The biological pathology of deficit schizophrenia (DS) remains unclear. Matrix metalloproteinase 9 (MMP9) might be associated with neural plasticity and glutamate regulation, involved in schizophrenia pathogenesis. This study explores gene expression and DNA methylation of MMP9 in peripheral blood mononuclear cells (PBMCs) and their relationship with clinical symptoms in DS and non-deficit schizophrenia (NDS). Pyrosequencing was used to determine DNA methylation at CpG sites in exon 4 and exon 5 of MMP9 in 51 DS patients, 53 NDS patients and 50 healthy subjects (HC). RT-qPCR was used to detect MMP9 expression. Clinical symptoms were assessed by BPRS, SANS and SAPS scales. MMP9 expression in PBMCs was significantly higher in DS than NDS and HC subjects. Compared to NDS patients, DS patients had significantly lower DNA methylation at individual CpG sites in exon 4 and exon 5 of MMP9. Correlation analysis showed that DNA methylation in exon 4 was negatively correlated with gene expression in DS group. Positive correlation was found between MMP9 expression and negative symptoms in total schizophrenic patients. The social amotivation factor of SANS and negative syndrome of BPRS was negatively correlated with DNA methylation of CpG5-1 in DS patients but not in NDS patients. DS patients showed a specific abnormality of peripheral MMP9 expression and DNA methylation, indicating a pathological mechanism underlying DS as a specific subgroup of schizophrenia.

[This corrects the article DOI: 10.3389/fgene.2018.00646.].

Brain-derived neurotrophic factor (BDNF) plays an important role in the treatment of schizophrenia with electroconvulsive therapy (ECT) or antipsychotic (AP) drugs. However, it is unclear whether BDNF is a mediator; we therefore assumed that baseline BDNF level can mediate the efficacy of ECT-AP treatment. A total of 160 patients with schizophrenia were examined; 80 received AP monotherapy and the other 80 were treated with a combination of ECT and AP. BDNF concentration was measured by enzyme-linked immunosorbent assay using the Emax Immunoassay System kit (Promega, Madison, WI, USA) according to the manufacturer's instructions.Log-linear analyses were used to examine the relationship between demographic characteristics, BDNF level, and clinical features and response status. The baseline BDNF levels and BDNF level increment were the best predictors of clinical outcome (OR1 = 3.358, P = 0.000; OR2 = 3.243, P = 0.000).The higher baseline BDNF levels and greater BDNF level increment were found to be associated with good outcome.

Deficit schizophrenia (DS) is a distinct subtype of schizophrenia characterized by primary and enduring negative symptoms. More severe executive dysfunctions were observed in DS patients, however, the associated neuroimaging characteristics, especially cerebellar functional anomalies in DS, remain largely unknown. We employed resting-state functional and structural MRI data of 106 male participants, including data from 29 DS patients, 39 non-deficit schizophrenia (NDS) patients and 38 healthy controls (HCs). Z-standardized fractional amplitude of low-frequency fluctuation (zfALFF) values were calculated in order to examine spontaneous regional brain activity. Cerebro-cerebellar functional connectivity and changes in the volume of gray matter in the cerebellum were also examined. Relative to the HCs, both DS and NDS patients exhibited decreased zfALFF in the bilateral cerebellar lobules VIII and IX. The zfALFF in the left Crus II was lower in DS patients compared to NDS patients. No significant difference was observed in the volume of cerebellar gray matter among the three groups. Compared with NDS patients, cerebro-cerebellar functional connectivity analysis revealed increased connectivity in the left orbital medial frontal cortex and right putamen regions in DS patients. Reduced zfALFF in the left Crus II in the DS group was significantly positively correlated with Stroop Color and Word scores, while negatively correlated with Trail-Making Test part B scores. The increased functional connectivity in the right putamen in DS patients was significantly positively correlated with Animal Naming Test and semantic Verbal Fluency Test scores. These results highlight cerebellar functional abnormality in DS patients and provide insight into the pathophysiological mechanism of executive dysfunction.

This study detected the differences in gene expression and DNA methylation of CpG sites in CXCL1 gene and further investigated their associations with clinical symptoms in deficit schizophrenia (DS) and non-deficit schizophrenia (NDS). Pyrosequencing and RT-qPCR were separately used to determine DNA methylation and mRNA expression of CXCL1 gene. Both DNA methylation and expression were significantly different among DS, NDS and healthy control (HC) groups. Correlation analysis revealed that CXCL1 gene expression was associated with the negative syndrome in NDS patients, while no association in DS patients was observed. All together, these results suggest that DS may be a specific subgroup of schizophrenia with the characteristic abnormality of peripheral CXCL1 DNA methylation and gene expression.

Inflammation and an exacerbated immune response are widely accepted contributing mechanisms to the genesis and progression of major neuropsychiatric disorders. However, despite the impressive advances in understanding the neurobiology of these disorders, there is still no approved drug directly linked to the regulation of inflammation or brain immune responses. Importantly, matrix metalloproteinases (MMPs) comprise a group of structurally related endopeptidases primarily involved in remodeling extracellular matrix (ECM). In the central nervous system (CNS), these proteases control synaptic plasticity and strength, patency of the blood-brain barrier, and glia-neuron interactions through cleaved and non-cleaved mediators. Several pieces of evidence have pointed to a complex scenario of MMPs dysregulation triggered by neuroinflammation. Furthermore, major psychiatric disorders’ affective symptoms and neurocognitive abnormalities are related to MMPs-mediated ECM changes and neuroglia activation. In the past decade, research efforts have been directed to broad-spectrum MMPs inhibitors with frustrating clinical results. However, in the light of recent advances in combinatorial chemistry and drug design technologies, specific and CNS-oriented MMPs modulators have been proposed as a new frontier of therapy for regulating ECM properties in the CNS. Therefore, here we aim to discuss the state of the art of MMPs and ECM abnormalities in major neuropsychiatric disorders, namely depression, bipolar disorder, and schizophrenia, the possible neuro-immune interactions involved in this complex scenario of MMPs dysregulation and propose these endopeptidases as promising targets for rational drug design.

There is much evidence of a relationship between alterations in the brain's regional cellular energy metabolism and blood flow in schizophrenic. Vascular endothelial growth factor (VEGF) plays a role in the pathogenesis of neuropsychiatric illnesses. So, we compared serum VEGF levels in drug-naïve first-episode psychotic (FEP) and chronically medicated schizophrenic to examine if a correlation existed between VEGF and psychopathological symptoms. The serum VEGF levels were assessed in 46 FEP patients, 47 chronic medicated patients and 50 healthy controls. Symptoms of schizophrenia were evaluated with the Positive and Negative Syndrome Scale (PANSS) and sandwich enzyme-linked immunosorbent assay (ELISA) was used to measure serum VEGF levels. VEGF levels were significantly lower in FEP patients compared to both chronically medicated schizophrenic patients and healthy controls, while VEGF levels in chronically medicated patients were markedly higher than in healthy controls. Furthermore, a significant correlation was detected between the levels and the PANSS negative subscale among patient groups. However, no significant correlation was observed between VEGF and clinical variables in patients. This study suggested that imbalanced neurotrophic factors may be associated with the onset of schizophrenia, but subsequent increased VEGF may be related to medication or other factors in disease progression.

Objectives: As the name implies, vascular endothelial growth factor (VEGF) enhances angiogenesis, promotes vascular permeability, and stimulates neurogenesis in the adult brain. Furthermore, animal model studies have shown that electroconvulsive therapy (ECT), which is primarily utilised in cases of treatment-resistant schizophrenia (TRS), regulates the expression of VEGF. The current study focuses largely on the effect of ECT on VEGF serum concentration, and the relationship between VEGF and therapeutic effects in patients diagnosed with TRS. Methods: Participants comprised 40 TRS patients and 43 healthy controls. Clinical severity was assessed (i.e. 1 day before commencement of ECT and 1 day following ECT) using the positive and negative syndrome scale (PANSS). Blood samples were also collected for VEGF measurements at corresponding time points. Results: Pre-treatment serum VEGF levels were significantly lower in TRS patients compared to healthy controls. VEGF concentrations increased significantly following ECT, whereas no difference was found in controls. Moreover, there was a positive correlation between the change in VEGF and therapeutic effects. Conclusions: Elevated serum VEGF in TRS treated with ECT is positively associated with therapeutic effects, suggesting that alterations in VEGF levels may constitute an index by which to evaluate the improvement in clinical condition.

OBJECTIVES:Many research indicate that the tardive dyskinesia (TD) is generally linked with long-term antipsychotic therapy for schizophrenia. Glial cell line-derived neurotrophic factor (GDNF) is a critical role in the protection of catecholaminergic, dopaminergic, and cholinergic neurons. Thus, we examined the serum GDNF levels in schizophrenia patients with TD (WTD) and without TD (NTD) and compared with healthy controls (HC), respectively.METHODS:Totally 75 males with schizophrenia were recruited into this study. All were measured by the Diagnostic and Statistical Manual of Mental Disorders, fifth edition, the Positive and Negative Syndrome Scale, and the Abnormal Involuntary Movement Scale (AIMS). The patient group was divided into two subgroups: WTD (n = 32) and NTD (n = 43) according to the AIMS score. Fifty-three healthy controls matching in age and gender were also enlisted from the region. GDNF levels were examined with sandwich enzyme-linked immunosorbent assay.RESULTS:Analysis of variance indicated significant differences between the three groups (P = 0.012); GDNF levels in the WTD group were significantly different from those in the NTD (P = 0.030) and HC (P = 0.003) groups.CONCLUSION:Decreased GDNF levels in TD patients indicated that alterations in neurotrophic factors may be involved in the pathophysiology of TD, but the exact mechanisms need further investigation.

Vascular endothelial growth factor (VEGF) is implicated in angiogenesis, blood flow, and neuroplasticity, which have previously been shown to contribute to schizophrenia and the mechanisms of action of antipsychotic medication. The aim of the present study was to investigate whether baseline serum VEGF levels predict treatment responses to antipsychotic medication. Drug-free adults with schizophrenia were administered monotherapy with atypical antipsychotic drugs for 6 weeks. Participants’ psychiatric symptoms were assessed using the positive and negative symptom scale (PANSS) before and after treatment. Blood samples for VEGF measurements were collected from 201 participants comprising 83 healthy controls and 118 patients (i.e. only on admission). Baseline VEGF levels in adults with schizophrenia were significantly lower than those in the control group (t = 3.656, df = 199, P < 0.001). In particular, pretreatment VEGF levels were significantly higher in patients responding to drug treatment at follow-up (≥ 50% reduction in initial PANSS total) (t = 4.743, df = 116, P < 0.001). The predictive power of serum VEGF levels was investigated using receiver operating characteristic curves. The area under the curve was 0.774 (95% confidence interval 0.688–0.846); for fixed specificity of 78.8%, the corresponding sensitivity was 63.5%. Results from this preliminary experiment suggest high baseline serum concentrations of VEGF may predict a better response to antipsychotic medications in adults with schizophrenia. Further studies using larger sample sizes are needed to verify the findings.

Deficit schizophrenia (DS), characterized by primary and enduring negative symptoms, has been considered as a pathophysiologically distinct schizophrenic subgroup. Neuroimaging characteristics of DS, especially functional brain network architecture, remain largely unknown. Resting-state functional magnetic resonance imaging and graph theory approaches were employed to investigate the topological organization of whole-brain functional networks of 114 male participants including 33 DS, 41 non-deficit schizophrenia (NDS) and 40 healthy controls (HCs). At the whole-brain level, both the NDS and DS group exhibited lower local efficiency (Eloc) than the HC group, implying the reduction of local specialization of brain information processing (reduced functional segregation). The DS, but not NDS group, exhibited enhanced parallel information transfer (enhanced functional integration) as determined by smaller characteristic path length (Lp) and higher global efficiency (Eglob). The Lp and Eglob presented significant correlations with Brief Psychiatric Rating Scale (BPRS) total score in the DS group. At the nodal level, both the NDS and DS groups showed higher functional connectivity in the inferior frontal gyrus and hippocampus, and lower connectivity in the visual areas and striatum than the controls. The DS group exhibited higher nodal connectivity in the right inferior temporal gyrus than the NDS and HC group. The diminished expression of Scale for the Assessment of Negative Symptoms (SANS) subfactors negatively correlated with nodal connectivity of right putamen, while asociality/amotivation positively correlated with right hippocampus across whole patients. We highlighted the convergence and divergence of brain functional network dysfunctions in patients with DS and NDS, which provides crucial insights into pathophysiological mechanisms of the 2 schizophrenic subtypes.

Objectives: Evidence suggests that brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) are important in the regulation of synaptic plasticity, which plays a key role in the cognitive processes in psychiatric disorders. Our work aimed at exploring the associations between serum BDNF and GDNF levels and cognitive functions in first-episode drug-naive (FEDN) patients with schizophrenia.Methods: The BDNF and GDNF levels of 58 FEDN patients and 55 age- and sex-matched healthy controls were measured and test subjects were examined using several neurocognitive tests including the verbal fluency test (VFT), the trail making test (TMT), the digit span test (DST), and the Stroop test.Results: Patients performed significantly worse than controls in nearly all neurocognitive performances except the forward subscale part of the DST. BDNF levels were inversely correlated to TMT-part B scores and positively correlated to VFT-action in the FEDN group. GDNF levels showed a positive correlation with VFT-action scores and a negative correlation with TMT-part B scores of these patients.Conclusion: Current data suggests that cognitive dysfunction widely exists in the early stages of schizophrenia. BDNF and GDNF may be jointly contributed to the pathological mechanisms involved in cognitive impairment in FEDN patients with schizophrenia.

Glial cell line-derived neurotrophic factor (GDNF) plays an increasingly vital role in the pathogenesis of neuropsychiatric illnesses. Antipsychotic medications were shown to stimulate GDNF secretion from C6 glioma cells. The aims of this study were to investigate the serum concentration of GDNF, to monitor the therapeutic effect of atypical antipsychotics related to GDNF levels in drug-free schizophrenia patients, and to examine these levels in relation to psychotic symptoms. We recruited 138 drug-free schizophrenic patients and compared them with 77 matched healthy subjects. All patients were treated with atypical antipsychotic monotherapy. GDNF serum levels and psychiatric symptoms were assessed at baseline and after 2, 4, 6 and 8 weeks. GDNF levels gradually increased accompanied by a reduction in psychiatric symptoms during antipsychotic therapy. The levels of GDNF in responders were significantly increased after 8 weeks of treatment, however, no significant change was found in non-responders. Furthermore, a negative association between GDNF levels following pharmacotherapy and disease duration in schizophrenic subjects could be observed. The present study suggests that GDNF may be involved in the etiology of schizophrenia and pharmacological treatment.

Background Deficit schizophrenia (DS) has been proposed as a pathophysiologically distinct subgroup within schizophrenia. Earlier studies focusing on neurocognitive function of DS patients have yielded inconsistent findings ranging from substantial deficits to no significant difference relative to non-deficit schizophrenia patients (NDS). The present study investigated the severity and characteristic patterns of neurocognitive impairments in DS and NDS patients and their relationships with clinical variables. Methods Attention, ideation fluency, cognitive flexibility and visuospatial memory function were assessed in 40 DS patients, 57 NDS patients, and 52 healthy controls by a comprehensive neuropsychological battery. Results Both schizophrenia subgroups had overall more severe cognitive impairments than controls while DS performed worse on every neuropsychological measure except the Stroop interference than the NDS patients with age and education as the covariates. Profile analysis found significantly different patterns of cognitive profiles between two patients group mainly due to their differences in attention and cognitive flexibility functions. Age, education, illness duration and negative symptoms were found to have the correlations with cognitive impairments in the NDS group, while only age and the negative symptoms were correlated with the cognitive impairments in the DS group. Multiple regression analyses revealed that sustained attention and cognitive flexibility were the core impaired cognitive domains mediating other cognitive functions in DS and NDS patients respectively. Conclusions DS patients exemplified worse in almost all cognitive domains than NDS patients. Sustained attention and cognitive flexibility might be the key impaired cognitive domains for DS and NDS patients respectively. The present study suggested the DS as a specific subgroup of schizophrenia.

Some evidence suggests that neurotrophic growth factor systems might be involved in the etiology of major depressive disorder (MDD). Glial cell line‐derived neurotrophic factor (GDNF) is a neurotrophic factor from the transforming growth factor‐β family that plays a role in the development and function of the brain. This study aimed to test whether GDNF in serum was abnormal in MDD, and whether it was related to the cognitive impairment of MDD.

Some evidence suggests that testosterone might be involved in the cognitive impairments of schizophrenia. We assessed major cognitive domains and serum testosterone levels in male long‐term inpatients with schizophrenia. This study aimed to test whether testosterone in serum was abnormal in patients, and whether it was related to the cognitive impairment of schizophrenia.

We investigated the effects of smoking status on the serum prolactin levels in schizophrenia. The serum prolactin concentration was significantly higher in nonsmokers compared with smokers. Moreover, smoking was an independent predictor of prolactin concentration. These findings suggest that smoking has an impact on prolactin concentration in male schizophrenic patients.

Zhang X, Wang X, Sha W, Zhou H, Zhang Y. Val66Met polymorphism and serum brain-derived neurotrophic factor concentration in depressed patients.Objective: Accumulating evidence has suggested a pathophysiological role for brain-derived neurotrophic factor (BDNF) in major depressive disorder (MDD). The present study evaluated serum levels of BDNF and explored whether Val66Met BDNF gene polymorphism is correlated with changes in circulating BDNF levels in patients with MDD and control subjects.Methods: Subjects were 76 patients with MDD and 50 controls. Diagnosis of MDD was determined by the use of a structured clinical interview according to Diagnostic and Statistical Manual of Mental Disorder-IV (DSM-IV) criteria. The concentrations of BDNF were measured by using the enzyme-linked immunosorbent assay. The Val66Met BDNF gene polymorphism was examined by the polymerase chain reaction technique.Results: Serum BDNF was significantly lower in MDD patients than in normal control subjects (p < 0.001). There were no significant differences either in allele or genotype in the Val66Met polymorphism between the MDD and control groups. Moreover, genotype did not significantly correlate with the BDNF serum levels in the MDD or control groups.Conclusions: Our study suggests that there is a decrease in serum BDNF levels in untreated MDD patients. However, serum BDNF levels were not associated with the Val66Met polymorphism.

Electroconvulsive therapy (ECT) can be effective in patients with depression resistant to pharmacologic medication. We report that serum levels of glial cell-line derived neurotrophic factor (GDNF) were increased following ECT of patients with drug-resistant depression. When patients were sub-classified into ECT responders and non-responders, serum GDNF levels were significantly increased (58%) in responsive patients following ECT. No significant increase was seen in non-responders. These results suggest that successful ECT may be associated with elevated serum GDNF levels.