A Study of Individualized Diagnosis and Treatment for Depression with Atypical Features (iDoT-AFD): study protocol for a randomized clinical trial and prognosis study.

BACKGROUND: Major depressive disorder (MDD) with atypical features, namely depression with atypical features (AFD), is one of the most common clinical specifiers of MDD, closely associated with bipolar disorder (BD). However, there is still a lack of clinical guidelines for the diagnosis, treatment, and prognosis of AFD. Our study mainly focuses on three issues about how to identify AFD, what is the appropriate individualized treatment for AFD, and what are the predictive biomarkers of conversion to BD. METHODS: The Study of Individualized Diagnosis and Treatment for Depression with Atypical Features (iDoT-AFD) is a multicenter, prospective, open-label study consisting of a 12-week randomized controlled trial (RCT) and a continued follow-up until 4 years or reaching the study endpoint. It is enrolling 480 patients with AFD (120 per treatment arm), 100 patients with BD, and 100 healthy controls (HC). Multivariate dimension information is collected including clinical features, cognitive function, kynurenine pathway metabolomics, and multimodal magnetic resonance imaging (MRI) data. Firstly, multivariate informatics analyses are performed to recognize patients with AFD from participants including the first-episode and recurrent atypical depression, patients with BD, and patients with HC. Secondly, patients with atypical depression are randomly allocated to one of the four treatment groups including "single application of selective serotonin reuptake inhibitor (SSRI) or serotonin-noradrenaline reuptake inhibitor (SNRI)", "SSRI/SNRI combined with mood stabilizer," "SSRI/SNRI combined with quetiapine (≥ 150 mg/day)," or "treatment as usual (TAU)" and then followed up 12 weeks to find out the optimized treatment strategies. Thirdly, patients with atypical depression are followed up until 4 years or switching to BD, to explore the risk factors of conversion from atypical depression to BD and eventually build the risk warning model of conversion to BD. DISCUSSION: The first enrolment was in August 2019. The iDoT-AFD study explores the clinical and biological markers for the diagnosis, treatment, and prognosis of AFD and further provides evidence for clinical guidelines of AFD. TRIAL REGISTRATION: ClinicalTrials.gov NCT04209166. Registered on December 19, 2019.

Differences in cognitive functions of atypical and non-atypical depression based on propensity score matching.

BACKGROUND: Clinical and etiological heterogeneity have hindered our understanding of depression, thus driving the studies of major depressive disorder (MDD) subtypes. Atypical depression (AD) is a subtype of MDD with atypical features. Cognitive impairment is one of the factors that contribute to the suffering of patients with MDD. Therefore, this study investigated the characteristics and differences in cognitive functioning of AD and non-atypical depression (non-AD) using the MATRICS Consensus Cognitive Battery (MCCB). METHODS: A total of 101 patients with AD and 252 patients with non-AD were assessed with the MCCB and clinical scales. Propensity score matching (PSM) was used to balance confounders between groups. After PSM, between-group differences were compared for cognitive and clinical variables. In addition, multiple linear regression analyses were performed to explore the effects of cognitive and clinical variables on the quality of life. RESULTS: The AD group scored significantly lower in attention/vigilance and social cognition in all cognitive domains than the non-AD group. Attention/vigilance and social cognition were significant positive predictors of quality of life, whereas atypical symptoms and depressive severity were significant negative predictors. CONCLUSIONS: This study suggests significant differences in cognitive functions between the AD and non-AD subtypes. Atypical symptoms and impaired cognition have a negative impact on patients' quality of life. Attention/vigilance and social cognition are worse in AD than non-AD, which the atypical features of patients with AD may explain. The pathological mechanisms and treatment strategies of AD should be further explored in the future to promote individualized treatment strategies.

PAID study design on the role of PKC activation in immune/inflammation-related depression: a randomised placebo-controlled trial protocol.

BACKGROUND: Inflammation that is mediated by microglia activation plays an important role in the pathogenesis of depression. Microglia activation can lead to an increase in the levels of proinflammatory cytokines, including TNF-α, which leads to neuronal apoptosis in the specific neural circuits of some brain regions, abnormal cognition and treatment-resistant depression (TRD). Protein kinase C (PKC) is a key regulator of the microglia activation process. We assume that the abnormality in PKC might result in abnormal microglia activation, neuronal apoptosis, significant changes in emotional and cognitive neural circuits, and TRD. In the current study, we plan to target at the PKC signal pathway to improve the TRD treatment outcome. METHODS AND ANALYSIS: This is a 12-week, ongoing, randomised, placebo-controlled trial. Patients with TRD (N=180) were recruited from Shanghai Mental Health Center, Shanghai Jiao Tong University. Healthy control volunteers (N=60) were recruited by advertisement. Patients with TRD were randomly assigned to 'escitalopram+golimumab (TNF-α inhibitor)', 'escitalopram+calcium tablet+vitamin D (PKC activator)' or 'escitalopram+placebo' groups. We define the primary outcome as changes in the 17-item Hamilton Depression Rating Scale (HAMD-17). The secondary outcome is defined as changes in anti-inflammatory effects, cognitive function and quality of life. DISCUSSION: This study might be the first randomised, placebo-controlled trial to target at the PKC signal pathway in patients with TRD. Our study might help to propose individualised treatment strategies for depression. TRIAL REGISTRATION NUMBER: The trial protocol is registered with ClinicalTrials.gov under protocol ID 81930033 and ClinicalTrials.gov ID NCT04156425.

Hypothalamic-Pituitary-End-Organ Axes: Hormone Function in Female Patients with Major Depressive Disorder.

Classic hypothalamic-pituitary-end-organ feedback loops - the hypothalamic-pituitary-adrenal axis (HPAA), hypothalamic-pituitary-thyroidal axis (HPTA), and hypothalamic-pituitary-gonadal axis (HPGA) - are associated with the neuroendocrine and immune systems in major depressive disorder (MDD). Female patients with MDD present with evident neuroendocrine and immunological changes. Glucocorticoid, thyroid hormone, and reproductive steroid levels fluctuate with menstrual cycles, which might lead to glucocorticoid receptor resistance, impairment of triiodothyronine conversion, and sex hormone secretion disorders. In this review, we summarize the independent and interactive functions of these three axes in female MDD patients. The similar molecular structure of steroids implies an interrelationship between the hypothalamic-pituitary-end-organ axes and the competitive inhibitory effects at the receptor level, especially when considering the HPAA and HPGA.

Neural biomarker of functional disability in major depressive disorder: A structural neuroimaging study.

BACKGROUND: Most patients with the major depressive disorder (MDD) have varying degrees of impaired social functioning, and functional improvement often lags behind symptomatic improvement. However, it is still unclear if certain neurobiological factors underlie the deficits of social function in MDD. The aim of this study was to investigate the biomarkers of social function in MDD using structural magnetic resonance imaging (MRI). METHODS: 3T anatomical MRI was obtained from 272 subjects including 46 high-functioning (high-SF, Sheehan Disability Scale (SDS) rating < 18) and 63 low-functioning (low-SF, SDS score ≥ 18) patients with MDD and 163 healthy controls (HC). Voxel-based morphometry (VBM) was employed to locate brain regions with grey matter (GM) volume differences in relation to social function in MDD. Regions showing GM differences in relation to social function at baseline were followed up longitudinally in a subset of 38 patients scanned after 12-week treatment. RESULTS: Volume of right parahippocampal gyrus (rPHG) was significantly reduced in low-SF patients with MDD when compared to high-SF ones (FDR-corrected p < 0.05). Over 12 weeks of follow-up, though SF improved overall, the high and low-SF subgroups continued to differ in their SF, but had no progressive changes in PHG volume. LIMITATIONS: Limited functional assessment, high drop-out rate and median-based grouping method. CONCLUSIONS: Greater GM volume (GMV) of the rPHG may mark better social function in patients with MDD.

Exploring the Effects of Temperament on Gray Matter Volume of Frontal Cortex in Patients with Mood Disorders.

BACKGROUND: Patients with bipolar disorder (BD) and patients with major depressive disorder (MDD) have relatively specific temperament and structural abnormalities of brain regions related to emotion and cognition. However, the effects of temperament factors on the structure of frontal and temporal cortex is still unclear. The aims of this study were to explore the differences and relationships between temperament characteristics and the gray matter volume of frontal and temporal cortex in patients with BD or MDD. METHODS: T1-weighted magnetic resonance imaging (MRI) data, demographic and clinical information were obtained from 279 depressed patients (90 patients with BD, 189 patients with MDD) and 162 healthy controls (HC). Temperament was assessed with the Chinese short version of Temperament Evaluation of Memphis, Pisa and San Diego - Auto questionnaire (TEMPS-A). The Desikan-Killiany atlas was used for yielding gray matter volume by FreeSurfer 6.0 software suite. A total of 22 frontal and temporal regions were chosen as regions of interest (ROIs). RESULTS: Compared with patients with MDD, patients with BD had higher TEMPS-A total scores and scores on cyclothymic, irritable and hyperthymic subscales. The gray matter volume in bilateral rostral middle frontal gyrus (RMFG), left temporal pole and right superior frontal gyrus were reduced in patients with BD. Patients with MDD only had lower gray matter volume in bilateral temporal pole. In the pooled patients, there were negative associations between hyperthymia and gray matter volume in right RMFG. CONCLUSION: Patients with BD and MDD had different temperament characteristics. The prominent temperament subscales in patients with BD were cyclothymia, irritable and hyperthymia. Patients with greater hyperthymia had lower gray matter volume in right frontal gyrus. Temperament may reflect an endophenotype in patients with mood disorders, especially in BD.

Probing the clinical and brain structural boundaries of bipolar and major depressive disorder.

Bipolar disorder (BD) and major depressive disorder (MDD) have both common and distinct clinical features, that pose both conceptual challenges in terms of their diagnostic boundaries and practical difficulties in optimizing treatment. Multivariate machine learning techniques offer new avenues for exploring these boundaries based on clinical neuroanatomical features. Brain structural data were obtained at 3 T from a sample of 90 patients with BD, 189 patients with MDD, and 162 healthy individuals. We applied sparse partial least squares discriminant analysis (s-PLS-DA) to identify clinical and brain structural features that may discriminate between the two clinical groups, and heterogeneity through discriminative analysis (HYDRA) to detect patient subgroups with reference to healthy individuals. Two clinical dimensions differentiated BD from MDD (area under the curve: 0.76, P < 0.001); one dimension emphasized disease severity as well as irritability, agitation, anxiety and flight of ideas and the other emphasized mostly elevated mood. Brain structural features could not distinguish between the two disorders. HYDRA classified patients in two clusters that differed in global and regional cortical thickness, the distribution proportion of BD and MDD and positive family history of psychiatric disorders. Clinical features remain the most reliable discriminant attributed of BD and MDD depression. The brain structural findings suggests that biological partitions of patients with mood disorders are likely to lead to the identification of subgroups, that transcend current diagnostic divisions into BD and MDD and are more likely to be aligned with underlying genetic variation. These results set the foundation for future studies to enhance our understanding of brain-behavior relationships in mood disorders.

Altered resting-state fMRI signals and network topological properties of bipolar depression patients with anxiety symptoms.

BACKGROUND: This study aims to explore the changes in functional neuroimaging in bipolar depression patients with anxiety symptoms (BDP-A). METHODS: Forty-five BDP-A patients, 22 bipolar depression patients without anxiety symptoms (BDP-NA), and 48 healthy controls (HC) were finally involved. The low-frequency oscillation characteristics, functional connectivity (FC), and network properties among the three groups of participants were analyzed. RESULTS: Compared with the BDP-NA group, BDP-A patients exhibited significantly decreased amplitude of low-frequency fluctuation (ALFF) in the left middle frontal gyrus (MFG), superior occipital gyrus, and inferior parietal, but supramarginal and angular gyri (IPL). Enhanced FC from left IPL to middle temporal gyrus, from left precentral gyrus (PreCG) to bilateral angular gyri, medial superior frontal gyrus, and left superior frontal gyrus (SFG)/MFG were also revealed. Compared with HC, the BDP-A group showed remarkably increased ALFF in the left MFG/PreCG, right superior parietal gyrus, while decreased ALFF in the left inferior frontal gyrus, opercular part, and SFG. In addition, higher regional homogeneity in the left MFG/PreCG was found. LIMITATIONS: The limitations are as follows: (1) relatively small sample size; (2) not all the patients were drug-naive; (3) lack of pure anxiety disorder patients as a controlled group; (4) mental health conditions of HC were not systemic evaluated. CONCLUSIONS: BDP-A patients showed significant differences in resting-state fMRI properties when compared with BDP-NA or HC group. These results may infer the dysfunction of the dorsal attention network, the default network, and the fronto-limbic system as well as disrupted brain network efficiency in BDP-A patients.

Variants in the Upstream Region of the Insulin Receptor Substrate-1 Gene Is Associated with Major Depressive Disorder in the Han Chinese Population.

INTRODUCTION: Major depressive disorder (MDD) is one of the most prevalent and disabling mental disorders, although its underlying genetic mechanism remains unknown. Insulin receptor substrate-1 (IRS-1) is one of the critical downstream molecules in the insulin resistance signaling pathway, linking depression and diabetes. Therefore, we hypothesized that IRS-1 would be a susceptible gene for MDD, and we aimed to examine the genetic association between IRS-1 and MDD. METHODS: This case-control study included 583 patients with MDD and 564 controls, and the genotypic and allelic distributions of the IRS-1 gene's four single nucleotide polymorphisms (SNPs) were detected by TaqMan SNP genotyping technology. Of the 583 patients, 191 underwent a further detailed interview about symptom severity and family history of mental illness. The chi-square or t test was used to analyze the data, and analyses were performed using SPSS19.0 software. RESULTS: A haplotype in the 5'-upstream region of IRS-1 consisting of rs13411764 and rs3820926 was a risk factor of MDD. Patients with a family history of mental illness were more likely to have a GG genotype in rs13411764 and a G-T haplotype containing rs13411714-rs3820926. DISCUSSION: The findings imply that the haplotype consisting of rs13411764 and rs3820926 in the upstream of IRS-1 is a risk factor for MDD. This haplotype could affect IRS-1 expression levels, and it is mostly inherited from parents. Thus, the presence of variants in the upstream region of IRS-1 is a risk factor of MDD, and this study could serve as a convincing reference for further studies.

Effects of tumor necrosis factor-α polymorphism on the brain structural changes of the patients with major depressive disorder.

Single Nucleotide Polymorphic (SNP) variations of proinflammatory cytokines such as Tumor Necrosis Factor-α (TNF-α) have been reported to be closely associated with the major depressive disorder (MDD). However, it is unclear if proinflammatory genetic burden adversely affects the regional gray matter volume in patients with MDD. The aim of this study was to test whether rs1799724, an SNP of TNF-α, contributes to the neuroanatomical changes in MDD. In this cross-sectional study, a total of 144 MDD patients and 111 healthy controls (HC) well matched for age, sex and education were recruited from Shanghai Mental Health Center. Voxel-based morphometry (VBM) followed by graph theory based structural covariance analysis was applied to locate diagnosis x genotype interactions. Irrespective of diagnosis, individuals with the high-risk genotype (T-carriers) had reduced volume in left angular gyrus (main effect of genotype). Diagnosis x genotype interaction was exclusively localized to the visual cortex (right superior occipital gyrus). The same region also showed reduced volume in patients with MDD than HC (main effect of diagnosis), with this effect being most pronounced in patients carrying the high-risk genotype. However, neither global nor regional network of structural covariance was found to have group difference. In conclusion, a genetic variation which can increase TNF-α expression selectively affects the anatomy of the visual cortex among the depressed subjects, with no effect on the topographical organization of multiple cortical regions. This supports the notion that anatomical changes in depression are in part influenced by the genetic determinants of inflammatory activity.

Abnormal white matter integrity in Chinese young adults with first-episode medication-free anxious depression: a possible neurological biomarker of subtype major depressive disorder.

BACKGROUND: Almost half of patients with major depressive disorder (MDD) also have clinically meaningful levels of anxiety. Anxious depression is a distinct clinical subtype of MDD, which has poor response to pharmacotherapy; however, the neural mechanisms behind are largely unknown. In the present study, we explored the white matter (WM) integrity traits of anxious depression in first-episode and medication-free (medication-naïve and medication washout) Chinese young adult patients by detecting differences in diffusion tensor imaging (DTI) with the tract-based spatial statistics (TBSS) method. SUBJECTS AND METHODS: DTI was obtained from 39 first-episode, medication-free anxious depressive patients, 45 nonanxious depressive patients, and 50 demographically similar healthy controls. All subjects underwent clinical assessments. TBSS was carried out to investigate the difference in WM integrity among three groups within DTI parameter maps. WM integrity was measured using fractional anisotropy (FA), mean diffusivity, axial diffusivity, and radial diffusivity (RD). The correlations between WM integrity and clinical features were also computed. RESULTS: When compared with nonanxious patients, lower FA values in anxious depressive patients were found in multiple regions of the brain, mainly involving left uncinate fasciculus (UF), superior longitudinal fasciculus (SLF), and forceps major and minor. Higher RD in forceps major and minor and SLF were also detected. The decreased FA values and increased RD values correlated with both anxiety level and depression level in the pooled depressive group. CONCLUSION: The anxious depressive patients had more abnormalities in WM integrity at the early phase than the nonanxious group. Alternations in WM integrity in fiber pathways, including SLF, UF, and forceps major and minor, may play a critical role in the neuropathology of anxious depression and might help to identify anxious MDD from nonanxious MDD. Further study with larger sample size, larger age range, and longitudinal design is needed to confer a robust inference to better understand the dynamic neurological change and neuropathology of WM integrity in anxious MDD.

The association of duration and severity of disease with executive function: Differences between drug-naïve patients with bipolar and unipolar depression.

BACKGROUND: The aims of this study were to investigate the differences in executive function and the relationship with clinical factors between drug-naïve patients with bipolar depression (BDD) and unipolar depression (UPD). METHODS: Drug-naïve patients with BDD, UPD and healthy controls (HC) were recruited (30 cases in each group). All patients were assessed with Hamilton Rating Scale for Anxiety (HAM-A), Hamilton Rating Scale for Depression-17 (HAM-D), and Young Mania Rating Scale (YMRS). Executive function was evaluated by Stroop color-word test (CWT) and Wisconsin Card Sorting Test (WCST). RESULTS: In the BDD group, only the CWT number of missing was higher than HCs (P = 0.047). In the UDP group, CWT number of correct was lower, CWT number of missing was higher, and the WCST indices were worse than the HC group (P < 0.05). The WCST percentage of errors (PE) and percentage of conceptual level responses (PCLR) in the UPD group were worse than the BDD group (P < 0.05). In the BDD group, no correlations between CWT and WCST indices and clinical features were detected after correcting for multiple comparisons (P > 0.05). In the UDP group, the WCST PE, PCLR, number of categories completed (CC), and the percentage of perseverative responses (PPR) were correlated to the number of mood episodes (P < 0.01). LIMITATION: This was a small-sample cross-sectional study. The possibility of UPD transforming to bipolar disorder (BD) in future could not be ruled out. CONCLUSION: Our results suggested only small differences in executive function between drug-naïve patients with BDD and UPD, but in this sample only the UPD group showed differences with HCs. The executive function of drug-naïve BDD patients may be associated with duration of current depressive episode, while for UDP patients executive function indices were significantly correlated with number of mood episodes.

Different levels of pro- and anti-inflammatory cytokines in patients with unipolar and bipolar depression.

BACKGROUND: Immune system dysregulation is critical in the physiopathology of major depressive disorder (MDD) and bipolar disorder (BD). However, it is unclear whether both diseases present the same inflammatory patterns during depressive episodes. We explored the differences in pro- and anti-inflammatory cytokines between unipolar and bipolar depression (BDD) and the trajectory of these cytokines after acute-phase treatment. METHODS: Sixty-four MDD patients, 61 BDD patients, and 62 healthy controls (HCs) were enrolled. We assessed the clinical features and cytokines plasma levels at baseline and week 12. The pro-inflammatory cytokines (IL-6, TNF-α) and anti-inflammatory cytokines (IL-4, IL-13) of all subjects were assessed by multiplexed sandwich ELISA-based quantitative arrays. RESULTS: Before acute-phase treatment, the initial levels of TNF-α and IL-13 were significantly lower in the BDD patients than in the MDD patients. The results demonstrated that there was no relationship between each cytokine level and clinical features of unipolar and bipolar depressions. After 12 weeks, TNF-α, IL-4, and IL-13 levels became lower in MDD patients than in the other two groups regardless of the patients' response to treatment while the levels of TNF-α and IL-4 increased only in the BDD responders. LIMITATIONS: The effects of different drugs on inflammatory cytokines in MDD or BDD could not be explored further due to the relatively small sample size. CONCLUSION: Even within the same depressive states, MDD and BDD patients present different inflammatory features, particularly in regard to pro-inflammatory TNF-α and anti-inflammatory IL-13. In addition, the fluctuations of cytokines induced by medication may provide a hint regarding the prediction of treatment response.

Serum IL-1ra, a novel biomarker predicting olanzapine-induced hypercholesterolemia and hyperleptinemia in schizophrenia.

Olanzapine (OLZ) is efficacious whereas leads to adverse metabolic effects thus lead to higher risk of cardiovascular diseases (CVD) on schizophrenia. Cytokines have been found associated with metabolic disorders. Therefore, pretreatment prediction of OLZ-induced adverse metabolic effects is urgently needed. To investigate if baseline cytokine levels could become biomarkers for pathogenesis of schizophrenia or prediction for OLZ-induced adverse metabolic effects, we recruited 75 participants, including 23 schizophrenia inpatients, who were antipsychotic-free over the past 6 months or first episode and drug-naive and 52 matched health controls, in our prospective cohort study and cross-sectional study. We simultaneously examined 7 serum cytokine levels (IFN-γ, IL-1ra, IL-1ß, IL-8, TNF-α, MCP-1, VEGF) before OLZ treatment by using liquid suspension array technique and obtained clinical correlates at 4-week intervals in total 8 weeks. The psychopathology was assessed with the Positive and Negative Symptom Scale (PANSS). The metabolic parameters were BMI, TG, total cholesterol, LDL, HDL, ApoA1, ApoB, lipoprotein a, fasting glucose, HbA1c, insulin, and leptin. At baseline, IL-1ra and MCP-1 levels in schizophrenia were significantly higher than health controls (t = 4.55, P = 0.0001, t = 3.08 P = 0.003). BMI, fasting insulin, cholesterol, triglyceride, LDL, ApoB and leptin were significantly increased in patients with schizophrenia after 8 weeks of olanzapine treatment. Correlation analysis showed that the baseline IL-1ra level were significantly correlated with the increased levels of cholesterol (P = 0.004), LDL (P = 0.005), ApoB (P = 0.018) and leptin (P = 0.010), but not with the increased BMI, insulin or triglycerides. Further stepwise multiple linear regression analysis indicated that IL-1ra levels prior to treatment remained significantly associated with increased levels of cholesterol, LDL, ApoB and leptin. Above all, higher IL-1ra and MCP-1 levels may be biomarkers indicating pathogenesis of schizophrenia. Higher serum levels of IL-1ra may predict subsequent higher possibility of hypercholesterolemia and hyperleptinemia following OLZ treatment in schizophrenia patients.

Increased ratio of high sensitivity C-reactive protein to interleukin-10 as a potential peripheral biomarker of schizophrenia and aggression.

BACKGROUND: Many studies have indicated that immune dysfunction might be involved in the physiopathology of schizophrenia and aggression. This study aimed to investigate the correlation between high-sensitivity C-reactive protein (hsCRP), interleukin (IL)-10 and clinical characteristics, especially aggression, and to explore the potential role of hsCRP and IL-10 as plasma biomarkers of schizophrenia. METHODS: Forty-one patients with schizophrenia and forty healthy individuals were enrolled. Psychopathological severity and aggression were assessed using the Positive and Negative Syndrome Scale (PANSS) and Modified Overt Aggression Scale (MOAS). Plasma concentrations of hsCRP and IL-10 were assessed by enzyme-linked immunosorbent assay (ELISA). RESULTS: (1) Higher levels of hsCRP (p<0.001), lower levels of logIL-10 (p<0.001) and higher ratio of hsCRP to IL-10 (p<0.001) were observed in the plasma of patients with schizophrenia, compared to healthy controls; (2) ROC (receiver operating characteristic) curve analysis revealed that ratio of hsCRP/IL-10 (predictive value: 0.783, p<0.01; sensitivity: 85.4%; specificity: 67.5%) was more applicable as a biomarker to distinguish patients with schizophrenia from the control group than hsCRP and IL-10 alone (predictive value: 0.718, p<0.01; 0.275, p<0.001, respectively); (3) we found positive correlations between hsCRP and the total score and verbal aggression score of MOAS (r=0.654, p<0.01; r=0.678, p<0.05), and between hsCRP/IL-10 and the total score of MOAS (r=0.636, p<0.01). CONCLUSIONS: Our results suggest the possible function of hsCRP and IL-10 in the pathogenesis of schizophrenia and the possible value of hsCRP/IL-10 as a potential peripheral biomarker of schizophrenia. This finding also suggests a relationship between hsCRP, IL-10 and their ratio with aggression in patients with schizophrenia.

Ratio of mBDNF to proBDNF for Differential Diagnosis of Major Depressive Disorder and Bipolar Depression.

There is a high rate of misdiagnosis between major depressive disorder (MDD) and bipolar disorder (BD) in clinical practice. Our previous work provided suggestive evidence for brain-derived neurotrophic factor (BDNF) in differentiating BD from MDD. In this study, we aimed to investigate the role of mature BDNF (mBDNF) and its precursor (proBDNF) in distinguishing bipolar depression (BP) from MDD during acute depressive episode. A total of 105 participants, including 44 healthy controls, 37 MDD patients and 24 BP patients, were recruited. Enzyme-linked immunosorbent assay kits were applied to measure plasma mBDNF levels and proBDNF levels of all participants. Plasma mBDNF levels were significantly decreased in BP group than those in MDD group (P = 0.001) and healthy controls (P = 0.002). Significantly higher ratio of mBDNF to proBDNF (M/P) at baseline was showed in MDD group than those in BP group as well as in healthy controls (P = 0.000 and P = 0.000, respectively). The optimal model for discriminating BP was the M/P ratio (area under the ROC curve = 0.858, 95 % CI 0.753-0.963). Furthermore, the M/P ratio was restored to normal levels after antidepressants treatment in MDD group. In summary, our data demonstrated that both plasma mBDNF levels and M/P ratio were lower in BP compared with MDD. These findings further support M/P ratio as a potential differential diagnostic biomarker for BP among patients in depressive episodes.

Plasma levels of Th17-related cytokines and complement C3 correlated with aggressive behavior in patients with schizophrenia.

Increasing evidence indicates that immune inflammatory processes, especially autoimmune reaction, should be considered in the pathophysiology of schizophrenia and aggressive behavior. The present study aimed to explore the correlation between immune factors (C3 and Th17-related cytokines) and aggressive behavior in schizophrenia patients. Forty schizophrenia patients and forty age- and gender-matched healthy controls participated in the study. Blood samples were assessed by ELISA upon enrollment. Positive and negative syndrome scale (PANSS) and modified overt aggression scale (MOAS) were used to estimate the severity and aggressive symptoms of schizophrenia patients. Plasma levels of IL-17, IL-23, and TGF-ß1 in schizophrenia patients were significantly higher than those in healthy controls [(37.63±17.82) vs. (29.34±10.38)pg/ml, p=0.02; (101.40±135.26) vs. (13.09±5.94) pg/ml, p=0.01; (2864.57±2163.61) vs. (1839.69±1797.73)pg/ml, p=0.04], whereas C3 levels were significantly lower in schizophrenia patients [( 120,479.67± 65,612.50) vs. ( 208,060.21± 217,008.21)ng/ml, p=0.02]. IL-17, IL-23, and TGF-ß1 levels were positively related to total scores of MOAS (p=0.02, p=0.02 and p=0.03, respectively) and PANSS (p=0.04, p=0.04 and p=0.02, respectively), whereas C3 levels were negatively related to total PANSS scores (p=0.03). IL-17 and IL-23 levels were positively correlated with PANSS excited component scores (p=0.04 and p=0.01, respectively). Our findings suggested that the Th17-related cytokine levels were positively related to the severity of schizophrenia and aggressive behavior, whereas C3 levels were negatively related to the severity of schizophrenia. This study demonstrated that elevated levels of Th17-related cytokines and decreased levels of C3 could be potential biomarkers for schizophrenia and aggressive behavior.

Higher Plasma S100B Concentrations in Schizophrenia Patients, and Dependently Associated with Inflammatory Markers.

Glial damage and immune dysfunction are involved in pathogenesis of schizophrenia. However, interaction between glial damage and immune dysfunction in schizophrenia is undefined. This study aims to compare plasma S100 calcium binding protein (S100B) levels between schizophrenia patients and healthy participants, and to determine if immune markers are independently related with concentration of S100B in schizophrenia patients. Forty-one schizophrenia patients and thirty-three healthy volunteers were enrolled. Enzyme-linked immunosorbent assay (ELISA) was used to assess the concentrations of plasma S100B and inflammatory markers. We found that concentrations of S100B were elevated in schizophrenia patients than healthy participants (p < 0.05), and were negatively related with the severity of symptoms (p = 0.046). Receiver operating characteristic (ROC) curve analysis showed that different S100B levels between schizophrenia and healthy participants can be used as a clinical diagnostic factor (predictive value: 0.666, p = 0.015). Multiple linear regression analysis found that length of illness (Beta = -0.161), plasma levels of inflammatory regulation factors (including TGF-ß1, logIL-23 and logIL-10) (Beta = 0.119, 0.475, 0.514) were independently associated with concentrations of S100B (Adjusted R(2) = 0.897, p < 0.001). Therefore, our results suggest the possible function of S100B in pathogenesis of schizophrenia, and implicate the important role of autoimmune response and balance to glial dysfunction in patients with schizophrenia.

Safety and survival benefit of surgical management for elderly gastric cancer patients.

OBJECTIVE: To study the safety and survival outcome of surgical management for elderly gastric cancer patients. Methods: Patients proven of gastric cancer who aged ≥80 years during November 2002 to July 2011 were retrospectively analyzed. The detailed information of patients' characteristics and surgical management was retrieved. Follow-up of overall survival status was performed to analyze the surgical effectiveness. RESULTS: Totally, 92 (48 in surgery and 44 in non-surgery group) out of 187 eligible patients recorded adequate information and analyzed finally. There were 34 patients undergone radical gastrectomy, 6 palliative gastrectomy, 1 gastrojejunostomy and 7 exploratory laparotomy. Median follow-up durations were 25 (9-111) and 28 (8-114) months in surgery and non-surgery groups, respectively (p=0.797). Clinical-pathological T stage and node status were comparable. Clinical-pathological distal metastasis status was 15 and 26 M1 cases for surgery and nonsurgery, respectively (p=0.006). Incidence of postoperative complications and hospital mortality were 25.0% and 2.1%, respectively. The 2-year survival rates of M0 subgroups were 35.7% and 0% for surgery and nonesurgery, respectively (HR=3.98, p=0.022). CONCLUSIONS: The safety of surgery for well-selected ≥ 80-year elderly gastric cancer patients was potentially acceptable and the patients of early or locally advanced diseases could obtain survival benefits by surgery.

Prognostic role of circulating tumor cells and disseminated tumor cells in patients with prostate cancer: a systematic review and meta-analysis.

Circulating tumor cells (CTCs) and disseminated tumor cells (DTCs) displayed their roles in prognosis prediction in prostate cancer. The objective of the present study was to conduct a systematic review and meta-analysis of published literature while investigating the correlation between survival outcome and CTCs or DTCs counts in patients with prostate cancer. Relevant literature was searched in Pubmed and Embase. Survival data of included study were extracted. Forrest plots were used to estimate the effect of CTCs/DTCs on the survival of patients. Publication bias was evaluated using Begg's test. The estimated HRs and 95 % confidence interval for the effect of CTCs/DTCs on overall survival (OS) and biochemical relapse-free survival (bRFS) or disease-free survival (DFS) were 2.43 [2.07, 2.86] (p<0.00001) and 2.15 [1.69, 2.73] (p<0.00001), respectively. Subgroup analysis revealed that CTCs were also relevant to poor prognosis (hazard ratio (HR) 2.43 [2.05, 2.89] for OS, HR 2.46 [2.08, 2.90] for bRFS/DFS). A similar result was yielded in DTCs (1.47 [1.21, 1.80] for DFS). CTCs/DTCs could also predict poor OS in metastatic prostate cancer (2.37 [1.99, 2.82], p<0.00001) and in localized stage (HR 1.84 [1.47, 2.28], p<0.00001). In addition, CTCs/DTCs detected by different methods, especially by CellSearch system (HR for OS 2.36 [1.95, 2.85] and HR for bRFS/DFS 2.53 [1.66, 3.85]), were relevant to poor prognosis. Available evidence supported the notion of the strong prognostic value of CTCs. CTCs are promising biomarkers that are clinically implemented in the therapeutic decision-making process in patients with prostate cancer.