Xiancang Ma

Targeting of NMDA Receptors in the Treatment of Major Depression

Major depressive disorder (MDD) is a common, recurrent mental illness that affects millions of people worldwide. Accumulating evidence suggests that the N-methyl-D-aspartate (NMDA) receptor, a subtype of glutamate receptors, plays an important role in the neurobiology and treatment of this disease. Currently, the non-competitive NMDA receptor antagonist ketamine is considered as one of the most attractive candidate drugs in therapy of treatment-resistant depression. A recent study demonstrated ketamines rapid antidepressant activity in patients with treatment-resistant MDD and bipolar disorder. The response rate for ketamine ranged from 25% to 85% at 24 hours post-infusion and from 14% to 70% at 72 hours post-infusion, with generally mild adverse effects. Based on the role of the NMDA receptor in depression, a number of therapeutic drugs which interact with this receptor have been developed. In this article, we reviewed recent findings concerning the role of glutamatergic signaling in the neurobiology of MDD and potential, novel therapeutic drugs, such as ketamine, memantine, AZD6765, traxoprodil, MK-0657, GLYX-13, NRX-1047, D-cycloserine, sarcosine, all of which target this system.

Reliability and Validity of the CogState Battery Chinese Language Version in Schizophrenia

Background Cognitive impairment in patients with schizophrenia is a core symptom of this disease. The computerized CogState Battery (CSB) has been used to detect seven of the most common cognitive domains in schizophrenia. The aim of this study was to examine the reliability and validity of the Chinese version of the CSB (CSB-C), in Chinese patients with schizophrenia. Methodology/Principal Findings Sixty Chinese patients with schizophrenia and 58 age, sex, and education matched healthy controls were enrolled. All subjects completed the CSB-C and the Repeated Battery for the Assessment of Neuropsychological Status (RBANS). To examine the test-retest reliability of CSB-C, we tested 33 healthy controls twice, at a one month interval. The Cronbach α value of CSB-C in patients was 0.81. The test-retest correlation coefficients of the Two Back Task, Gronton Maze Learning Task, Social Emotional Cognition Task, and Continuous Paired Association Learning Task were between 0.39 and 0.62 (p<0.01) in healthy controls. The composite scores and all subscores for the CSB-C in patients were significantly (p<0.01) lower than those of healthy controls. Furthermore, composite scores for patients on the RBANS were also significantly lower than those of healthy controls. Interestingly, there was a positive correlation (r  =  0.544, p<0.001) between the composite scores on CSB-C and RBANS for patients. Additionally, in the attention and memory cognitive domains, corresponding subsets from the two batteries correlated significantly (p<0.05). Moreover, factor analysis showed a two-factor model, consisting of speed, memory and reasoning. Conclusions/Significance The CSB-C shows good reliability and validity in measuring the broad cognitive domains of schizophrenia in affected Chinese patients. Therefore, the CSB-C can be used as a cognitive battery, to assess the therapeutic effects of potential cognitive-enhancing agents in this cohort.

Impaired processing speed and attention in first-episode drug naive schizophrenia with deficit syndrome

Although first-episode drug naive patients with schizophrenia are known to show cognitive impairment, the cognitive performances of these patients, who suffer deficit syndrome, compared with those who suffer non-deficit syndrome is undetermined. The aim of this study was to compare cognitive performances in first-episode drug-naive schizophrenia with deficit syndrome or non-deficit syndrome. First-episode drug naive patients (n=49) and medicated patients (n=108) with schizophrenia, and age, sex, and education matched healthy controls (n=57 for the first-episode group, and n=128 for the medicated group) were enrolled. Patients were divided into deficit or non-deficit syndrome groups, using the Schedule for Deficit Syndrome. Cognitive performance was assessed using the CogState computerized cognitive battery. All cognitive domains in first-episode drug naive and medicated patients showed significant impairment compared with their respective control groups. Furthermore, cognitive performance in first-episode drug naive patients was significantly worse than in medicated patients. Interestingly, the cognitive performance markers of processing speed and attention, in first-episode drug naive patients with deficit syndrome, were both significantly worse than in equivalent patients without deficit syndrome. In contrast, no differences in cognitive performance were found between the two groups of medicated patients. In conclusion, this study found that first-episode drug naive schizophrenia with deficit syndrome showed significantly impaired processing speed and attention, compared with patients with non-deficit syndrome. These findings highlight processing speed and attention as potential targets for pharmacological and psychosocial interventions in first-episode schizophrenia with deficit syndrome, since these domains are associated with social outcomes.

Association of the GDNF gene with depression and heroin dependence, but not schizophrenia, in a Chinese population.

The association of seven GDNF tag SNPs with depression, heroin dependence (HD) and schizophrenia was evaluated in Chinese. An increased risk of HD and depression was associated with rs2910709 T/T genotype and rs884344 C allele, respectively, suggesting GDNF is a novel susceptibility gene for depression and HD.

Integrating genome-wide association study and expression quantitative trait locus study identifies multiple genes and gene sets associated with schizophrenia

&NA; Schizophrenia is a serious mental disease with high heritability. To better understand the genetic basis of schizophrenia, we conducted a large scale integrative analysis of genome‐wide association study (GWAS) and expression quantitative trait loci (eQTLs) data. GWAS summary data was derived from a published GWAS of schizophrenia, containing 9394 schizophrenia patients and 12,462 healthy controls. The eQTLs dataset was obtained from an eQTLs meta‐analysis of 5311 subjects, containing 923,021 cis‐eQTLs for 14,329 genes and 4732 trans‐eQTLs for 2612 genes. Genome‐wide single gene expression association analysis was conducted by SMR software. The SMR analysis results were further subjected to gene set enrichment analysis (GSEA) to identify schizophrenia associated gene sets. SMR detected 49 genes significantly associated with schizophrenia. The top five significant genes were CRELD2 (p value = 1.65 × 10−11), DIP2B (p value = 3.94 × 10−11), ZDHHC18 (p value = 1.52 × 10−10) and ZDHHC5 (p value = 7.45 × 10−10), C11ORF75 (p value = 3.70 × 10−9). GSEA identified 80 gene sets with p values <0.01. The top five significant gene sets were COWLING_MYCN_TARGETS (p value <0.001) and CHR16P11 (p value <0.001), ACTACCT_MIR196A_MIR196B (p value = 0.002), CELLULAR_COMPONENT_DISASSEMBLY (p value = 0.002) and GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN (p value = 0.002). Our results provide useful information for revealing the genetic basis of schizophrenia. HighlightsThe first large scale integrative study of GWAS and eQTLs was conducted for schizophrenia.SMR analysis identified 49 significant genes, whose expression levels were related to schizophrenia.Enrichment analysis detected 80 gene sets significantly associated with schizophrenia.Our results expand the understanding of the genetic mechanism of schizophrenia.

Methylation of glucocorticoid receptor gene promoter modulates morphine dependence and accompanied hypothalamus–pituitary–adrenal axis dysfunction

Previous studies demonstrated that dysfunction of the hypothalamus–pituitary–adrenal (HPA) axis played an important role in morphine dependence. Nonetheless, the molecular mechanism underlying morphine‐induced HPA axis dysfunction and morphine dependence remains unclear. In the current study, 5′‐aza‐2′‐deoxycytidine (5‐aza), an inhibitor of DNA methyltransferases (DNMTs), was used to examine the effects of glucocorticoid receptor (GR) promoter 17 methylation on chronic morphine–induced HPA axis dysfunction and behavioral changes in rats and the underlying mechanism. Our results showed that chronic but not acute morphine downregulated the expression of nuclear GR protein and GR exon 17 variant mRNA, and upregulated the methylation of GR 17 exon promoter in the hippocampus of rats. Meanwhile, 5‐aza per se had no effect on observed molecular and behavior change. In contrast, pretreatment of 5‐aza into rat hippocampus reversed chronic morphine–induced hypermethylation of GR 17 promoter and decrease in GR expression. Moreover, pretreatment of 5‐aza attenuated chronic morphine‐enhanced HPA axis reactivity and the naloxone‐precipitated somatic signs in morphine‐dependent rats. Our results suggest that chronic morphine induced hypermethylation of GR 17 promoter, which then downregulated the expression of hippocampal GR, and was thus involved in chronic morphine–induced dysfunction of the HPA axis and the modulation of morphine dependence. Moreover, chronic morphine–induced hypermethylation of GR 17 promoter may be at least partially due to the increase in hippocampal DNMT 1 expression and its binding at GR 17 promoter in the rat hippocampus.

Reduced white matter connectivity associated with auditory verbal hallucinations in first-episode and chronic schizophrenia: A diffusion tensor imaging study

This study aims to explore whether auditory verbal hallucinations (AVH) in schizophrenia are associated with the white matter abnormalities in tracts connecting language, auditory and memory/limbic networks in first-episode and chronic schizophrenia patients. 21 first-episode (FE-AVH) and 12 chronic (chronic-AVH group) patients who suffered from auditory verbal hallucinations and 26 healthy controls (HC group) were enrolled. Diffusion tensor imaging with tract-based spatial statistics was performed to assess the white matter changes between the two patient groups and HC group. Decreased fractional anisotropy and increased radial diffusivity were found in the patient groups compared to the HC group in multiple white matter tracts including the corpus callosum, superior longitudinal fasciculus, inferior fronto-occipital fasciculus, uncinate fasciculus, cingulum, external capsule and anterior limb of the internal capsule. The chronic-AVH group showed more widespread white matter impairment than the FE-AVH group. Furthermore, increased axial diffusivity was also observed in some discrete regions of the chronic-AVH group. Auditory verbal hallucinations in schizophrenia are accompanied by white matter abnormalities in tracts connecting the language, auditory and memory/limbic networks. Chronic-AVH schizophrenia patients may present with more severe neurodegeneration relative to first-episode patients.

Impaired visual, working, and verbal memory in first-episode, drug-naive patients with major depressive disorder in a Chinese population

Cognitive impairment has been observed in patients with major depressive disorder (MDD). However, it remains unclear whether the deficits in specific cognitive domains are present in first-episode, drug-naïve patients or medicated patients. In the present study, using the CogState battery (CSB) Chinese language version, we evaluated the visual, working, and verbal memory in first-episode drug-naive patients and medicated patients with MDD in a Chinese population. We measured the cognitive function in first-episode drug-naïve patients (n = 36), medicated MDD patients (n = 71), and age- and sex-matched healthy control subjects (n = 59) in a Chinese population. The CSB composite scores in both first-episode drug-naive patients and medicated patients were significantly poorer than those in the healthy control subjects. The CSB sub-scores, including visual, working, and verbal memory were also significantly poorer in both patient groups than those in the healthy control subjects. In contrast, processing speed, attention/vigilance, executive function, spatial working memory, and social cognition were no different from healthy controls, whereas the executive function was significantly better in the medicated patients than in the healthy control subjects and first-episode drug-naïve patients. These findings suggest an impairment in the visual, working, and verbal memory in first-episode, drug-naive MDD patients in a Chinese population.