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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

Neuroplasticity dysregulation is implicated in the early pathophysiology of schizophrenia. Nogo-A, a myelin- and neuron-associated inhibitor of structural plasticity, has been less studied in first-episode schizophrenia (FES) than brain-derived neurotrophic factor (BDNF). This study examined short-term changes in serum Nogo-A and BDNF in drug-naïve patients with FES. Thirty-nine drug-naïve FES patients and 43 healthy controls (HC) were assessed. Serum Nogo-A and BDNF were measured at baseline in both groups and re-measured in FES after achieving ≥20 % reduction in Positive and Negative Syndrome Scale total score (PANSS). Baseline Nogo-A levels were higher in FES than HC (p = .022) and increased further after treatment (p < .001). Baseline BDNF did not differ between groups (p = .069) and showed no significant change after treatment (p = .094). PANSS total and subscale scores decreased significantly after treatment (all p < .001). Baseline Nogo-A modestly discriminated FES from HC (AUC = 0.648, 95 % CI = 0.53-0.77, sensitivity 66.7 %, specificity 60.5 %). In multivariable analysis, only smoking independently predicted FES (OR = 3.69, 95 % CI = 1.48-9.23, p = .005), whereas Nogo-A was not retained. Serum Nogo-A is elevated at illness onset in FES and increases during early treatment, suggesting that peripheral Nogo-A may be associated with early illness-related and/or treatment-related biological changes. Although Nogo-A does not show sufficient performance as a stand-alone diagnostic biomarker, these findings should be interpreted cautiously given the relatively small sample size and naturalistic treatment design. Nogo-A may warrant further investigation as part of broader multi-marker approaches in early schizophrenia. Show less

Major Depressive Disorder (MDD) is a debilitating and multifactorial neuropsychiatric condition that significantly contributes to the global burden of disease. Its clinical spectrum encompasses persistent low mood, anhedonia, cognitive decline, neurovegetative disturbances, and suicidality. This review synthesizes current evidence on the neurovascular, neurochemical, genetic, and psychosocial mechanisms underlying MDD. A narrative review approach was employed, incorporating data from peer-reviewed publications retrieved through systematic searches in biomedical databases. Emphasis was placed on recent findings that elucidate the interplay between neurobiological dysfunction and systemic influences in MDD pathogenesis. MDD pathophysiology is intricately linked to dysregulation of monoaminergic neurotransmission, aberrant hypothalamic-pituitary-adrenal (HPA) axis activity, and chronic neuroinflammation. Glial cell impairment, particularly involving astrocytes and microglia, disrupts synaptic homeostasis and neurovascular integrity. Genetic analyses estimate a heritability range of 30-50%, with genome-wide association studies identifying susceptibility loci in synaptic and immune pathways. Epigenetic modifications and perturbations of the gut- brain axis modulate vulnerability and progression. Oxidative stress and attenuated neurotrophic signalling, especially involving brain-derived neurotrophic factor (BDNF), further exacerbate neural circuit dysfunction. Sociodemographic determinants, including sex, psychosocial stressors, and socioeconomic adversity, also shape disease onset and trajectory. Although therapeutic modalities exist, limitations in early detection, treatment response, and long-term remission underscore the need for individualized strategies. Emerging approaches integrating epigenetic biomarkers and systems biology hold potential for precision psychiatry. A systems-level, biopsychosocial understanding of MDD is essential to advance targeted, personalized interventions, ultimately improving clinical outcomes in this complex disorder. Show less