Search

Background: Increasing evidence has indicated that dysfunction of miR-124 and target gene regulator of G protein signaling 4 (RGS4) may be involved in the etiology and treatment of major depressive disorder (MDD). However, the molecular mechanisms are not fully understood. This study aimed to investigate whether common genetic variations in these two genes are associated with MDD and therapeutic response to antidepressants in the Chinese population. Methods: Three polymorphisms including rs531564 (a functional single-nucleotide polymorphism [SNP] in MIR124-1), rs10759 (a microRNA-binding site SNP in RGS4), and rs951436 (a promoter SNP in RGS4) were genotyped in 225 Chinese MDD patients and 436 controls. Among the MDD patients, 147 accepted antidepressant treatment for 8 weeks with therapeutic evaluation at baseline, week 2, week 4, week 6, and week 8 using the 17-item Hamilton Rating Scale for Depression. Multifactor dimensionality reduction (MDR) was used to identify gene-gene interactions. Results: No significant association with MDD was discovered in single-SNP analyses. However, by MDR analysis, the three-locus model of gene-gene interaction was the best for predicting MDD risk. In pharmacogenetic study, a significant association was found in genotypic frequencies of rs951436 between the remitter and non-remitter groups (p=0.026, correction p=0.078). For further analysis, the rs951436 heterozygote carriers had threefold probabilities of achieving clinical complete remission (odds ratio =3.00, 95% confidence interval =1.33-6.76, p=0.007, correction p=0.021) as compared with rs951436 homozygotes (AA+CC) after 8 weeks of treatment. Conclusion: An interaction effect of MIR124-1 and RGS4 polymorphisms may play a more important role than individual factors for MDD development. Moreover, RGS4 gene polymorphisms may be associated with antidepressant response among the Han population. [ABSTRACT FROM AUTHOR]

Background: Nucleus Accumbens (NAc) is a vital brain region for the process of reward and stress, whereas microRNA plays a crucial role in depression pathology. However, the abnormality of NAc miRNA expression during the stress-induced depression and antidepressant treatment, as well as its biological significance, are still unknown.Methods: We performed the small RNA-sequencing in NAc of rats from three groups: control, chronic unpredictable mild stress (CUMS), and CUMS with an antidepressant, Escitalopram. We applied an integrative pipeline for analyzing the miRNA expression alternation in different model groups, including differential expression analysis, co-expression analysis, as well as a subsequent pathway/network analysis to discover both miRNA alteration pattern and its biological significance.Result: A total of 423 miRNAs were included in analysis.18/8 differential expressing (DE) miRNA (adjusted p < 0.05, |log2FC| > 1) were observed in controls Vs. depression/depression Vs. treatment, 2 of which are overlapping. 78% (14/18) of these miRNAs showed opposite trends of alteration in stress and treatment. Two micro RNA, miR-10b-5p and miR-214-3p, appeared to be hubs in the regulation networks and also among the top findings in both differential analyses. Using co-expression analysis, we found a functional module that strongly correlated with stress (R = 0.96, P = 0.003), and another functional module with a moderate correlation with anhedonia (R = 0.89, P = 0.02). We also found that predicted targets of these miRNAs were significantly enriched in the Ras signaling pathway, which is associated with both depression, anhedonia, and antidepressant treatment.Conclusion: Escitalopram treatment can significantly reverse NAc miRNA abnormality induced by chronic stress. However, the novel miRNA alteration that is absent in stress pathology also emerges, which means that antidepressant treatment is unlikely to bring miRNA expression back to the same level as the controls. Also, the Ras-signaling pathway may be involved in explaining the depression disease etiology, the clinical symptom, and treatment response of stress-induced depression. [ABSTRACT FROM AUTHOR]

Recently, increasing evidence has indicated that dysfunction of microRNA-124 (miR-124) might be involved in the pathophysiology and treatment of major depressive disorder (MDD) in some animal models of depression. However, the role of miR-124 in MDD patients remains unclear. The objective of this study was to investigate whether the miR-124 expression levels in peripheral blood mononuclear cells (PBMCs) were associated with MDD and to evaluate the effects of antidepressant treatment on miR-124 levels. Quantitative real-time PCR was applied to detect miR-124 expression in 32 pre- and post-treatment MDD patients and 30 healthy controls. Our results showed that expression levels of miR-124 from PBMCs in MDD patients were significantly higher than those in healthy controls (p < 0.001), and that the area under the curve of miR-124 from ROC analysis was 0.762 with a sensitivity of 83.33% and specificity of 66.67% in distinguishing MDD patients from healthy controls. In addition, the expression levels of miR-124 were significantly down-regulated after eight weeks of treatment (p < 0.001). MiRNA target gene prediction and functional annotation analysis indicated that altered miR-124 was involved in affecting some important biological processes and pathways related to MDD. These results provide new information on miR-124 involvement in the biological alterations of MDD and in antidepressant effects. [ABSTRACT FROM AUTHOR]

Rationale: Clinical observations indicate that atypical antipsychotics, especially clozapine, induce obsessive-compulsive (OC) symptoms in schizophrenia patients. Recent data from neuroimaging and clinical trials suggest a role for altered glutamate neurotransmission in the etiology of OC disorder (OCD), and SLC1A1, GRIN2B, and GRIK2 have all been reported to regulate glutamate transmission and affect OCD pathophysiology. Objectives: This study aimed to determine whether SLC1A1, GRIN2B, and GRIK2 are associated with clozapine-induced OC symptoms. Methods: A total of 250 clinically stable schizophrenia patients receiving clozapine treatment were recruited. The Yale-Brown Obsessive Compulsive Scale (Y-BOCS) was used to evaluate the severity of OC symptoms. Based on their Y-BOCS scores, 250 patients were divided into the OC and non-OC groups (patients with or without OC symptoms, respectively). Additionally, three reported OCD susceptibility polymorphisms, SLC1A1 (rs2228622), GRIN2B (rs890), and GRIK2 (rs1556995), were genotyped. Results: Trends of association with OC symptoms were observed in rs2228622A and rs890T alleles. SLC1A1 and GRIN2B interaction was found in the significant two-locus gene-gene interaction model ( p = 0.0021), using the multifactor dimensionality reduction method. Further analysis showed a significant interaction between SLC1A1 and GRIN2B on the Y-BOCS score ( F = 7.650, p < 0.001), and individuals with AA/TT genotypes had a significantly higher mean Y-BOCS score than those with other genotypes, except AG/TT. Conclusions: These results suggest that SLC1A1, GRIN2B, and interactions between the two may potentially confer a susceptibility to OC symptoms in schizophrenia patients receiving clozapine. [ABSTRACT FROM AUTHOR]

The prevalence of the metabolic syndrome (MetS) is higher among patients receiving atypical antipsychotics (AAPs) treatment, and even among AAPs, treatment with clozapine has been shown to be associated with a higher long-term incidence rate of MetS. Likewise, brain-derived neurotrophic factor (BDNF) deficiency has been reported to result in metabolic traits, such as increased food intake, hyperphagia and obesity, etc. In this study, we hypothesized that a functional polymorphism (Val66Met) in the BDNF gene may confer susceptibility to clozapine-induced MetS, potentially in a sex-specific manner, since an interaction between Val66Met polymorphism and sex was observed in our previous studies. A total of 199 schizophrenia patients being treated with clozapine 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 genotyped the Val66Met polymorphism, and measured the serum levels of fasting glucose (GLU), triglyceride (TG) and high density lipoprotein cholesterol (HDL). There was a trend indicating a significant association between the homozygous Met/Met genotype and MetS in male patients (OR = 2.39; 95% CI: 1.05–5.41; p = 0.039; corrected p = 0.078). Among the six risk factors listed in the ATPIII criteria, we found a significant association between fasting GLU levels and Val66Met polymorphism in males (p = 0.005; corrected p = 0.03), but not in females (p = 0.65). Post-hoc analysis in males revealed that the Met/Met carriers had significant higher levels of fasting GLU than those with Val/Val or Val/Met genotypes (p = 0.007; corrected p = 0.042 and p = 0.002; corrected p = 0.012, respectively). In conclusion, we observed a weak association between the Val66Met polymorphism and clozapine-induced MetS in a sex-specific manner. While preliminary, such findings prompt further, large-scale longitudinal studies to replicate these findings. [ABSTRACT FROM AUTHOR]

Abstract: Inflammation contributes to the pathophysiology of depression. Chemokine-like receptor-1 (CMKLR1) plays an important role both in the development of inflammation and in the mechanism of antidepressant effect of Omega-3 polyunsaturated fatty acids (Omega-3 PUFAs), ecosapeatanolicacid (EPA). The present study was to investigate the modification of CMKLR1 in chronic restraint stress (CRS) rats. CMKLR1 was examined in different brain region from CRS rats by using western blot and quantitative real-time PCR. The CMKLR1 expression in the hippocampus, prefrontal cortex and cerebellum was determined on 3, 7, 10 and 21 days of repeated restraint stress and was compared to controls. The results showed that the protein and mRNA level of CMKLR1 in the prefrontal cortex and hippocampus were significantly increased on day 3 and then decreased on day 7, 10 and 21 in the CRS rats. The protein and mRNA level of CMKLR1 in cerebellum was similar to that of control group throughout the whole experiment. Changed expression of brain CMKLR1 is suggested to be involved in the mechanism of depression. [Copyright &y& Elsevier]

Despite there is a wide range of antidepressants available, with various mechanisms of actions, the efficacy of current therapeutic options is yet satisfactory. Previous shreds of evidence have indicated that genetics, cognitive, neuroendocrine, as well as personality factors, are all intrinsically linked and contribute to the diversity of treatment outcomes. We, therefore, sought to investigate this hypothesis in this study. Based on 610 samples treated with a selection of serotonin reuptake inhibitor (SSRI), serotonin-norepinephrine reuptake inhibitors (SNRI), noradrenergic and specific serotonergic antidepressant (NaSSA) or tricyclic antidepressant (TCA), we compared the therapeutic effects of these four classes of drugs by survival analyses. Pharmacogenomic and survival analyses were carried out to explore the hereditary factors for curative effect and the accumulation of genetic factors was further discussed through pathway analysis and the global test. We built a machine learning-based prediction model that integrates genetic and non-genetic factors (including cognition, endocrinology, personality intelligence) to distinguish drug efficacy in single class drug situations. The values of the non-genetic makers after 6 weeks' treatment were collected to evaluate the efficacy of the model. Our results from the 6-week antidepressant therapeutic study indicated that SSRI and SNRI are better treatments than those of TCA and NaSSA in the Chinese population. Among all possible paired single-agent survival analyses, citalopram and venlafaxine were more effective than mirtazapine. Allele C carriers at rs6354 (SLC6A4) and allele G carriers at rs12150214 (SLC6A4) were significantly prone to poorer treatment response to fluoxetine. Besides, the combination of three loci (rs929377-rs6191-rs32897) located in HPA pathway was significantly associated with the treatment outcome of fluoxetine. In female MDD patients, the minor allele of rs6323 and rs1137070 on the MAOA gene likely lead to a worse response to venlafaxine. Furthermore, genetic variants linked to drug efficacy tended to concentrate on the neurotrophin pathway in depressed patients comorbid with anxiety. From multivariate models, more severe cognitive deficits, psychopathic personality and lower levels of operational intelligence, and higher levels of cortisol predicted worse response status with SSRI or SNRI after 6-week treatment. Notably, genetic factors in the multi-dimensional prediction model for both classes of drugs include loci in HTR2A and CRHBP genes. SSRI and SNRI are more suitable for the treatment of Chinese people with depression. SLC6A4 genetic variants, as well as HPA pathway, play an important role in the fluoxetine antidepressant therapeutic response while the polymorphism of MAOA gene involved in the pharmacological action of venlafaxine among female MDD patients. The presence of anxiety in MDD patients was related to the neurotrophin pathway. Genetic, cognitive, neuroendocrine, and personality intelligence factors combined have an ensemble impact on the medication effect of patients with major depression, leading to more precise and personalized medicine for specific groups of people. • SSRI and SNRI are better treatments in the Chinese population • SLC6A4 gene and HPA pathway play an important role in the fluoxetine antidepressant therapeutic response • The polymorphism of MAOA gene involved in the pharmacological action of venlafaxine among female patients • anxiety in MDD patients was related to the neurotrophin pathway • Genetic, cognition and concomitant symptom are critical factors in the selection of antidepressants for specific patients [ABSTRACT FROM AUTHOR]