Hippocampal pituitary adenylate cyclase-activating polypeptide mediates rapid antidepressant-like effects of Yueju pill.

Yueju pill, a classic Chinese Medicine formulated, was recently found to produce rapid antidepressant-like effects in a PKA-CREB signaling-dependent manner. In our study, we found that the Yueju pill induced a remarkable increase in PACAP. The intracerebroventricular injection of PACAP agonist induced a rapid antidepressant-like effect; conversely, the intrahippocampal infusion of a PACAP antagonist reversed the antidepressant response of the Yueju pill. Mice with hippocampal PACAP knockdown via viral-mediated RNAi displayed depression-like behavior. PACAP knockdown also blunted the antidepressant effect of the Yueju pill. PACAP knockdown resulted in down-regulated CREB and expression of the synaptic protein PSD95 at both baselines and after administration of the Yueju pill. However, administration of the Yueju pill in the knockdown mice promoted PACAP and PKA levels. Chronically stressed mice showed deficient hippocampal PACAP-PKA-CREB signaling and depression-like behavior, which were reversed by a single dose of the Yueju pill. In this study, we demonstrated that the up-regulation of PACAP induced activating of PKA-CREB signaling would play a part in the rapid antidepressant-like effects of the Yueju pill. We also identified iridoids fraction of Gardenia jasminoides Ellis (GJ-IF), a vital component of the Yueju pill, was identified to recapitulate rapid antidepressant-like behavior through increased hippocampal PACAP expression of the Yueju pill. The promotion of hippocampal PACAP may collectively represent a novel mechanism of rapid antidepressant-like effect.

Plasma Levels of Brain-Derived Neurotrophic Factor and S100B in Relation to Antidepressant Response to Ketamine.

BACKGROUND: Evidence demonstrates that brain-derived neurotrophic factor (BDNF) and S100 calcium-binding protein B (S100B) have a pivotal role in the pathogenesis of major depressive disorder (MDD) and they are proposed as predictors of antidepressant response. Ketamine produces rapid antidepressant effects in MDD and pre-clinical studies suggest the necessity of increased BDNF levels for the antidepressant action of ketamine. However, studies observing the change of blood BDNF levels after ketamine intervention are inconsistent and studies about the role of plasma S100B in ketamine administration in MDD patients are lacking. METHOD: We evaluated mature BDNF (mBDNF), S100B levels in plasma and their associations with depression severity in 30 Selective Serotonin Reuptake Inhibitor (SSRI)-resistant MDD patients enrolled in a randomized controlled trial of ketamine compared (n = 20) to a placebo (n = 10) control (saline). Severity of depression was assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS). RESULTS: Plasma mBDNF and S100B were not significantly changed after 1-2 days of single ketamine compared to placebo. Plasma mBDNF and S100B levels did not significantly differ in responders compared to non-responders of ketamine treatment. The change of plasma mBDNF levels was positively correlated with the improvement of MADRS score after 1-2 weeks of open-label ketamine treatment (rho = 0.495, p = 0.031), though this change did not survive correction for multiple comparisons. CONCLUSION: These findings do not support the hypothesis that ketamine treatment increases BDNF plasma levels in MDD patients. No effect of ketamine treatment on S100B plasma levels was seen.

P11 (S100A10) as a potential predictor of ketamine response in patients with SSRI-resistant depression.

BACKGROUND: Ketamine can act as antidepressant in patients with major depressive disorder (MDD) who are treatment-resistant. P11 has been implicated in ketamine's mechanism of action and proposed as biomarker for treatment response to other antidepressants. This study explores the effect of ketamine on peripheral p11 and the potential role for p11 as response marker for ketamine treatment. METHODS: Thirty Selective Serotonin Reuptake Inhibitor resistant MDD patients were randomized to either 0.5 mg/kg ketamine or placebo intravenous treatment. Using multicolor Flow Cytometry, peripheral p11 levels were measured before and 1-2 days after treatment. RESULTS: P11 levels were decreased within the ketamine group in both cytotoxic T cell and T helper cells populations, although this did not significantly differ from changes seen in the placebo group. Baseline p11 levels in cytotoxic T cells were significantly correlated with antidepressant response to ketamine treatment. LIMITATIONS: This study was part of a larger study examining the effect of ketamine on the serotonin system in MDD patients, therefore the number of study subjects was limited to that of the primary study. CONCLUSIONS: High baseline p11 levels in cytotoxic T cells were associated with a stronger reduction of depressive symptoms in MDD patients after ketamine treatment. Future studies should confirm if peripheral p11 levels could be used as a predictor of ketamine treatment response.

P11 deficiency increases stress reactivity along with HPA axis and autonomic hyperresponsiveness.

Patients suffering from mood disorders and anxiety commonly exhibit hypothalamic-pituitary-adrenocortical (HPA) axis and autonomic hyperresponsiveness. A wealth of data using preclinical animal models and human patient samples indicate that p11 deficiency is implicated in depression-like phenotypes. In the present study, we used p11-deficient (p11KO) mice to study potential roles of p11 in stress responsiveness. We measured stress response using behavioral, endocrine, and physiological readouts across early postnatal and adult life. Our data show that p11KO pups respond more strongly to maternal separation than wild-type pups, even though their mothers show no deficits in maternal behavior. Adult p11KO mice display hyperactivity of the HPA axis, which is paralleled by depression- and anxiety-like behaviors. p11 was found to be highly enriched in vasopressinergic cells of the paraventricular nucleus and regulates HPA hyperactivity in a V1B receptor-dependent manner. Moreover, p11KO mice display sympathetic-adrenal-medullary (SAM) axis hyperactivity, with elevated adrenal norepinephrine and epinephrine levels. Using conditional p11KO mice, we demonstrate that this SAM hyperactivity is partially regulated by the loss of p11 in serotonergic neurons of the raphe nuclei. Telemetric electrocardiogram measurements show delayed heart rate recovery in p11KO mice in response to novelty exposure and during expression of fear following auditory trace fear conditioning. Furthermore, p11KO mice have elevated basal heart rate in fear conditioning tests indicating increased autonomic responsiveness. This set of experiments provide strong and versatile evidence that p11 deficiency leads to HPA and SAM axes hyperresponsiveness along with increased stress reactivity.

Shared genetic risk factors for depression and stroke.

BACKGROUND: The comorbidity of major depressive disorder (MDD) and stroke are common in clinic. There is a growing body of evidence suggesting a bi-directional relationship between stroke and depression. However, the mechanisms underlying the relationship between MDD and stroke are poorly investigated. Considering that both MDD and stroke can be heritable and are influenced by multiple risk genes, shared genetic risk factors between MDD and stroke may exist. OBJECTIVE: The objective is to review the existing evidence for common genetic risk factors for both MDD and stroke and to outline the possible pathophysiological mechanisms mediating this association. METHODS: A systematic review and meta-analysis was performed. Gene association studies regarding stroke and depression were searched in the database PubMed, CNKI, and Chinese Biomedical Literature Database before December 2018. Statistical analysis was performed using the software Revman 5.3. RESULTS: Genetic polymorphisms of 4 genes, methylenetetrahydrofolate reductase (MTHFR) and apolipoprotein E (ApoE) have been demonstrated to associate with the increased risk for both MDD and stroke, while the association between identified polymorphisms in angiotensin converting enzyme (ACE) and serum paraoxonase (PON1) with depression is still under debate, for the existing studies are insufficient in sample size. These results suggest the possible pathophysiological mechanisms that are common to these two disorders, including immune-inflammatory imbalance, increased oxidative and nitrative stress, dysregulation of lipoprotein and lipid metabolism, and changes of cerebrovascular morphology and function. Other associated genes with few or conflicting results have also been included, and a few studies have investigated the effects of the described polymorphisms on MDD and stroke comorbidity, such as post stroke depression. CONCLUSION: These findings suggest that shared genetic pathways may contribute to the comorbidity of MDD and stroke. Studies to evaluate the shared genetic variations between MDD and stroke may provide insights into the molecular mechanisms that trigger disease progression.

Serum BICC1 levels are significantly different in various mood disorders.

PURPOSE: Mood disorders are recurrent chronic disorders with fluctuating mood states and energy, and misdiagnosis is common when based solely on clinical interviews because of overlapping symptoms. Because misdiagnosis may lead to inappropriate treatment and poor prognosis, finding an easily implemented objective tool for the discrimination of different mood disorders is very necessary and urgent. However, there has been no accepted objective tool until now. Recently, BICC1 has been identified as a candidate gene relating to major depressive disorder (MDD). Therefore, the aim of this study is to evaluate the ability of serum BICC1 to discriminate between various mood disorders, including MDD and the manic and depressive phases of bipolar disorder, namely bipolar mania (BM) and bipolar depression (BD). PATIENTS AND METHODS: Serum BICC1 levels in drug-free patients with MDD (n=30), BM (n=30), and BD (n=13), and well-matched healthy controls (HC, n=30) were measured with ELISA kits. Pearson correlation analyses were used to analyze the correlations between serum BICC1 levels and clinical information. Receiver operating characteristic (ROC) curve analysis was used to analyze the differential discriminative potential of BICC1 for different mood disorders. RESULTS: One-way ANOVA indicated that serum BICC1 levels were significantly increased in all patient groups compared with the HC group and significantly different between each pair of patient groups. Correlation analyses found no relationship between serum BICC1 levels and any clinical variables in any study group. ROC curve analysis showed that serum BICC1 could discriminate among all three mood disorders from each other accurately with fair-to-excellent discriminatory capacity (area under the ROC curve from 0.787 to 1.0). CONCLUSION: The findings of this preliminary study indicated significant differences in serum BICC1 levels in patients with different mood disorders. This study provides preliminary evidence that serum BICC1 may be regarded as a promising, objective, easy-to-use tool for diagnosing different mood disorders.

Higher serum VGF protein levels discriminate bipolar depression from major depressive disorder.

Misdiagnosis between major depressive disorder (MDD) and bipolar depression (BD) is quite common. Our previous study found significantly lower serum VGF (non-acronymic) in MDD patients. However, it is unclear whether same changes occur in BD patients. Therefore, we aimed to investigate the relationship between serum VGF levels in BD and MDD patients. General information, scores of 17-item Hamilton Depression Rating Scale (HDRS), and fasting blood samples of all participants including 30 MDD patients, 20 BD patients, and 30 healthy controls (HC) were collected. Serum VGF levels were measured by Enzyme-linked immunosorbent assay kits. Pearson correlation analysis was used to analyze correlations between serum VGF levels and clinical information. Receiver operating characteristic (ROC) curve and likelihood ratios (LRs) were used to analyze the differential potential of serum VGF. Serum VGF levels were significantly lower in MDD patients but higher in BD patients compared with HC (both PTukey < 0.01). No correlation was found between serum VGF levels and any data of subjects. The optimal cutoff for serum VGF in discriminating BD patients from MDD patients was ≥1093.85 pg/ml (AUC = 0.990, sensitivity of 95%, specificity of 100% and accuracy of 95%). LRs further confirmed the differential efficiency of serum VGF in distinguishing BD and MDD patients with +LR of infinity and -LR of 0. The results suggest that serum VGF level changed significantly in MDD and BD patients and serum VGF may be an indicator for differentiating BD patients from MDD patients.

Genetic variations in the p11/tPA/BDNF pathway are associated with post stroke depression.

BACKGROUND: The effects of BDNF on post stroke depression (PSD) may be influenced by genetic variations in intracellular signal transduction pathways, such as the p11/tPA/BDNF pathway. In this study, we aimed to determine the association of polymorphisms in candidate genes of the gene transduction pathway with PSD, as well as the effects of the interactions between genes in our Chinese sample. METHODS: Two-hundred-fifty-four Chinese samples with acute ischaemic stroke included 122 PSD patients and 132 nonPSD patients. Sixty-five single nucleotide polymorphisms (SNPs) in six genes (p11, tPA, PAI-1, BDNF, TrkB and p75NTR) of the p11/tPA/BDNF pathway with minor allele frequencies > 5% were successfully genotyped from an initial series of 76 SNPs. The severity of depressive symptoms was assessed by the 17-item Hamilton Depression Rating scale score. Environmental factors were measured with the life events scale and social support rating scale for all patients. SNP and haplotype associations were analysed using gPLINK software. Gene-gene interactions were evaluated with generalized multifactor dimensionality reduction software. RESULTS: The results showed that TrkB polymorphisms (rs11140793AC genotype, rs7047042CG genotype, rs1221CT genotype, rs2277193TC genotype and rs2277192AG genotype) were significantly associated with PSD. Three haplotypes (AT, GG, and AAT) of TrkB were significantly associated with PSD. Seven haplotypes (GC, AG, ACG, CGC, GCT, ACGC and ACAT) of BDNF were significantly correlated with PSD. We identified significant gene-gene interactions between the p11 (rs11204922 SNP), tPA (rs8178895, rs2020918 SNPs) and BDNF (rs6265, rs2049046, rs16917271, rs727155 SNPs) genes in the PSD group. We also identified significant gene-gene interactions between the BDNF (rs2049046, rs7931247 SNPs) and TrkB (rs7816 SNP) genes with increased occurrence of PSD and sig gene-gene interactions between the BDNF gene (rs6265, rs56164415, rs2049046, rs4923468, rs2883187, rs16917271, rs1491850, rs727155, rs2049048 SNPs) and p75NTR gene (rs2072446, rs11466155) in the PSD group. CONCLUSION: These findings provides evidence that the TrkB gene, BDNF and TrkB haplotypes, and gene-gene interactions between p11, tPA and BDNF are all associated with PSD, which suggests that genetic variations in the p11/tPA/BDNF pathway may play a central role in regulating the underlying mechanism of PSD.

A risk prediction model for post-stroke depression in Chinese stroke survivors based on clinical and socio-psychological features.

BACKGROUND: Post-stroke depression (PSD) is a frequent complication that worsens rehabilitation outcomes and patient quality of life. This study developed a risk prediction model for PSD based on patient clinical and socio-psychology features for the early detection of high risk PSD patients. RESULTS: Risk predictors included a history of brain cerebral infarction (odds ratio [OR], 3.84; 95% confidence interval [CI], 2.22-6.70; P < 0.0001) and four socio-psychological factors including Eysenck Personality Questionnaire with Neuroticism/Stability (OR, 1.18; 95% CI, 1.12-1.20; P < 0.0001), life event scale (OR, 0.99; 95% CI, 0.98-0.99; P = 0.0007), 20 items Toronto Alexithymia Scale (OR, 1.06; 95% CI, 1.02-1.10; P = 0.002) and Social Support Rating Scale (OR, 0.91; 95% CI, 0.87-0.90; P < 0.001) in the logistic model. In addition, 11 rules were generated in the tree model. The areas under the curve of the ROC and the accuracy for the tree model were 0.85 and 0.86, respectively. METHODS: This study recruited 562 stroke patients in China who were assessed for demographic data, medical history, vascular risk factors, functional status post-stroke, and socio-psychological factors. Multivariate backward logistic regression was used to extract risk factors for depression in 1-month after stroke. We converted the logistic model to a visible tree model using the decision tree method. Receiver operating characteristic (ROC) was used to evaluate the performance of the model. CONCLUSION: This study provided an effective risk model for PSD and indicated that the socio-psychological factors were important risk factors of PSD.

Combined serum levels of multiple proteins in tPA-BDNF pathway may aid the diagnosis of five mental disorders.

Mental disorders are severe, disabling conditions with unknown etiology and are commonly misdiagnosed when clinical symptomology criteria are solely used. Our previous work indicated that combination of serum levels of multiple proteins in tissue plasminogen activator (tPA)-brain-derived neurotrophic factor (BDNF) pathway improved accuracy of diagnosis of major depressive disorder (MDD). Here, we measured serum levels of tPA, plasminogen activator inhibitor-1 (PAI-1), BDNF, precursor-BDNF (proBDNF), tropomyosin-related kinase B (TrkB) and neurotrophin receptor p75 (p75NTR) in patients with paranoid schizophrenia (SZ, n = 34), MDD (n = 30), bipolar mania (BM, n = 30), bipolar depression (BD, n = 22), panic disorder (PD, n = 30), and healthy controls (HCs, n = 30) by Enzyme-linked immunosorbent assay kits. We used receiver operating characteristic (ROC) curve to analyze diagnostic potential of these proteins. We found, compared with HCs, that serum tPA and proBDNF were lower in SZ, BM and BD; TrkB was lower in SZ and BD; and p75NTR was declined in SZ and BM. ROC analysis showed that combined serum level of tPA, PAI-1, BDNF, proBDNF, TrkB and p75NTR was better than any single protein in accuracy of diagnosis and differentiation, suggesting that the combination of multiple serum proteins levels in tPA-BDNF pathway may have a potential for a diagnostic panel in mental disorders.

The protein and mRNA expression levels of glial cell line-derived neurotrophic factor in post stroke depression and major depressive disorder.

Previous studies have indicated that the level of glial cell line-derived neurotrophic factor (GDNF) may be correlated with stroke and depression. Here, we investigated whether GDNF can be a discriminant indicator for post stroke depression (PSD). 159 participants were divided into four groups: PSD, stroke without depression (Non-PSD), major depressive disorder (MDD) and normal control (NC) group, and the protein and mRNA expression levels of GDNF in serum were measured. The results showed that only MDD group had statistical difference in protein and mRNA levels compared with the other three groups (Bonferroni test, P < 0.05). The results of receiver operating curve (ROC) analysis supported GDNF as general distinguishing models in PSD and MDD groups with the area under the curve (AUC) at 0.797 (P < 0.001) and 0.831 (P < 0.001) respectively. In addition, the Spearman analysis demonstrated that the GDNF protein level negatively correlated with the value of Hamilton depression rating scale (HAMD) in PSD patients (correlation coefficient = -0.328, P = 0.047). Together, these findings suggest the protein and mRNA expression levels of GDNF decreased in patients with depression. GDNF may serve as a potential biomarker for differential diagnosis of PSD from MDD patients.

Reduced serum VGF levels were reversed by antidepressant treatment in depressed patients.

OBJECTIVES: VGF, a non-acronymic neuropeptide, is important in the pathogenesis of major depressive disorder (MDD) and in the functioning and efficacy of some antidepressant drugs. In this study we assessed whether serum VGF levels change in MDD patients and if antidepressant treatments can restore these changes. METHODS: We measured serum VGF concentrations using sandwich ELISA in drug-free MDD patients before treatment began (n = 26) and at 8 weeks after antidepressant treatment (n = 26) with escitalopram and duloxetine, two common antidepressants. The severity of depression was assessed with the 17-item Hamilton Depression Rating Scale (HDRS). RESULTS: VGF serum levels were significantly lower in MDD patients compared to controls (P = .002), even after controlling for the effects of age and education (P = .037), and they were reversed by 8 weeks of drug treatment (P < .0001). Both escitalopram and duloxetine restored the decreased serum VGF levels (P < .05). We observed no correlation between VGF levels and HDRS scores in pre-treatment MDD patients (P = .879). CONCLUSIONS: The results suggest that VGF may be implicated in the pathophysiology of MDD and in the mechanisms underlying the action of antidepressants, and serum VGF may be regarded as a trait parameter for MDD.

Towards a multi protein and mRNA expression of biological predictive and distinguish model for post stroke depression.

Previous studies suggest that neurotrophic factors participate in the development of stroke and depression. So we investigated the utility of these biomarkers as predictive and distinguish model for post stroke depression (PSD). 159 individuals including PSD, stroke without depression (Non-PSD), major depressive disorder (MDD) and normal control groups were recruited and examined the protein and mRNA expression levels of vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptors (VEGFR2), placental growth factor (PIGF), insulin-like growth factor (IGF-1) and insulin-like growth factor receptors (IGF-1R). The chi-square test was used to evaluate categorical variable, while nonparametric test and one-way analysis of variance were applied to continuous variables of general characteristics, clinical and biological changes. In order to explore the predictive and distinguish role of these factors in PSD, discriminant analysis and receiver operating characteristic curve were calculated. The four groups had statistical differences in these neurotrophic factors (all P < 0.05) except VEGF concentration and IGF-1R mRNA (P = 0.776, P = 0.102 respectively). We identified these mRNA expression and protein analytes with general predictive performance for PSD and Non-PSD groups [area under the curve (AUC): 0.805, 95% CI, 0.704-0.907, P < 0.001]. Importantly, there is an excellent predictive performance (AUC: 0.984, 95% CI, 0.964-1.000, P < 0.001) to differentiate PSD patients from MDD patients. This was the first study to explore the changes of neurotrophic factors family in PSD patients, the results intriguingly demonstrated that the combination of protein and mRNA expression of biological factors could use as a predictive and discriminant model for PSD.

Plasminogen Activator Inhibitor-1 in depression: Results from Animal and Clinical Studies.

Evidence suggests that plasminogen activator inhibitor-1 (PAI-1) is a stress-related factor, and serum PAI-1 levels are increased in patients with major depressive disorders (MDD). Herein, we analysed PAI-1 protein levels in the brain, cerebrospinal fluid (CSF) and serum of rodents exposed to chronic unpredictable mild stress or treated with escitalopram. In addition, we examined PAI-1 concentrations in serum obtained from 17 drug-free depressed patients before and after escitalopram treatment. We found that PAI-1 expression was increased in area 1 of the cingulate cortex and prelimbic cortex of the medial prefrontal cortex as well as in the hippocampal cornu ammonis 3 and dentate gyrus in stressed rats. A downregulation of PAI-1 following chronic escitalopram treatment was also found. PAI-1 levels were higher in the CSF and serum in stressed rats than in controls, although the difference did not reach statistical significance in the serum. Escitalopram treatment significantly decreased PAI-1 levels in the serum, but not in the CSF. MDD patients had significantly greater serum PAI-1 concentrations than controls. Our results suggest that PAI-1 is implicated in the pathophysiology of depression.

The Role of Neuropeptide Y mRNA Expression Level in Distinguishing Different Types of Depression.

Previous studies demonstrate that the protein of neuropeptide Y (NPY) is abnormal in depression patients, but the changes of NPY in different types of depression are unclear. This study was aimed to examine protein and mRNA expression levels of NPY in 159 cases with four groups including post-stroke depression (PSD) group, stroke without depression (Non-PSD) group, major depressive disorder (MDD) group and normal control (NC) group. The protein and gene expression analysis were performed by enzyme-linked immunosorbent assay (ELISA) and quantitative polymerase chain reaction-based methods. One way analysis of variance (ANOVA), chi-square tests and nonparametric test were used to evaluate general characteristics, clinical and biological materials. In order to explore the role of NPY in different types of depression, the partial correlations, binary logistic regression analysis and receiver operating characteristic (ROC) curve were calculated for PSD and MDD groups. There are significant differences of NPY protein (Fdf(3) = 5.167, P = 0.002) and mRNA expression levels ([Formula: see text] = 20.541, P < 0.001) among four groups. Bonferroni multiple comparisons found that the NPY protein was significantly decreased in PSD (FBonferroni = -7.133, P = 0.002) and Non-PSD group (FBonferroni = -5.612, P = 0.018) compared with NC group. However, contrasted with MDD group, the mRNA expression was increased in PSD and Non-PSD group by nonparametric test (all P < 0.05). In binary logistic analyses, NPY mRNA expression was independent predictors of PSD (odds ratio: 1.452, 95% CI, 1.081-1.951, P = 0.013). The ROC curve showed NPY mRNA had a general prognostic accuracy (area under the curve: 0.766, 95% CI, 0.656-0.876, P < 0.001). This is the first study to explore the distinguishing function of NPY in different types of depression. It will provide help in the identification of different subtypes of depression.