Introduction: It is known that symptoms of major depressive disorder (MDD) are associated with neurodegeneration, that lipopolysaccharide (LPS) can induce symptoms of MDD, and that blood LPS levels are elevated in neurodegeneration. However, it is not known whether blood LPS and cytokine levels correlate with MDD, cognition and brain structure, and this is tested in this study. Methods and analysis: This cross-sectional study includes individuals with MDD (n = 100) and a control group of individuals with no one-year history of a mental disorder (n = 50). A comprehensive evaluation is performed, including the collection of basic sociodemographic information, data on smoking status, body mass index, course of MDD, past treatment, comorbid diseases, and current use of medications. Diagnosis of MDD is performed according to the WHO’s [2019] International Classification of Diseases and related health problems by psychiatrist and severity of MDD is evaluated using the Montgomery–Åsberg Depression Scale. The Cambridge Neuropsychological Test Automated Battery is used to evaluate cognitive functioning. Venous blood samples are taken to measure genetic and inflammatory markers, and multiparametric brain magnetic resonance imaging is performed to evaluate for blood-brain barrier permeability, structural and neurometabolic brain changes. Descriptive and inferential statistics, including linear and logistic regression, will be used to analyse relationships between blood plasma LPS and inflammatory cytokine concentrations in MDD patients and controls. The proposed sample sizes are suitable for identifying significant differences between the groups, according to a power analysis. Administrative information: Trial registration: Clinicaltrials.gov NCT06203015.

Background: Short versions of problematic internet use (PIU) questionnaires may provide a convenient and effective way of assessing internet-related problems in various contexts, ranging from research to clinical practice. The aim of this study was to investigate whether single yes/no question (Q-single) regarding “functional impairment due to PIU” could serve as a screening tool to indicate the potential absence of PIU, given the lack of functional impairment. Methods: Data from two online studies ( N = 524 and N = 272) assessing internet-related behaviors among students were used for the analyses. Participants completed questionnaires (the nine-item Problematic Internet Use Questionnaire [PIUQ-9], the Compulsive Internet Use Scale [CIUS], the nine-item Patient Health Questionnaire, depression module [PHQ-9], the seven-item Generalized Anxiety Disorder scale [GAD-7]), questions about their internet use time, besides answering the Q-Single question. Block-wise multiple linear regression analyses were used to determine the predictive effect of the Q-Single on PIU (as measured with the PIUQ-9 and the CIUS) and its association with depression and anxiety symptom scores (as measured with the PHQ-9 and the GAD-7). Results: The Q-Single demonstrated a high negative predictive value in screening the absence of PIU, however positive predictive value was low to moderate. Q-Single proved to be a good predictor of PIU ( β = 0.484, p < 0.001 [PIUQ-9] and β = 0.481, p < 0.001 [CIUS]) when controlling for age, gender, and internet use time. Adjusting for the same controlling variables, the Q-Single had a moderate association with depression symptoms ( β = 0.385, p < 0.001 [PHQ-9]) and anxiety symptoms ( β = 0.252, p < 0.001) [GAD-7]) supporting the validity of the single-question instrument. Conclusions: The finding that a single question could predict absence of PIU in students, implies that functional impairment is an important indicator of PIU.

Background: Diffusion-prepared pseudo-continuous arterial spin labelling (DP-pCASL) can quantify the cerebral blood flow (CBF) and the water exchange rate (kw) across the blood–brain barrier (BBB). Little is known about the BBB water exchange in major depressive disorder (MDD). Objective: We aimed to explore the associations between kw, CBF, peripheral inflammation, and MDD. Methods: Using DP-pCASL, we measured the global and selected regional kw and CBF together with blood plasma levels of lipopolysaccharide (LPS) and inflammatory cytokines in 85 patients with MDD and 51 controls. Results: The global CBF was significantly lower in MDD patients compared with controls (means of 51 and 57 mL/100 g/min, respectively; p = 0.006), with similar reductions found in the dorsolateral and ventromedial prefrontal, anterior, and posterior cingulate regions, while no differences were found in the amygdala and the isthmic cingulate. There were no differences in the kw between groups globally (means of 128 min⁻¹; p = 0.958) and in the studied regions. Among MDD patients, the kw was weakly correlated with the MADRS scores (r = 0.231, p = 0.034). There were no associations between kw, CBF, and inflammatory markers (LPS, IL-6, IL-10, TNF-α, IFN-γ). Logistic regression showed that a combination of the regional CBF < 59.22 mL/100 g/min together with LPS > 143.58 pg/mL and/or IL-10 > 0 pg/mL distinguished MDD patients from controls with a moderate accuracy of 83.1% (sensitivity = 94.1%, specificity = 64.7%, AUC = 0.876). Conclusions: DP-pCASL imaging confirmed previous findings of reduced CBF in MDD, which together with LPS and IL-10 concentrations were independent significant predictors of MDD. However, no changes in the BBB water exchange were found, suggesting that it may not be as significant as CBF in MDD pathophysiology.

Background: Inflammatory mechanisms contribute to major depressive disorder (MDD) in a subset of patients. Lipopolysaccharide (LPS), a potent inflammatory endotoxin, can induce depressive-like symptoms, but its relationship with specific depressive symptom profiles remains unclear. Methods: In total, 95 adults with MDD (mean age was 44 ± 14 years) were recruited from psychiatric inpatient and outpatient services. Depressive symptom severity was assessed using the Montgomery–Åsberg Depression Rating Scale (MADRS). Serum concentrations of LPS, IL-10, TNF-α, IL-6, and IFN-γ were measured by ELISA. Associations between inflammatory markers and depressive symptoms were examined using group comparisons, correlation analyses, multivariable linear regression, quantile regression, and mediation analyses adjusted for demographic and clinical covariates. Results: Patients with severe depression exhibited significantly lower circulating LPS levels than those with mild-to-moderate depression (95.6 vs. 165.2 pg/mL, p = 0.007), despite no significant differences in cytokine concentrations. LPS levels were inversely associated with depression severity, anhedonia factor score, and MADRS item 8 (“inability to feel”). Lower LPS concentrations were independently predicted by higher inability to feel, reduced appetite and combined pharmacotherapy use. Quantile regression demonstrated heterogeneity across the LPS distribution, with symptom–LPS associations evident among patients with higher LPS concentrations. Higher LPS levels were associated with greater apparent sadness, concentration difficulties, and reduced sleep, but lower levels of anhedonia, less reduced appetite, less lassitude, lower inner tension, and lower suicidality. Mediation analyses indicated that anhedonia mediated the association between LPS levels and depression severity. Conclusions: Higher circulating LPS may characterize a biologically distinct subgroup of MDD patients with lower symptom severity and less anhedonia, supporting biological heterogeneity within MDD.

Background: Major depressive disorder (MDD) lacks established biological markers, although immune dysregulation and gut-derived inflammation have been implicated in a subset of patients; however, their diagnostic utility across levels of depression severity and impact of psychotropic treatment remain unclear. Methods: This cross-sectional study examined circulating lipopolysaccharide (LPS) and cytokines (TNF-α, IL-6, IL-10, IFN-γ) in 95 patients with MDD and 51 healthy controls (HC), evaluating their diagnostic utility across depression severity and the influence of psychotropic medication. Depression severity was assessed using the Montgomery–Åsberg Depression Rating Scale, with patients stratified into mild-to-moderate and severe groups. Results: Compared with HC, patients with MDD showed elevated LPS and TNF-α levels and reduced IL-10, while IL-6 and IFN-γ did not differ. LPS elevation was specific to mild-to-moderate MDD, whereas TNF-α was consistently elevated across all severity levels. A combined model including LPS, TNF-α, and IL-10 demonstrated the highest diagnostic accuracy for MDD (AUC = 0.778) and mild-to-moderate MDD (AUC = 0.818). TNF-α alone was the strongest predictor of severe MDD (AUC = 0.677), while LPS alone distinguished mild-to-moderate from severe MDD (AUC = 0.679). These associations remained significant after adjusting for age, sex, BMI, smoking status, and psychotropic medication use. LPS levels were higher in mild-to-moderate MDD during antidepressant monotherapy and lower with combination therapy regardless of severity. Conclusions: Mild-to-moderate MDD is associated with elevated LPS, reflecting gut-derived inflammation and a distinct subtype, whereas severe MDD is linked to TNF-α. These biomarkers may aid in distinguishing MDD subtypes and inform targeted therapeutic strategies.