying molecular basis remains unclear. This work aimed to investigate the role of ER-mitochondria communication during ER stress-induced NLRP3 inflammasome activation in both peripheral and central innate immune systems, by using THP-1 human monocytes and BV2 microglia cells, respectively, as in vitro models. Markers of ER stress, mitochondrial dynamics and mass, as well as NLRP3 inflammasome activation were evaluated by Western Blot, IL-1ß secretion was measured by ELISA, and ER-mitochondria contacts were quantified by transmission electron microscopy. Mitochondrial Ca2+ uptake and polarization were analyzed with fluorescent probes, and measurement of aconitase and SOD2 activities monitored mitochondrial ROS accumulation. ER stress was demonstrated to activate the NLRP3 inflammasome in both peripheral and central immune cells. Studies in monocytes indicate that ER stress-induced NLRP3 inflammasome activation occurs by a Ca2+-dependent and ROS-independent mechanism, which is coupled with upregulation of MAMs-resident chaperones, closer ER-mitochondria contacts, as well as mitochondrial depolarization and impaired dynamics. Moreover, enhanced ER stress-induced NLRP3 inflammasome activation in the immune system was found associated with pathological conditions since it was observed in monocytes derived from bipolar disorder (BD) patients, supporting a pro-inflammatory status in BD. In conclusion, by demonstrating that ER-mitochondria communication plays a key role in the response of the innate immune cells to ER stress, this work contributes to elucidate the molecular mechanisms underlying NLRP3 inflammasome activation under stress conditions, and to disclose novel potential therapeutic targets for diseases associated with sterile inflammation.

Sex Differences in Brain Disorders.

A remarkable feature of the brain is its sexual dimorphism. Sexual dimorphism in brain structure and function is associated with clinical implications documented previously in healthy individuals but also in those who suffer from various brain disorders. Sex-based differences concerning some features such as the risk, prevalence, age of onset, and symptomatology have been confirmed in a range of neurological and neuropsychiatric diseases. The mechanisms responsible for the establishment of sex-based differences between men and women are not fully understood. The present paper provides up-to-date data on sex-related dissimilarities observed in brain disorders and highlights the most relevant features that differ between males and females. The topic is very important as the recognition of disparities between the sexes might allow for the identification of therapeutic targets and pharmacological approaches for intractable neurological and neuropsychiatric disorders.

Factors associated with lifetime suicide attempts in bipolar disorder: results from an Italian nationwide study.

The purpose of the present study was to detect demographic and clinical factors associated with lifetime suicide attempts in Bipolar Disorder (BD). A total of 1673 bipolar patients from different psychiatric departments were compared according to the lifetime presence of suicide attempts on demographic/clinical variables. Owing to the large number of variables statistically related to the dependent variable (presence of suicide attempts) at the univariate analyses, preliminary multiple logistic regression analyses were realized. A final multivariable logistic regression was then performed, considering the presence of lifetime suicide attempts as the dependent variable and statistically significant demographic/clinical characteristics as independent variables. The final multivariable logistic regression analysis showed that an earlier age at first contact with psychiatric services (odds ratio [OR] = 0.97, p < 0.01), the presence of psychotic symptoms (OR = 1.56, p < 0.01) or hospitalizations (OR = 1.73, p < 0.01) in the last year, the attribution of symptoms to a psychiatric disorder (no versus yes: OR = 0.71, partly versus yes OR = 0.60, p < 0.01), and the administration of psychoeducation in the last year (OR = 1.49, p < 0.01) were all factors associated with lifetime suicide attempts in patients affected by BD. In addition, female patients resulted to have an increased association with life-long suicidal behavior compared to males (OR: 1.02, p < 0.01). Several clinical factors showed complex associations with lifetime suicide attempts in bipolar patients. These patients, therefore, require strict clinical monitoring for their predisposition to a less symptom stabilization. Future research will have to investigate the best management strategies to improve the prognosis of bipolar subjects presenting suicidal behavior.

MicroRNAs, Stem Cells in Bipolar Disorder, and Lithium Therapeutic Approach.

Bipolar disorder (BD) is a severe, chronic, and disabling neuropsychiatric disorder characterized by recurrent mood disturbances (mania/hypomania and depression, with or without mixed features) and a constellation of cognitive, psychomotor, autonomic, and endocrine abnormalities. The etiology of BD is multifactorial, including both biological and epigenetic factors. Recently, microRNAs (miRNAs), a class of epigenetic regulators of gene expression playing a central role in brain development and plasticity, have been related to several neuropsychiatric disorders, including BD. Moreover, an alteration in the number/distribution and differentiation potential of neural stem cells has also been described, significantly affecting brain homeostasis and neuroplasticity. This review aimed to evaluate the most reliable scientific evidence on miRNAs as biomarkers for the diagnosis of BD and assess their implications in response to mood stabilizers, such as lithium. Neural stem cell distribution, regulation, and dysfunction in the etiology of BD are also dissected.

Quantitative Proteomic Approach for Discriminating Major Depressive Disorder and Bipolar Disorder by Multiple Reaction Monitoring-Mass Spectrometry.

Because major depressive disorder (MDD) and bipolar disorder (BD) manifest with similar symptoms, misdiagnosis is a persistent issue, necessitating their differentiation through objective methods. This study was aimed to differentiate between these disorders using a targeted proteomic approach. Multiple reaction monitoring-mass spectrometry (MRM-MS) analysis was performed to quantify protein targets regarding the two disorders in plasma samples of 270 individuals (90 MDD, 90 BD, and 90 healthy controls (HCs)). In the training set (72 MDD and 72 BD), a generalizable model comprising nine proteins was developed. The model was evaluated in the test set (18 MDD and 18 BD). The model demonstrated a good performance (area under the curve (AUC) >0.8) in discriminating MDD from BD in the training (AUC = 0.84) and test sets (AUC = 0.81) and in distinguishing MDD from BD without current hypomanic/manic/mixed symptoms (90 MDD and 75 BD) (AUC = 0.83). Subsequently, the model demonstrated excellent performance for drug-free MDD versus BD (11 MDD and 10 BD) (AUC = 0.96) and good performance for MDD versus HC (AUC = 0.87) and BD versus HC (AUC = 0.86). Furthermore, the nine proteins were associated with neuro, oxidative/nitrosative stress, and immunity/inflammation-related biological functions. This proof-of-concept study introduces a potential model for distinguishing between the two disorders.

Factors influencing lithium versus valproate prescription preference in the maintenance treatment of bipolar patients: a report from the Italian Early Career Psychiatrists (SOPSI-GG).

BACKGROUND: Objective of the present manuscript is to investigate, among Italian early career psychiatrists (ECPs), prescriber and patient-related factors associated with lithium or valproate preference to treat patients affected by Bipolar Disorder (BD). METHODS: An on-line survey was carried out among 252 ECPs, investigating their prescription patterns in relation to lithium and the differences with prescription of valproate. Collected data were compared according to lithium or valproate prescription preference in the long-term treatment of BD by χ2 tests for qualitative variables. RESULTS: Over two thirds of ECPs preferred lithium over valproate for the maintenance treatment of BD. Less than half of the sample used lithium as first-line agent for mania or major depression, and less than one third for mixed episodes. Factors associated with lithium preference as first-line maintenance treatment include perception of having a good knowledge of lithium (p < 0.001) and complete satisfaction with education on lithium (p < 0.001). One of the main factors to prefer valproate was the concern about long-term side effects of lithium (p < 0.001). CONCLUSIONS: Type of education, source of information, clinical experience and safety concerns influence the choice of lithium versus valproate in the long-term treatment of BD. Present findings may guide educational training of ECPs.KEY POINTSLithium has been less prescribed in the last years for long-term treatment of Bipolar Disorder.Educational and clinical factors seem to influence the attitude to prescribe lithium.Only half of the Italian early career psychiatrists declare to have at least an adequate knowledge of lithium.Residency program in psychiatry should consider the implementation of education on lithium.

Antisocial Personality Disorder in Bipolar Disorder: A Systematic Review.

Background and Objectives: Bipolar Disorder (BD) is a severe psychiatric disorder that worsens quality of life and functional impairment. Personality disorders (PDs), in particular Cluster B personality, have a high incidence among BD patients and is considered a poor prognostic factor. The study of this co-morbidity represents an important clinical and diagnostic challenge in psychiatry. Particularly, clinical overlap has been shown between antisocial personality disorder (ASPD) and BD that could worsen the course of both disorders. We aimed to detect the frequency of ASPD in bipolar patients with greater accuracy and the impact of ASPD on the clinical course of BD. Materials and Methods: A systematic literature search was conducted in PubMed, Embase, MEDLINE and the Cochrane Library through December 2020 without language or time restriction, according to PRISMA statement guidelines. Results: Initially, 3203 items were identified. After duplicates or irrelevant paper deletion, 17 studies met the inclusion criteria and were included in this review. ASPD was more frequent among BD patients, especially in BD type I. BD patients with ASPD as a comorbidity seemed to have early onset, higher number and more severe affective episodes, higher levels of aggressive and impulsive behaviors, suicidality and poor clinical outcome. ASPD symptoms in BD seem to be associated with a frequent comorbidity with addictive disorders (cocaine and alcohol) and criminal behaviors, probably due to a shared impulsivity core feature. Conclusions: Considering the shared symptoms such as impulsive and dangerous behaviors, in patients with only one disease, misdiagnosis is a common phenomenon due to the overlapping symptoms of ASPD and BD. It may be useful to recognize the co-occurrence of the disorders and better characterize the patient with ASPD and BD evaluating all dysfunctional aspects and their influence on core symptoms.

Failure of activation of striatum during the performance of executive function tasks in adult patients with bipolar disorder.

BACKGROUND: Although numerous studies have used functional neuroimaging to identify executive dysfunction in patients with bipolar disorder (BD), the findings are not consistent. The aim of this meta-analysis is to identify the most reliable functional anomalies in BD patients during performance of Executive Function (EF) tasks. METHODS: A web-based search was performed on publication databases to identify functional magnetic resonance imaging studies of BD patients performing EF tasks and a voxel-based meta-analytic method known as anisotropic Effect Size Signed Differential Mapping (ES-SDM) was used to identify brain regions which showed anomalous activity in BD patients compared with healthy controls (HC). RESULTS: Twenty datasets consisting of 463 BD patients and 484 HC were included. Compared with HC, BD patients showed significant hypo-activation or failure of activation in the left striatum (p = 0.00007), supplementary motor area (BA 6, p = 0.00037), precentral gyrus (BA 6, p = 0.0014) and cerebellum (BA 37, p = 0.0019), and hyper-activation in the left gyrus rectus (BA 11, p ≈ 0) and right middle temporal gyrus (BA 22, p = 0.00031) during performance of EF tasks. Sensitivity and subgroup analyses showed that the anomaly of left striatum is consistent across studies and present in both euthymic and BD I patients. CONCLUSIONS: Patients with BD consistently showed abnormal activation in the cortico-striatal system during performance of EF tasks compared with HC. Failure of activation of the striatum may be a reliable marker for impairment in performance of especially inhibition tasks by patients with BD.

A miRNome analysis of drug-free manic psychotic bipolar patients versus healthy controls.

The lifetime presence of psychotic symptoms is associated with more clinical severity, poorer outcome and biological changes in patients affected by bipolar disorder (BD). Epigenetic mechanisms have been evoked to explain the onset of psychotic symptoms in BD as well as the associated biological changes. The main objective of the present study was to evaluate the expression profiles of circulating microRNAs (miRNAs) in drug-free manic psychotic bipolar patients versus healthy controls (HC), to identify possible non-invasive molecular markers of the disorder. 15 drug-free manic psychotic bipolar patients and 9 HC were enrolled and 800 miRNAs expression profile was measured by Nanostring nCounter technology on plasma samples and validated through qPCR. Overall, twelve miRNAs showed a significantly altered expression between the two groups (p < 0.05). Functional annotation of predicted miRNAs targets by MultiMIR R tool showed repression in bipolar patients of genes with a role in neurodevelopment and neurogenesis, and upregulation of genes involved in metabolism regulation. We identified a signature of circulating miRNA characteristic of manic psychotic bipolar patients, suggesting a possible role in neurodevelopment and metabolic processes regulation.

Gender-related differences in patients with bipolar disorder: a nationwide study.

OBJECTIVE: The possible presence of gender-related differences in patients with bipolar disorder (BD) may have diagnostic and therapeutic implications. This multicenter study aimed to investigate gender differences in BD in the largest Italian database collected to date, on behalf of the Italian Chapter of the International Society of Bipolar Disorders. METHODS: A total of 1674 patients (males: n = 714; females: n = 960) from different psychiatric departments were compared according to gender on demographic/clinical variables. Owing to the large number of variables statistically related to the dependent variable (gender) at the univariate analyses, preliminary multiple logistic regression analyses were performed. A final multivariable logistic regression was then performed, considering gender as the dependent variable and statistically significant demographic/clinical characteristics as independent variables. RESULTS: The results of the final multivariable logistic regression analysis with previous statistically significant demographic and clinical variables were the following: female gender was less frequently associated with employment (odds ratio [OR] = 0.7, P < 0.01), lifetime single marital status (OR = 0.45, P < 0.01), and substance abuse in the last year (OR = 0.35, P < 0.01), whereas it was more frequently associated with a major number of lifetime major depressive episodes (OR = 1.78, P < 0.01) and psychiatric visits in the last year (OR = 1.38, P = 0.01). CONCLUSION: Few significant differences were found between genders in BD, particularly for those clinical features that are associated with poor prognosis (substance abuse for males and number of depressive episodes for females). Transcultural studies are needed to identify cultural versus illness-related variables possibly explaining the different clinical presentation of BD in relation to gender.

ITGB4 deficiency in bronchial epithelial cells directs airway inflammation and bipolar disorder-related behavior.

BACKGROUND: Chronic persistent airway inflammation has been associated with the comorbidity of asthma and bipolar disorder (BD). However, the direct relevance between airway inflammation and BD-like psychiatric comorbidity is almost unknown. Integrin ß4 (ITGB4) is downregulated on the airway epithelial of asthma patients, which might play a critical role in the parthenogenesis of airway inflammation. So this study aimed to examine the role of ITGB4 deficiency in mediating airway inflammation and further leading to the BD-like behaviors. METHODS: ITGB4-/- mice were generated by mating ITGB4fl/fl mice with CCSP-rtTAtg/-/TetO-Cretg/tg mice. Mania-like behavior tests were performed, including hyperlocomotion, D-amphetamine-induced hyperactivity, open-field test, and elevated plus-maze test. Depressive-like behavior tests were carried out, including sucrose preference, forced swimming, and learned helplessness. Inflammatory cells (Th17, Th1, Th2) in the lung were examined by flow cytometry. Futhermore, inflammatory cytokines (IL-4, IL-13) in bronchoalveolar lavage fluid and sera were detected by ELISA. Protein expression of the IL-4Rα on choroid plexus, microglial marker (IBA1), and synapse-associated proteins (synaptophysin, SYP) in the hippocampus and prefrontal cortex were examined by western blotting. Additionally, proinflammatory cytokines (IL-1ß, IL-6, and TNF-α) in the hippocampus and prefrontal cortex were detected by immunohistochemistry. Inflammatory disorder in the lung, hippocampus, and prefrontal cortex was tested by hematoxylin and eosin (H&E) staining. And cell apoptosis in the hippocampus and prefrontal cortex was measured by TUNEL test. RESULTS: ITGB4-/- mice exhibited mania-like behavior, including hyperlocomotion, D-amphetamine-induced hyperactivity, and reduced anxiety-like behavior. While under stressful conditions, ITGB4-/- mice manifested depressive-like behavior, including anhedonia, behavioral despair, and enhanced learned helplessness. At the same time, ITGB4-/- mice mainly exerted Th2-type inflammation in periphery, like the number and major cytokines IL-4 and IL-13 of Th2-type inflammation. ITGB4-/- mice also showed a significant increase of microglia and pro-inflammatory cytokines such as IL-1ß, IL-6, and TNF-α in the hippocampus and prefrontal cortex. Additionally, neuron damage, increased neuron apoptosis, and the decrease of SYP were found in ITGB4-/- mice. CONCLUSIONS: These findings confirmed that airway inflammatory induced by ITGB4 deficiency is the important incentive for the BD-like behavior during asthma pathogenesis. The ITGB4-deficient mice provide a validated animal model for us to study the possible mechanism of BD-like psychiatric comorbidity of asthma patients.

Socio-demographic and clinical characterization of patients with Bipolar Disorder I vs II: a Nationwide Italian Study.

Bipolar disorders (BDs) are prevalent, comorbid and disabling conditions, associated with the highest suicide risk among psychiatric illnesses. In the last few years, new efforts to better characterize the socio-demographic and clinical profiles of BD type I vs II have been documented by several reports, with novel and insightful findings in the field. The present multicenter study aimed to provide a comprehensive and reliable representation of the Italian reality, through the analysis of the largest national sample of bipolar patients collected so far. A total of 1500 patients (BD I n = 963 and BD II n = 537) from different psychiatric departments, participating in the Italian Chapter of the "International Society of Bipolar Disorders" (ISBD), were assessed and divided into two groups on the basis of their diagnostic subtype, and different socio-demographic and clinical variables were compared between the two subgroups. Chi-squared tests for categorical variables and t tests for continuous variables were performed for group comparison. Furthermore, a multivariable logistic regression was performed, considering diagnostic bipolar subtype (type I or II) as dependent variable, and socio-demographic/clinical characteristics as independent variables. BD I vs II patients showed an overall less favorable socio-demographic and clinical profile. In addition, the multivariable logistic regression showed that BD II vs BD I was predicted by the absence of lifetime suicide attempts (OR = 1.58, p = 0.01), a later age of diagnosis (OR = 1.03, p < 0.01), less hypomanic episodes in the last year (OR = 2.29, p < 0.0001) and absence of psycho-educational interventions in the last year (OR = 0.51, p < 0.01). BD I and II patients were found to significantly differ in relation to specific clinical variables, which should be considered within updated diagnostic-therapeutic algorithms.

Clinical utility of resting-state functional connectivity magnetic resonance imaging for mood and cognitive disorders.

Although functional magnetic resonance imaging (fMRI) has long been used to assess task-related brain activity in neuropsychiatric disorders, it has not yet become a widely available clinical tool. Resting-state fMRI (rs-fMRI) has been the subject of recent attention in the fields of basic and clinical neuroimaging research. This method enables investigation of the functional organization of the brain and alterations of resting-state networks (RSNs) in patients with neuropsychiatric disorders. Rs-fMRI does not require participants to perform a demanding task, in contrast to task fMRI, which often requires participants to follow complex instructions. Rs-fMRI has a number of advantages over task fMRI for application with neuropsychiatric patients, for example, although applications of task fMR to participants for healthy are easy. However, it is difficult to apply these applications to patients with psychiatric and neurological disorders, because they may have difficulty in performing demanding cognitive task. Here, we review the basic methodology and analysis techniques relevant to clinical studies, and the clinical applications of the technique for examining neuropsychiatric disorders, focusing on mood disorders (major depressive disorder and bipolar disorder) and dementia (Alzheimer's disease and mild cognitive impairment).

Italian Bipolar II vs I patients have better individual functioning, in spite of overall similar illness severity.

Introduction Bipolar disorders (BDs) comprise different variants of chronic, comorbid, and disabling conditions, with relevant suicide and suicide attempt rates. The hypothesis that BD types I (BDI) and II (BDII) represent more and less severe forms of illness, respectively, has been increasingly questioned over recent years, justifying additional investigation to better characterize related sociodemographic and clinical profiles. METHODS: A sample of 217 outpatients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR)-described BD (141 BDI, 76 BDII), without a current syndromal mood episode, was recruited, and sociodemographic and clinical characteristics of BDI and II patients were compared. RESULTS: BDII patients had significantly more favorable sociodemographics, in relation to occupational stability, cohabitation, and marital status. However, BDII compared with BDI patients had significantly longer duration of untreated illness, more frequent lifetime anxiety disorders comorbidity, longer most recent episode duration, higher rate of depressive first/most recent episode, and more current antidepressant use. In contrast, BDI compared with BDII patients had significantly more severe illness in terms of earlier age at onset; higher rate of elevated first/most recent episode, lifetime hospitalizations, and involuntary commitments; lower Global Assessment of Functioning score; and more current antipsychotic use. BDI and II patients had similar duration of illness, psychiatric family history, lifetime number of suicide attempts, current subthreshold symptoms, history of stressful life events, and overall psychiatric/medical comorbidity. CONCLUSION: BDII compared with BDI patients had more favorable sociodemographic features, but a mixture of specific unfavorable illness characteristics, confirming that BDII is not just a milder form of BD and requires further investigation in the field.

Cognitive Performance in Euthymic Patients with Bipolar Disorder vs Healthy Controls: A Neuropsychological Investigation.

OBJECTIVES: Cognitive impairment may affect patients with Bipolar Disorder (BD) beyond the acute episodes, qualifying as a potential endophenotype. However, which cognitive domains are specifically affected in euthymic patients with BD and the potential influence of confounding factors (e.g., age and concomitant pharmacological treatment) are still a matter of debate. The present study was, therefore, conducted to assess cognitive performance across specific domains in euthymic bipolar patients, not older than 50 years (to avoid potential age-related bias) versus healthy controls (HCs). METHODS: A cognitive task battery, including the Wisconsin Card Test, Span Attention Test, Tower of London, Trail Making Test, Verbal Fluency Test, Matrices Scores and N-Back, was administered to 62 subjects (30 bipolar patients and 32 matched HCs) and differences between the groups analyzed. RESULTS: Bipolar patients performed significantly worse than HCs in the Span Forward task, in the expression of Verbal Fluency Test (Category) and in the N-Back task (all p<.05), with marginal differences between BD I and BD II patients. CONCLUSION: The present study pointed out significant differences in terms of cognitive performance between euthymic bipolar patients and HCs, supporting the notion that specific cognitive functions may remain impaired even after the resolution of the acute episodes in subjects suffering from BD. Future studies on larger samples are warranted to confirm the present results and further explore potential differences in cognitive impairment across specific bipolar subtypes.

Biomarkers of bipolar disorder based on metabolomics: A systematic review.

Bipolar disorder (BD) is a severe affective disorder characterized by recurrent episodes of depression or mania/hypomania, which significantly impair cognitive function, life skills, and social abilities of patients. There is little understanding of the neurobiological mechanisms of BD. The diagnosis of BD is primarily based on clinical assessment and psychiatric examination, highlighting the urgent need for objective markers to facilitate the diagnosis of BD. Metabolomics can be used as a diagnostic tool for disease identification and evaluation. This study summarized the altered metabolites in BD and analyzed aberrant metabolic pathways, which might contribute to the diagnosis of BD. Search of PubMed and Web of science for human BD studies related to metabolism to identify articles published up to November 19, 2022 yielded 987 articles. After screening and applying the inclusion and exclusion criteria, 16 untargeted and 11 targeted metabolomics studies were included. Pathway analysis of the potential differential biometabolic markers was performed using the Kyoto encyclopedia of genes and genomes (KEGG). There were 72 upregulated and 134 downregulated biomarkers in the untargeted metabolomics studies using blood samples. Untargeted metabolomics studies utilizing urine specimens revealed the presence of 78 upregulated and 54 downregulated metabolites. The targeted metabolomics studies revealed abnormalities in the metabolism of glutamate and tryptophan. Enrichment analysis revealed that the differential metabolic pathways were mainly involved in the metabolism of glucose, amino acid and fatty acid. These findings suggested that certain metabolic biomarkers or metabolic biomarker panels might serve as a reference for the diagnosis of BD.

Whole blood mitochondrial copy number in clinical populations with mood disorders: A meta-analysis: Blood mitochondrial copy number and mood disorders.

Major depressive disorder (MDD) and bipolar disorder (BD), are globally prevalent, contributing to significant disease burden and adverse health outcomes. These mood disorders are associated with changes in many aspects of brain reward pathways, yet cellular and molecular changes in the brain are not readily available in clinical populations. Therefore, the use of biomarkers as proxies for changes in the brain are necessary. The proliferation of mitochondria in blood has emerged as a potentially useful biomarker, yet a clear consensus on how these mood disorders impact mitochondrial DNA copy number (mtDNAcn) has not been reached. To determine the current available consensus on the relationship of mood disorder diagnosis and blood mtDNcn, we performed a meta-analysis of available literature measuring this biomarker. Following PRISMA guidelines for a systematic search, 22 papers met inclusion criteria for meta-analysis (10 MDD, 10 BD, 2 both MDD and BD). We extracted demographic, disorder, and methodological information with mtDNAcn. Using the metafor package for R, calculated effect sizes were used in random effects or meta regression models for MDD and BD. Overall, our data suggest blood mtDNAcn may be a useful biomarker for mood disorders, with MDD and BD Type II associated with higher mtDNAcn, and BD Type I associated with lower mtDNAcn. Initially, we observed a trending increase in mtDNAcn in patients with MDD, which reached significance when one study with outlying demographic characteristics was excluded. Subgroup and meta-regression analysis indicated the relationship between mtDNAcn and diagnosis in patients with BD is dependent on BD type, while no relationship is detectable when BD types are mixed. Further study of blood mtDNAcn could predict downstream health outcomes or treatment responsivity in individuals with mood disorders.

The mediating role of family functioning between childhood trauma and depression severity in major depressive disorder and bipolar disorder.

BACKGROUND: Childhood trauma (CT) and family functioning exert significant influences on the course and long-term outcome of major depressive disorder (MDD) and bipolar disorder (BD) patients. Hence, we examined the intricate relationship between CT, family function, and the severity of depressive episodes in MDD and BD patients. METHODS: 562 patients with depressive episodes (336 MDD and 226 BD) and 204 healthy controls (HCs) were included in this retrospective study. The 17-item Hamilton Depression Rating Scale (HAMD-17), Childhood Trauma Questionnaire (CTQ), and Family Adaptability and Cohesion Evaluation Scale (FACES II-CV) were assessed. Pearson correlation analysis and mediation analysis were performed. RESULTS: CT had both a direct and indirect impact on depression severity in MDD and BD groups. In MDD, family adaptability mediated the impact of all CT subtypes on depression severity (Effect = 0.113, [0.030, 0.208]). In BD, family cohesion played a mediating role between emotional neglect (EN) and HAMD-17 scores (Effect = 0.169, [0.008, 0.344]). Notable differences were observed in onset age, illness duration, episode frequency, family history, and CT subtypes between MDD and BD (P < 0.05). LIMITATIONS: This study has several limitations including recall bias, lack of objective family functioning measures, small sample size, and cross-sectional design. CONCLUSIONS: Family functioning mediated the impact of CT on depressive symptoms severity in MDD and BD patients. MDD patients with a history of CT exhibited reduced family adaptability, while BD patients with a history of EN had weaker familial emotional bonds. Our findings highlighted the importance of family-focused preventive interventions in mitigating the long-term effects of CT.