Gaohua Wang

Association of corticotropin-releasing hormone receptor1 gene SNP and haplotype with major depression

The dysregulation of the activity of the hypothalamic-pituitary-adrenocortical (HPA) axis system is one of the major neuroendocrine abnormalities in major depression (MD). Many pieces of evidence supported that corticotropin-releasing hormone (CRH) play a role in the pathophysiology of major depression. In this article, whether genetic variations in the corticotropin-releasing hormone receptor1 (CRHR1) gene might be associated with increased susceptibility to major depression was studied by using a gene-based association analysis of single-nucleotide polymorphisms (SNPs). Three SNPs were identified in CRHR1 gene and genotyped in the samples of patients diagnosed with major depression and matched controls. We observed significant allele (P=0.0008) and genotype (P=0.0002) association with rs242939, and the haplotype defined by alleles G-G-T for the represent rs1876828, rs242939 and rs242941 was significantly over-represented in major depression patients compared to controls. These results support the idea that the CRHR1 gene is likely to be involved in the genetic vulnerability for major depression.

Association study of corticotropin-releasing hormone receptor1 gene polymorphisms and antidepressant response in major depressive disorders.

Hypothalamic-pituitary-adrenal (HPA) axis appears to play a key role in the pathogenesis of major depressive disorders (MDD). Treatment of certain selective serotonin reuptake inhibitors (SSRIs) has been shown to reduce the activity of corticotropin-releasing hormone (CRH) neurons and may contribute to their therapeutic action. It has been proposed that the downregulation of CRH activity is final and common step of antidepressant treatment. In this study, we tested whether the polymorphisms of three sites (rs1876828, rs242939 and rs242941) in corticotropin-releasing hormone receptor1 (CRHR1) gene are related to 6 weeks fluoxetine antidepressant effect in 127 Han Chinese patients with MDD. The results show that the rs242941 G/G genotype and homozygous GAG haplotype of the three single-nucleotide polymorphisms (SNPs) are associated with fluoxetine therapeutic response in MDD patients of high-anxiety (HA). The results support the idea that the CRHR1 gene is likely to be involved in the antidepressant response in MDD.

Brain-derived neurotrophic factor (BDNF) infusion restored astrocytic plasticity in the hippocampus of a rat model of depression

Brain-derived neurotrophic factor (BDNF) is closely associated with hippocampal plasticity in psychiatric disorders. Glial cells (particularly astrocytes) are the most abundant cell type in the central nervous system. Previous studies have demonstrated that distinct alterations of astrocytes are associated with major depressive disorder, but there is a paucity of data describing whether such alterations of astrocytic plasticity are present in depressive-like rat hippocampus after BDNF administration. In this paper, we investigated the effects of chronic unpredictable mild stress (CUMS) and BDNF infusion on astrocyte immunoreactivity in rat hippocampus using sucrose preference test, open field test, and Western blot analysis. Results revealed that CUMS induced anhedonic-like behaviors in sucrose consumption and open field performances, which were partially reversed by BDNF infusion. Moreover, CUMS produced decreased glial fibrillary acidic protein (GFAP) expression and increased s100 calcium binding protein b (s100b) expression in rat hippocampus, which were partially rescued by BDNF administration. Therefore, BDNF might restore astrocyte immunoreactivity in depressive-like rat hippocampus, providing insights into the potential pharmacological role of BDNF in stress-related disorders.

Prevalence of Toxoplasma infection in first-episode schizophrenia and comparison between Toxoplasma-seropositive and Toxoplasma-seronegative schizophrenia

Objective:  To compare the prevalence of Toxoplasma infection between the first‐episode schizophrenia and the controls and to compare the clinical features between the Toxoplasma‐seronegative and Toxoplasma‐seropositive patients with schizophrenia.

Association of the brain-derived neurotrophic factor gene and bipolar disorder with early age of onset in mainland China

Several evidences have suggested that the brain-derived neurotrophic factor (BDNF) gene may be involved in the pathogenesis of bipolar disorder (BPD), but not all studies get the same result. The paper investigated two genetic polymorphisms of BDNF, C-270T and Val66Met, in a case-control design for their association with BPD. Sixty-seven patients of early age of onset and 130 patients of late age of onset were selected for study and 208 healthy individuals were used as controls. No significantly statistical differences of these two polymorphisms were found in genotypes or allele frequencies between either overall patients or late age of onset patients and normal control subjects. However, the frequency of the Val allele of the Val66Met polymorphism was found to have significantly increased in the subgroup patients with early age of onset as compared with the controls (genotype: chi(2)=6.602, d.f.=2, P=0.037; allele: chi(2)=6.223, d.f.=1, P=0.015). The study demonstrates that the BDNF C-270T and Val66Met polymorphisms are unlikely to contribute to the genetic predisposition to BPD as a whole. But Val66Met may be associated with susceptibility to the early age of onset subset of the disorder, further studies designed to explore the relationship in a larger population may be warranted.

Cytoskeletal alterations in rat hippocampus following chronic unpredictable mild stress and re-exposure to acute and chronic unpredictable mild stress

The intrinsic dynamic instability of the cytoskeletal microtubular system is essential for neuronal development and organization. The modulation of microtubule dynamics depends on the phosphorylation of neuronal microtubule-associated proteins (MAPs). Chronic unpredicted mild stress (CUMS) affects hippocampal structure and function in the rat. The aim of the present work was to investigate the possible alteration of cytoskeleton in the hippocampus of rats exposed to CUMS and re-exposed to CUMS to mimic depression and the recurrence of depression of human. We investigated the effects of CUMS, fluoxetine and re-exposure to CUMS on alpha-tubulin isoforms associated with microtubule dynamics, MAP-2 and phospho-MAP-2 in the hippocampus of rats. Our results showed that rats submitted to CUMS once showed a significant reduction in locomotion and sucrose preference which indicate a state of anhedonia. These behavioral alterations were accompanied by specific alterations in hippocampal alpha-tubulin isoforms and phospho-MAP-2 expression, indicating less microtubule dynamics and the possible mechanism. Treatment of fluoxetine could reverse CUMS-induced impairment. Moreover, there were more dramatically changes in behaviors, alpha-tubulin isoforms and phospho-MAP-2 of rats re-exposed to CUMS compared to the rats exposed to CUMS once. These findings provide evidence that rats exposed to CUMS and re-exposed to CUMS showed impairment of microtubule dynamics accompanied with the decreased level of phospho-MAP-2, providing insight into the role of cytoskeleton in the depression and recurrent of depression.

Human endogenous retroviral pol RNA and protein detected and identified in the blood of individuals with schizophrenia.

Retrovirus has been speculated as one of the potential infectious agents involved in the development of schizophrenia. Here we used nested RT-PCR to detect the RNA of HERV pol gene in blood from schizophrenic patients and normal human. We found retroviral pol genes expressed in blood from 20 of 58 (34.5%) individuals with recent-onset schizophrenia, but not from 38 normal persons (p<0.01). Sequence analysis revealed that the expressed gene was homologous to those of the human endogenous retroviral (HERV) family. The ERV9 family was the closest, with 90% homology in the gene sequence. In addition, Western blots showed that antibody against ERV9 pol protein in serum from the HERV+ schizophrenia patients, but not from control (p<0.01). Our data suggested that the transcriptional activation of certain retroviral elements might be associated with the development of schizophrenia in some patients. Further characterization of retroviral elements in subjects with schizophrenia may aid in better diagnosis and treatment of this disorder.

Risperidone Maintenance Treatment in Schizophrenia: A Randomized, Controlled Trial

OBJECTIVE Prevention of relapse is the crucial task in the maintenance treatment of schizophrenia. The investigators in this study sought to determine the duration of maintenance treatment needed with the initial therapeutic dose, in contrast to a reduced dose. METHOD In a multicenter open-label, randomized, controlled study, patients with schizophrenia who were clinically stabilized following an acute episode were randomly assigned to a no-dose-reduction group (initial optimal therapeutic dose continued throughout the study), a 4-week group (initial optimal therapeutic dose continued for 4 weeks, followed by a 50% dose reduction that was maintained until the end of the study), or a 26-week group (initial optimal therapeutic dose continued for 26 weeks, followed by a 50% dose reduction until the end of the study). All patients continued until the last recruited patient completed the 1-year follow-up. RESULTS Of the 404 patients who met the entry criteria and were randomly assigned, 374 completed the study. The estimated mean time from entry to relapse was 571 days in the 4-week group, 615 days in the 26-week group, and 683 days in the no-dose-reduction group, with estimated relapse rates of 30.5%, 19.5%, and 9.4%, respectively. Patients in the no-dose-reduction group experienced greater reduction in the severity of psychotic symptoms. CONCLUSIONS Patients who continued to receive the full risperidone dose used for their acute episode had fewer relapses than those who had dose reductions after 4 weeks or 26 weeks during the maintenance period. There was negligible difference in side effects among the three groups.

Chronic mild stress induces fluoxetine-reversible decreases in hippocampal and cerebrospinal fluid levels of the neurotrophic factor S100B and its specific receptor.

Chronic mild stress (CMS) affects the hippocampal structure and function in the rat. S100B, a calcium-binding protein secreted by astrocytes, has been shown to be increased in serum of patients with depression and associated with good therapeutic response and clinical outcome. This work aimed to study the impact of CMS and fluoxetine on depressive-like behaviors in rats, as well as the concomitant expression of the astroglial protein S100B and of its receptor RAGE (receptor for advanced glycation end products) in the hippocampus and Cerebrospinal fluid of the same group of animals. S100B and sRAGE (circulating soluble form of RAGE) were measured in CSF by ELISA, and S100B and RAGE were measured in hippocampal slices by Western blot. Our study has demonstrated that stress and depression decrease S100B and RAGE/SRAGE expression and antidepressant treatment reverses or blocks these effects. This result suggested that S100B/RAGE interactions may be involved in the development and maintenance of depression and may play an important role in the mechanism of antidepressants’ therapeutic action.

Antipsychotic polypharmacy in schizophrenia patients in China and its association with treatment satisfaction and quality of life: Findings of the third national survey on use of psychotropic medications in China:

Objective: This study examined the use, demographic and clinical correlates of antipsychotic polypharmacy (APP) and its associations with treatment satisfaction and quality of life (QOL) in schizophrenia patients in China. Method: A total of 4239 patients in 45 nationwide Chinese psychiatric hospitals/centers were interviewed in 2012 in the third cross-sectional study, with the first two having been conducted in 2002 and 2006. Patients’ socio-demographic and clinical characteristics, including psychopathology, side effects, satisfaction with treatment and QOL, were recorded using a standardized protocol and data collection procedure. Results: The proportion of APP prescriptions in 2012 was 34.2%, which was significantly higher than the frequency of APP in 2002 (26.1%) and 2006 (26.4%) (p<0.001). Of patients on APP, 91.1% received two antipsychotics, 8.6% received three and 0.3% received four or more antipsychotics. Multiple logistic regression analyses revealed that compared to those on antipsychotic monotherapy, patients on APP and their families had lower satisfaction with treatment, had higher QOL in the mental domain, younger age of onset, more side effects, higher doses of antipsychotics and were more likely to receive first-generation antipsychotics and less likely to receive benzodiazepines (total R2=0.31, p<0.001). Conclusions: APP was found in about one in three schizophrenia patients. The prevalence of APP seems to have been increasing since 2002. Considering the increased frequency of drug-induced side effects and the patients’ and their relatives’ dissatisfaction with antipsychotic treatment, further examination of the rationale and appropriateness of APP and its alternatives is warranted.