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Inflammation has emerged as a prominent feature of bipolar disorder (BD) pathophysiology, drawing attention to brain barriers known to regulate immune-brain interactions. While perturbation of the blood-brain barrier has been reported in BD, the blood-cerebrospinal fluid (CSF) barrier formed largely by the choroid plexus (ChP) remains underexamined. To address this gap in knowledge, we used a multiplex array to measure cytokine protein abundance in postmortem ChP tissue from individuals with BD and unaffected controls, revealing elevated levels of CCL2 and SPP1, factors associated with monocyte and macrophage recruitment and activation. In contrast, expression of cytokines involved in tissue homeostasis, trophic support, and immune signaling, including OSM, IGF-1, CX3CL1, TGFB3, GDNF, LIF, BDNF, SCF, and FGFs, was reduced. Several cytokines, including CCL2 and PLGF, exhibited condition-specific divergent age trajectories. Bulk RNA sequencing of the same cohort revealed a modest set of differentially expressed genes, including transcripts associated with oxidative stress, mitochondrial function, and immune regulation that were upregulated in BD. Notably, the BD CSF biomarker NELL2 was downregulated in the ChP. Gene set enrichment analysis highlighted activation of inflammatory and cellular stress pathways, as well as reduced expression of junction-related gene programs. These findings suggest a shift in ChP function in BD characterized by increased pro-inflammatory signaling and reduced trophic and barrier-supportive activity. Together, these data identify the ChP as an active site of immune dysregulation in BD and support the broader notion of brain barrier dysfunction in mood disorder pathology. Show less

There is a significant association between depressive episodes of bipolar disorder and non-suicidal self-injury (NSSI). Mindfulness-based cognitive therapy (MBCT) represents an evolution of cognitive behavioural therapy and serves as a comprehensive psychological intervention. Preliminary research suggests that MBCT may enhance cognitive flexibility and attentional adjustment in patients with depressive episodes of bipolar disorder by modulating brain activity. The aim of this study was to explore the effects of MBCT on behaviour, cognitive function, and serum precursor of brain-derived neurotrophic factor (proBDNF) levels in adolescents with depressive episodes of bipolar disorder. A total of 149 adolescent patients with bipolar disorder and depression with NSSI were randomly assigned. The Chinese version of the Adolescent Non-suicidal Self-Injury Assessment Questionnaire (ANSAQ) was used to measure NSSI symptoms. One group received MBCT in addition to treatment as usual (TAU) (n = 75), while the other group received TAU alone (n = 74). At baseline and at weeks 4 and 8 after treatment initiation, participants were assessed using the Barratt Impulsiveness Scale (BIS), the Hamilton Anxiety Scale (HAMA), the Repeatable Battery for the Assessment of Neuropsychological Status, and the Hamilton Depression Scale (HAMD). In addition, serum precursor Brain-Derived Neurotrophic Factor (proBDNF) levels were determined using an enzyme-linked immunosorbent assay. After 4 and 8 weeks of treatment, the MBCT group showed significantly greater improvement than the control group across the three BIS dimensions (motor impulsiveness, cognitive impulsiveness, and non-planning impulsiveness) (P < 0.001). HAMD scores in the MBCT group were significantly lower than those in the TAU group (4 weeks: MBCT:16.89 ± 1.45 vs TAU:17.27 ± 1.47, P < 0.05; 8 weeks: MBCT:9.24 ± 1.43 vs TAU:11.01 ± 1.84, P < 0.001). Similarly, HAMA scores were lower in the MBCT group (4 weeks: MBCT:13.14 ± 1.30 vs TAU:14.13 ± 1.65, P < 0.05; 8 weeks: MBCT:7.16 ± 1.68 vs TAU:8.17 ± 1.40, P < 0.001). Regarding cognitive function, the MBCT group demonstrated significantly higher scores in immediate memory (4 weeks: MBCT:72.31 ± 11.08 vs TAU:68.31 ± 9.36 P < 0.05; 8 weeks:MBCT:74.80 ± 13.06 vs TAU:71.87 ± 13.64, P < 0.05), delayed memory (4 weeks: MBCT:74.46 ± 11.50 vs TAU:70.20 ± 11.76, P < 0.05; 8 weeks: MBCT:76.54 ± 13.07 vs TAU:71.90 ± 12.60, P < 0.001), attention (4 weeks: MBCT:77.53 ± 11.41 vs TAU: 73.01 ± 13.21, P<0.05; 8 weeks: MBCT:84.56 ± 12.77 vs TAU:76.87 ± 11.38, P < 0.001), language ability (4weeks: MBCT:76.47 ± 12.17 vs TAU:72.13 ± 13.25 P < 0.05;8 weeks: MBCT:79.89 ± 15.02 vs TAU:74.83 ± 12.97, P < 0.05) and visuospatial ability (4 weeks:MBCT:89.04 ± 10.92 vs TAU:84.01 ± 12.67 P < 0.05;8 weeks:MBCT:90.23 ± 13.62 vs TAU:87.67 ± 12.74 P < 0.05) . In addition, serum proBDNF levels in the MBCT group were significantly lower than those in the TAU group at both 4 weeks (MBCT:1.34 ± 0.09 ng/mL vs TAU:1.40 ± 0.06 ng/mL, P < 0.05) and 8 weeks (MBCT:1.27 ± 0.07 ng/mL vs TAU:1.31 ± 0.04 ng/mL, P < 0.05). MBCT can effectively reduce impulsive behaviour, alleviate depressive and anxiety symptoms related to self-injurious behaviour in adolescents with bipolar depression, and decrease serum proBDNF levels. Additionally, immediate memory, delayed memory, attention, language, and visuospatial ability were significantly improved following treatment. Show less

Recent evidence suggests that reduced peripheral levels of brain-derived neurotrophic factor (BDNF) may be involved in the pathophysiology of bipolar disorder (BD), although its relevance in young populations remains uncertain. This systematic review synthesized studies that evaluated serum BDNF levels in children and adolescents with BD, examining its potential as a risk marker. Following PRISMA 2020 guidelines and a protocol registered in PROSPERO, searches were conducted in the Cochrane, MEDLINE, SciELO, and Scopus databases. Studies including participants aged 0-19 years diagnosed with BD according to DSM criteria were included. Studies with mixed samples (adults, children and adolescents) without separate age-group analyses were excluded. After screening and eligibility assessment, seven studies were included. Five of them included a control group, from which a meta-analysis was performed. Moderate methodological heterogeneity was observed and corrected after sensitivity analysis, reinforcing the robustness of the findings, although no statistically significant difference in serum BDNF levels was found between patients with bipolar disorder and controls. Current evidence does not support BDNF as a diagnostic biomarker for pediatric BD. Future studies with greater sample power and methodological standardization are needed to clarify its role in the risk and course of early-onset bipolar disorder. Show less

Brain-derived neurotrophic factor (BDNF) is a key regulator of neuroplasticity, synaptic integrity and cognitive function and its dysregulation has been implicated across major psychiatric disorders. However, its transdiagnostic association with cognitive performance remains incompletely understood. In this cross-sectional study, 160 participants were examined, including individuals with schizophrenia (SCZ), bipolar disorder (BD), major depressive disorder (MDD) and healthy controls (HC) (n = 40 per group). Serum BDNF concentrations were measured using enzyme-linked immunosorbent assay (ELISA). Cognitive performance was assessed using the Montreal Cognitive Assessment (MoCA), Trail Making Tests (TMT-A/B) and Digit Span (Forward/Backward). Significant group differences were observed for both serum BDNF levels and cognitive performance. Serum BDNF concentrations were lowest in SCZ (18.2 ± 4.6 ng/mL) and MDD (19.5 ± 5.1 ng/mL), intermediate in BD (23.7 ± 5.9 ng/mL) and highest in HC (26.3 ± 6.2 ng/mL) (F(3156) = 15.47, p < 0.001). Cognitive impairment followed a parallel gradient, with SCZ exhibiting the most severe deficits (p < 0.001). Across the full cohort, serum BDNF showed moderate positive associations with global cognition (MoCA: r = 0.42, p < 0.001) and working memory (Digit Span Backward: r = 0.38, p < 0.001) and a negative association with executive dysfunction as indexed by TMT-B completion time (r = -0.46, p < 0.001). These findings indicate that serum BDNF is modestly but consistently associated with cognitive performance across major psychiatric disorders, supporting its role as a transdiagnostic neurobiological correlate of impaired neuroplasticity rather than a disorder-specific or deterministic biomarker. Show less

Diagnosis of affective disorders among adolescent population links with the high risk of suicide attempt. The use of clinical psychological scales and biological markers may help to understand the background of suicidal process. Here we present the exploratory data study on retrospective suicide attempt risk factors and classification model of diagnosis conversion from major depressive disorder to bipolar disorder among adolescent population. This retrospective classification study was conducted on 45 adolescent/early-adulthood patients with the diagnosis of major depressive disorders. The psychological profile of patients was assessed with the use of standard clinical scales, like: Defence Style Questionnaire, Barrat Impulsiveness Scale, Beck Depression Inventory, Family APGAR, Emotional Intelligence Questionnaire and Temperament and Character Inventory. We assessed also the baseline concentration of blood-serum proteins: brain-derived neurotrophic factor, proBDNF, epidermal growth factor, macrophage migration inhibitory protein, and Stem Cell Factor. Suicide attempt history was determined at baseline (lifetime occurrence). The machine learning were used to assess the classification of the risk of suicidal attempt as well as diagnosis conversion from major depression to bipolar disorder. The winning models of machine learning were logistic regression and random forest. Regarding the suicidal attempt risk classification, significant coefficient were found mainly in Hamilton Depression Rating Scale (both factor and item assessment) and Temperament and Character Inventory (AUC = 0.74 (95% CI: 0.53-0.91), permutation p = 0.003). Serum biomarkers showed no discriminative ability (AUC = 0.35-0.40, p > 0.5) for suicide attempts in the past. We found not reliable clinical and biological data on the diagnosis conversion prediction. Clinical psychological scales, not peripheral biomarkers, distinguished suicide attempters in this exploratory analysis. Show less

Valproic acid (VPA) is recognized for its neurotrophic properties and is widely used in psychiatric and peripheral disorders, while dextromethorphan (DM) has demonstrated anti-inflammatory and neuroprotective effects. This study examined whether adjunctive DM provides additional benefits on cognitive or immunomodulatory beyond standard VPA treatment in bipolar disorder (BD). BD aged 20-65 received open-label VPA (500-2500 mg/day; target blood level 50-100 μg/dl) for one week and were then randomized to VPA plus placebo (BDVPA) or VPA plus extended-release DM (BDVPA + DM; 30 or 60 mg/day) for twelve weeks. Neuropsychological measures (Continuous Performance Test, CPT; Wechsler Memory Scale-Revised, WMS-R), symptom severity, cytokines, and BDNF were assessed at baseline and post-treatment. A total of 109 participants (mean age 31.04 years, SD = 10.04) were enrolled; 96 completed cognitive testing and blood sampling (66 BD Show less

Numerous hypotheses have been proposed for the pathophysiology of bipolar disorder (BD). This study aimed to evaluate serum neuroserpin (NSP), tissue plasminogen activator (tPA), interleukin-6 (IL-6), brain-derived neurotrophic factor (BDNF), high-sensitivity C-reactive protein (hsCRP), and sedimentation levels in patients with BD, based on the inflammatory and fibrinolytic system hypothesis, to understand the etiopathogenesis of BD. The second aim of our study was to determine the risk of developing BD type 1 by examining the relationship between tPA and NSP in patients diagnosed with BD type 1. The study included 80 euthymic outpatients with BD type 1 and 80 healthy controls (HC). Individuals with a Hamilton Depression Rating Scale (HAM-D) score of less than 7 and a Young Mania Rating Scale (YMRS) score of less than 4 who did not show any symptoms of mania, depression, or hypomania for the last 6 months were included in the study. In both groups, serum levels of NSP, tPA, IL-6, BDNF, hsCRP, and sedimentation were measured. Compared to the healthy control group, the NSP and tPA levels were lower in the BD group (p<0.001). We found no linear relationship when we analyzed the relationship between tPA and NSP by excluding other variables. (p: 0.027). These findings suggest that tPA and NSP may serve as potential biomarkers for the euthymic period of BD type 1. These biomarkers may provide guidance in understanding the pathophysiology of bipolar disorder. Show less

Research on the different aspects of bipolar disorder (BD) in special populations, such as youth with autism spectrum disorder (ASD) is limited. This case-controlled study aimed to investigate the serum levels of brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), and nerve growth factor (NGF) in youth with ASD with and without comorbid BD. Forty young subjects (13.47 ± 2.89 years) diagnosed with ASD with comorbid BD were included in the case group, and 40 age/gender-matched subjects with diagnosis of ASD without any mood disorders were included in the control group. The serum levels of BDNF, GDNF, and NGF were measured using enzyme-linked immunosorbent assays. The Childhood Autism Rating Scale (CARS) was used to assess ASD severity in the subjects. Serum BDNF levels were significantly lower in the case group than in the control group (p = 0.002). No significant differences were observed in GDNF and NGF levels between the two groups (p > 0.05). The severity of ASD was significantly higher in the case group (p = 0.001). Low serum BDNF levels may be associated with BD comorbidity in youth with ASD. Given the difficulty in diagnosing BD in this population, serum BDNF levels may be a biomarker associated with the development/diagnosis of BD in youth with ASD. Further studies with larger sample sizes are required to validate these findings. Show less