Untargeted Plasma Metabolomic Profiling in Patients with Depressive Disorders: A Preliminary Study.

Depressive disorder is a multifactorial disease that is based on dysfunctions in mental and biological processes. The search for biomarkers can improve its diagnosis, personalize therapy, and lead to a deep understanding of the biochemical processes underlying depression. The purpose of this work was a metabolomic analysis of blood serum to classify patients with depressive disorders and healthy individuals using Compound Discoverer software. Using high-resolution mass spectrometry, blood plasma samples from 60 people were analyzed, of which 30 were included in a comparison group (healthy donors), and 30 were patients with a depressive episode (F32.11) and recurrent depressive disorder (F33.11). Differences between patient and control groups were identified using the built-in utilities in Compound Discoverer software. Compounds were identified by their accurate mass and fragment patterns using the mzCloud database and tentatively identified by their exact mass using the ChemSpider search engine and the KEGG, ChEBI, FDA UNII-NLM, Human Metabolome and LipidMAPS databases. We identified 18 metabolites that could divide patients with depressive disorders from healthy donors. Of these, only two compounds were tentatively identified using the mzCloud database (betaine and piperine) based on their fragmentation spectra. For three compounds ((4S,5S,8S,10R)-4,5,8-trihydroxy-10-methyl-3,4,5,8,9,10-hexahydro-2H-oxecin-2-one, (2E,4E)-N-(2-hydroxy-2-methylpropyl)-2,4-tetradecadienamide and 17α-methyl-androstan-3-hydroxyimine-17ß-ol), matches were found in the mzCloud database but with low score, which could not serve as reliable evidence of their structure. Another 13 compounds were identified by their exact mass in the ChemSpider database, 9 (g-butyrobetaine, 6-diazonio-5-oxo-L-norleucine, 11-aminoundecanoic acid, methyl N-acetyl-2-diazonionorleucinate, glycyl-glycyl-argininal, dilaurylmethylamine, 12-ketodeoxycholic acid, dicetylamine, 1-linoleoyl-2-hydroxy-sn-glycero-3-PC) had only molecular formulas proposed, and 4 were unidentified. Thus, the use of Compound Discoverer software alone was not sufficient to identify all revealed metabolites. Nevertheless, the combination of the found metabolites made it possible to divide patients with depressive disorders from healthy donors.

Serum Levels of S100B Protein and Myelin Basic Protein as a Potential Biomarkers of Recurrent Depressive Disorders.

Nowadays, nervous tissue damage proteins in serum are considered promising drug targets and biomarkers of Mood Disorders. In a cross-sectional naturalistic study, the S100B, MBP and GFAP levels in the blood serum were compared between two diagnostic groups (patients with Depressive Episode (DE, n = 28) and patients with Recurrent Depressive Disorder (RDD, n = 21)), and healthy controls (n = 25). The diagnostic value of serum markers was assessed by ROC analysis. In the DE group, we did not find changed levels of S100B, MBP and GFAP compared with controls. In the RDD group, we found decreased S100B level (p = 0.011) and increased MBP level (p = 0.015) in comparison to those in healthy controls. Provided ROC analysis indicates that MBP contributes to the development of a DE (AUC = 0.676; 95%Cl 0.525-0.826; p = 0.028), and S100B and MBP have a significant effect on the development of RDD (AUC = 0.732; 95%Cl 0.560-0.903; p = 0.013 and AUC = 0.712; 95%Cl 0.557-0.867; p = 0.015, correspondingly). The study of serum markers of nervous tissue damage in patients with a current DE indicates signs of disintegration of structural and functional relationships, dysfunction of gliotransmission, and impaired secretion of neurospecific proteins. Modified functions of astrocytes and oligodendrocytes are implicated in the pathophysiology of RDD.

Association of Single Nucleotide Polymorphisms of Cytokine Genes with Depression, Schizophrenia and Bipolar Disorder.

Immune gene variants are known to be associated with the risk of psychiatric disorders, their clinical manifestations, and their response to therapy. This narrative review summarizes the current literature over the past decade on the association of polymorphic variants of cytokine genes with risk, severity, and response to treatment for severe mental disorders such as bipolar disorder, depression, and schizophrenia. A search of literature in databases was carried out using keywords related to depressive disorder, bipolar disorder, schizophrenia, inflammation, and cytokines. Gene lists were extracted from publications to identify common genes and pathways for these mental disorders. Associations between polymorphic variants of the IL1B, IL6, and TNFA genes were the most replicated and relevant in depression. Polymorphic variants of the IL1B, IL6, IL6R, IL10, IL17A, and TNFA genes have been associated with schizophrenia. Bipolar disorder has mainly been associated with polymorphic variants of the IL1B gene. Interestingly, the IL6R gene polymorphism (rs2228145) was associated with all three diseases. Some cytokine genes have also been associated with clinical presentation and response to pharmacotherapy. There is also evidence that some specific polymorphic variants may affect the expression of cytokine genes. Thus, the data from this review indicate a link between neuroinflammation and severe mental disorders.

Cytokine level in patients with mood disorder, alcohol use disorder and their comorbidity.

OBJECTIVES: Because alcohol use disorder (AUD) is often accompanied by mood disorder (MD) and both alcoholism and depression result in activation of the immune system, this study compares serum cytokine levels in the presence of co-morbidity with those in either AUD or MD alone. METHODS: In this naturalistic prospective study the levels of 15 different cytokines were measured in serum samples of patients with MD (n = 43), participants with combined AUD-MD (n = 44) and AUD without MD (n = 42). The levels were compared cross-sectionally among themselves and with those in 50 healthy volunteers. RESULTS: Pro-inflammatory IFN-2α levels were consistently significantly higher and anti-inflammatory IL-1RA significantly lower in all study groups in comparison to healthy volunteers. In the MD only group we found increased IL-6 (p = 0.001), IL-7 (p = 0.001) and IL-13 (p = 0.006) levels, and decreased TNFα (p = 0.0001), IL-1RA (p = 0.012), IL-10 (p = 0.002) compared with group MD + AUD. Patients with AUD only showed elevated levels of IL-1ß (p = 0.046), IL-2 (p = 0.004), IL-7 (p = 0.0001), IL-4 (p = 0.049) and IL-13 (p = 0.015) in contrast with MD + AUD group. CONCLUSIONS: Because the interactions of alcohol with peripheral and cerebral immune systems are multifaceted, the pertinent connection to the mechanism how alcohol consumption contributes to the development of mood disorders cannot be properly explored.

Beta-Endorphin and Oxytocin in Patients with Alcohol Use Disorder and Comorbid Depression.

BACKGROUND: The neuropeptides ß-endorphin and oxytocin are released into the bloodstream as hormones from the pituitary gland but also have an important function as neuroregulators in the forebrain. The blood levels of both polypeptides have been shown to reflect depressive symptoms. ß-Endorphin, in particular, is also involved in abstinence from alcohol. METHODS: The serum levels of ß-endorphin and oxytocin were measured during the early withdrawal phase in patients with alcohol use disorder (AUD) with (N = 35) or without (N = 45) depressive comorbidity and compared with those in healthy volunteers (N = 23). In addition to comparing the groups, the study examined whether serum levels correlated with various psychometric measures of dependence, depression and aggression, as well as with clinical characteristics of dependence. RESULTS: Both serum levels of beta-endorphin and oxytocin were significantly lower in patients than those in healthy controls (p = 0.011 for ß-endorphin and p = 0.005 for oxytocin, Kruskal-Wallis test). In patients with depressive comorbidity, the significance was greatest (p = 0.005 for ß-endorphin and p = 0.004 for oxytocin, U-test). There was no correlation with clinical or psychometric parameters (p > 0.05, Spearman test), but beta-endorphin levels did correlate significantly with physical aggression (p = 0.026, Spearman test). CONCLUSIONS: Serum levels of ß-endorphin and oxytocin are lower in patients with AUD, particularly in those with depressive comorbidity. ß-Endorphin levels correlated with physical aggression according to the Buss-Durkee (BDHI) estimates.

Serum BDNF's Role as a Biomarker for Motor Training in the Context of AR-Based Rehabilitation after Ischemic Stroke.

BACKGROUND: brain-derived neurotrophic factor (BDNF) may play a role during neurorehabilitation following ischemic stroke. This study aimed to elucidate the possible role of BDNF during early recovery from ischemic stroke assisted by motor training. METHODS: fifty patients were included after acute recovery from ischemic stroke: 21 first received classical rehabilitation followed by 'motor rehabilitation using motion sensors and augmented reality' (AR-rehabilitation), 14 only received AR-rehabilitation, and 15 were only observed. Serum BDNF levels were measured on the first day of stroke, on the 14th day, before AR-based rehabilitation (median, 45th day), and after the AR-based rehabilitation (median, 82nd day). Motor impairment was quantified clinically using the Fugl-Meyer scale (FMA); functional disability and activities of daily living (ADL) were measured using the Modified Rankin Scale (mRS). For comparison, serum BDNF was measured in 50 healthy individuals. RESULTS: BDNF levels were found to significantly increase during the phase with AR-based rehabilitation. The pattern of the sequentially measured BDNF levels was similar in the treated patients. Untreated patients had significantly lower BDNF levels at the endpoint. CONCLUSIONS: the fluctuations of BDNF levels are not consistently related to motor improvement but seem to react to active treatment. Without active rehabilitation treatment, BDNF tends to decrease.

Exploring Brain Derived Neurotrophic Factor and Cell Adhesion Molecules as Biomarkers for the Transdiagnostic Symptom Anhedonia in Alcohol Use Disorder and Comorbid Depression.

BACKGROUND: Alcohol Use Disorder (AUD) and depressive disorder often co-exist and have a shared heritability. This study aimed to investigate Brain-Derived Neurotrophic Factor (BDNF) and three Cell Adhesion Molecules (CAMs) as transdiagnostic biomarkers in AUD and depression co-morbidity. METHODS: In a cross-sectional study, patients with AUD (n=22), AUD and depression (n=19), and healthy controls (n=20) were examined. Depression and anxiety severity were assessed using the Hamilton Depression Rating Scale and the Hamilton Anxiety Rating Scale. Anhedonia, alcohol use and dependence, craving, and social adaptation were assessed through self-report questionnaires. BDNF and CAM concentrations in peripheral serum were measured after overnight fasting using a Luminex assay. After controlling for age and gender, biomarker levels were compared across groups. The association between biomarker concentrations and symptom severity scales were explored using correlation and multiple regression analyses. RESULTS: BDNF and Neuronal CAM were lower in patients with AUD with and without depression compared to healthy controls. No differences were observed for Vascular CAM-1 and Interstitial CAM-1. BDNF correlated negatively with anhedonia levels. BDNF, age and gender together explained 21% of variability in anhedonia levels. CONCLUSION: This pilot study suggests that peripheral levels of BDNF and NCAM might be reduced in AUD with and without comorbid mood disorder. Since low BDNF levels were associated with self- reported anhedonia across these conditions, BDNF and anhedonia might reflect transdiagnostic aspects involved in AUD and depression.

Association Between BDNF Gene Variant Rs6265 and the Severity of Depression in Antidepressant Treatment-Free Depressed Patients.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) plays an important role in neuronal plasticity, and its dysregulation has been associated with the pathogenesis of mood and anxiety disorders. Prolactin (PRL) is a pituitary hormone which is also produced as a cytokine by immune cells and could be a neurotrophic factor regulating the functional activity of stress-related mechanisms. AIM: To investigate the possible relationship between depressive state and BDNF and PRL genotypes or levels with special reference to severity of depression. METHODS: Participants of 18-70 years with a clinical diagnosis of depressive disorder of at least moderate severity were included. These patients had not been treated with antidepressant drugs before admission to hospital during the preceding period of the last 6 months, and 54.5% had never been treated with antidepressant drugs during their entire life. The DNA was genotyped for rs1341239 within the prolactin and for rs6265, rs7124442, and rs11030104 within the BDNF gene. Rs11030104 violated the Hardy-Weinberg equilibrium distribution and was excluded from further analyses. BDNF and prolactin concentration was measured in serum by MAGPIX multiplex analyzer (Luminex, USA) using MILLIPLEX® MAP kit (Merck, Germany). Genetic associations were determined by sequentially regressing prolactin, BDNF, 17-items Hamilton's Depression (HAMD-17) and Clinical Global Impression scale, Severity (CGI-S) ratings, and depression (absent/present) on the available SNPs. Genetic associations were evaluated assuming an additive model. RESULTS: A total of 186 depressed patients (of which 169 were women) and 94 healthy controls (67 women) were genotyped. After excluding subjects without genetic information on all three study SNPs, 217 remained of whom 138 suffered from depression. Within depressed patients we observed an association of rs6265 with HAMD-17: mean difference (MD) 2.33 (95%CI 0.49; 4.16; p = 0.014) and CGI-S: MD 0.38 (95%CI 0.09; 0.66; p = 0.011). No significant association was observed between the prolactin SNP rs1341239 and prolactin levels. Similarly the mean differences of BDNF SNPs did not show an association with BDNF: rs6265 -0.042 ln(pg/ml) (95%CI -0.198; 0.113), and rs7124442 0.006 ln(pg/ml) (95%CI -0.117; 0.130). No other association reached statistical significance. CONCLUSION: We observed a significant association between BDNF gene variant rs6265 and the severity of depression in newly admitted, antidepressant treatment-free, depressed patients. Actual PRL and BDNF levels were not elevated sufficiently in depressed patients to reach statistical significance and were not associated with the studied genotypes.

Investigating the potential role of BDNF and PRL genotypes on antidepressant response in depression patients: A prospective inception cohort study in treatment-free patients.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) is associated with response to antidepressant drugs in mood and anxiety disorders. Prolactin (PRL) is a pituitary hormone with behavioural effects, acting as a neurotrophic factor within the brain and may be involved in antidepressant response. OBJECTIVES: To investigate the relationship between BDNF and PRL genotypes with antidepressant drug response. METHODS: Prospective inception cohort of 186 Russian treatment-free participants (28 men and 158 women) between 18 and 70 years clinically diagnosed with depressive disorder who initiated antidepressant medication. DNA polymorphisms were genotyped for PRL rs1341239, BDNF rs6265 and rs7124442. Primary outcome was measured by differences in Hamilton Depression Rating Scale (∆HAM-D) scores between baseline/week two, week two/week four, and baseline/week four. Linear regression and independent t-test determined the significance between polymorphisms and ∆HAM-D. RESULTS: Comparisons between genotypes did not reveal any significant differences in scores during the first two weeks of treatment. In the latter two weeks, BDNF rs7124442 homozygous C patients responded significantly worse in comparison to homozygous T patients during this period. Further analysis within women and in post-menopausal women found a similar comparison between alleles. LIMITATIONS: Study lasted four weeks, which may be considered short to associate genuine antidepressant effects. CONCLUSIONS: Patients taking tricylic antidepressants were noted to have a significant improvement in ∆HAM-D compared to patients taking SSRIs. Homozygous C BDNF rs712442 patients were found to respond significantly worse in the last two weeks of treatment.