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Ruijie Geng,1 Haibin Li,1 Hao Wang,2 Chenyu Ye,1 Yemeng Mao,3 Xiao Huang1,4 1Department of Psychological Medicine, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China; 2Teaching Center of Experimental Medicine, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China; 3Department of Pharmacy, Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China; 4Department of Psychological Medicine, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen, Fujian, People’s Republic of ChinaCorrespondence: Xiao HuangDepartment of Psychological Medicine, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen, 361015, Fujian, People’s Republic of ChinaTel +86-0592-3501990Email huang.xiao@zs-hospital.sh.cnYemeng MaoDepartment of Pharmacy, Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, 600 South Wanping Road, Shanghai, 200030, People’s Republic of ChinaTel +86-21-64387250Email mao_yemeng@163.comObjective: This study aimed to explore the mechanism of venlafaxine in regulating the apoptosis of SHSY-5Y cells induced by hypoxia.Methods: The CoCl2-induced neuronal hypoxia model was established based on SHSY-5Y cells. The morphology and related protein expression of SHSY-5Y cells were detected by qPCR, ELISA and Western blot.Results: Under the condition of hypoxia-induced by CoCl2, the expression of HIF-1α in SHSY-5Y cells was up-regulated and the expression of β-catenin was down-regulated. After adding siRNA targeting HIF-1 α to the culture cell system, down-regulation of β -catenin expression in SHSY-5Y cells was restored. This confirmed the existence of the “hypoxia-HIF-1α-Wnt/β-catenin-depression” axis. Further studies have shown that venlafaxine can alleviate neuronal apoptosis induced by hypoxia by upregulating the Wnt/β-catenin signaling pathway.Conclusion: Venlafaxine regulates apoptosis induced by hypoxia through the Wnt/β-catenin signaling pathway, which provides a new theoretical basis for the treatment of depression.Keywords: venlafaxine, Wnt/β-catenin, SHSY-5Y cells, apoptosis

Background The serotonin receptor 1A and 1B (HTR1A/1B) gene have been suggested to be involved in the pathogenesis of major depressive disorder (MDD) and the antidepressant treatment response. Gene expression differences were partly mediated by genetic polymorphism and DNA methylation which might be affected by environmental factors. In the present study, we attempt to identify whether HTR1A/1B DNA methylation and genetic polymorphism could predict antidepressant treatment response. Methods 85 Chinese Han MDD patients were clinically assessed 8 weeks after of initiating escitalopram treatment for the first time. Antidepressant treatment response was assessed by changes in the Hamilton Depression Rating Scale-17 items (HAMD-17) score. The Life Events Scale (LES) and the Childhood Trauma Questionnaire (CTQ) were utilized as the assessment of previous life stress. The Illumina HiSeq platform was used to assess DNA methylation at 96 CpG sites located in HTR1A and HTR1B gene promoter regions. Six single nucleotide polymorphisms (SNPs) (HTR1A rs6294, rs116985176; HTR1B rs6296, rs6298, rs1228814, rs1778258) were genotype by using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) or PCR sequencing. Regression analyses were used to explore the relationship between DNA methylation and SNP and antidepressant response. Results We identified two CpG sites predictor of antidepressant treatment response (CpG 668, amplicon HTR1A_1, NC_000005.10, P = 0.025; CpG 1401, amplicon HTR1B_4, NC_000006.12, P = 0.033). The interaction of four CpG sites hypomethylation of HTR1A/1B with high recent stress might result in impaired antidepressant treatment response. What's more, the present data indicated that age, environments and antidepressant treatment might affect DNA methylation status. It was found that DNA methylation status could be influenced by antidepressant treatment in turn. However, HTR1A and HTR1B genotypes did not influence antidepressant response and DNA methylation status. Conclusions The results suggest that HTR1A/1B DNA hypomethylation and its interaction with recent life stress might drive impaired antidepressant treatment response. Meanwhile, DNA methylation, in turn, was modified by antidepressant treatment and environments. Our results offer new evidence for the role of epigenetic and genetic polymorphism in pharmacological response to antidepressants.

Schizophrenia is a kind of chronic mental disorder that leads to disability, and it is characterized by the incoordination of perception, mind, emotion and behaviour, and the disconnection between mental activities and reality. It is recurrent and hard to cure. Schizophrenia has caused both agony to patients and their families, and heavy economic burden to their families and society. The appearance of chlorpromazine, the first antipsychotic drug in the 1950s, brought about a revolutionary change in the treatment of schizophrenia. Even though the first-generation antipsychotic drug’s effectiveness for schizophrenia (especially the positive symptoms) was absolutely positive, it did not cause significant improvement in negative symptoms or cognitive impairment. Furthermore, these drugs could cause a variety of adverse reactions, such as extrapyramidal side effects, oversedation and so on. Therefore, a number of second-generation antipsychotic drugs gradually appeared on the market in the 1970s. Compared to the first-generation drugs, they were less likely to cause those side effects. In the meantime, some randomised controlled trials reported that the effectiveness of the second-generation antipsychotic drugs during the acute stage treatment of schizophrenia was significantly better than that of the first generation. Hence, a lot of hope was put into the second-generation antipsychotic drugs within the field of clinical psychiatry. However, as the drugs became more widely used, it was found that their long-term effect did not reach the expected level in many clinical observations and studies. In order to eliminate the pharmaceutical companies’ conflicts of interest in evidence-based medical studies, the National Institute of Mental Health granted a total of US$40 million funding to carry out the Clinical Anti-psychotic Trials of Intervention Effectiveness (CATIE) study in 57 centres of 24 states in the USA in 2005.1 According to the results of CATIE, there were no differences in the effectiveness of the second-generation antipsychotic drugs and perphenazine, the …

There is accumulating evidence indicating that long-term treatment with second-generation antipsychotics (SGAs) results in metabolic syndrome (MetS) and cognitive impairment. This evidence suggests an intrinsic link between antipsychotic-induced MetS and cognitive dysfunction in schizophrenia patients. Olanzapine is a commonly prescribed SGA with a significantly higher MetS risk than that of most antipsychotics. In this study, we hypothesized that olanzapine-induced MetS may exacerbate cognitive dysfunction in patients with schizophrenia.A sample of 216 schizophrenia patients receiving long-term olanzapine monotherapy were divided into two groups, MetS and non-MetS, based on the diagnostic criteria of the National Cholesterol Education Program's Adult Treatment Panel III. We also recruited 72 healthy individuals for a control group. Cognitive function was evaluated using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Plasma brain-derived neurotrophic factor (BDNF) and tumor necrosis factor-alpha (TNF-alpha) were measured by an enzyme-linked immunosorbent assay for 108 patients and 47 controls.Among the 216 schizophrenia patients receiving olanzapine monotherapy, MetS was found in 95/216 (44%). Patients with MetS had more negative symptoms, higher total scores in PANSS (Ps0.05) and lower immediate memory, attention, delayed memory and total scores in RBANS (Ps0.01). Stepwise multivariate linear regression analysis revealed that increased glucose was the independent risk factor for cognitive dysfunction (t=-2.57, P=0.01). Patients with MetS had significantly lower BDNF (F=6.49, P=0.012) and higher TNF-alpha (F=5.08, P=0.026) levels than those without MetS. There was a negative correlation between the BDNF and TNF-alpha levels in the patients (r=-0.196, P=0.042).Our findings provide evidence suggesting that the metabolic adverse effects of olanzapine may aggravate cognitive dysfunction in patients with schizophrenia through an interaction between BDNF and TNF-alpha.