Association between T-182C, G1287A polymorphism in NET gene and suicidality in major depressive disorder in Chinese patients.

Objective: Previous studies have implicated norepinephrine transporter gene (NET) polymorphisms in the etiology of major depressive disorder (MDD). A functional NET T-182C polymorphism (rs2242446) in the promoter region and a synonymous polymorphisms G1287A in the exon 9 (rs5569) were associated with MDD in different populations. However, few studies have focused on the relationship between these polymorphisms and MDD patients with suicidality. The objective of the present study was to examine whether the two polymorphisms are associated with MDD patients with suicidality in the Han Chinese population. Methods: Two hundred and sixty-three suicidal depressed patients and 241 non-suicidal depressed patients who met DSM-IV criteria for MDD were recruited from our hospital. Three hundred and three unrelated, age- and sex-matched healthy control subjects participated in this case-control study. Suicidality was assessed using Mini International Neuropsychiatric Interview (MINI) and the Hamilton rating scale for depression (HAMD). Genotypes of T-182C polymorphism (rs2242446) and G1287A (rs5569) were screened by polymerase chain reaction. Results: No statistical significant differences between patients and controls were found for any of the analysed polymorphisms, either in the genotype or allele distribution. Conclusions: Our results suggest that the investigated polymorphisms are not major susceptibility factors in the etiology of MDD with suicidality. However, the results must be verified in larger samples and different ethnicities.

Association study between 5-HT2A and NET gene polymorphisms and recurrent major depression disorder in Chinese Han population.

A functional NET T-182C polymorphism (rs2242446) in the promoter region, a synonymous polymorphisms G1287A in the exon 9(rs5569) and a functional serotonin 2A (5-HT2A) receptor (rs6311) genes in the promoter region were associated with MDD in different populations. However, few studies have focused on the relationship between these three polymorphisms and recurrent MDD patients in Chinese Han population. Three hundred MDD patients (112 males, 188 females) and three hundre unrelated healthy controls were enrolled in the study. POST-PCR ligase detection reaction genotype assay method was used for the genotypic analyses. There existed significant differences both in the frequencies of alleles and genotypes between patients and controls for the 5-HT2A receptor gene polymorphism (χ2=9.267, p=0.01 for genotype; χ2=7.615,p=0.006 for allele). No difference in genotype and allele distribution of G1287A, T182C were found in MDD patients and controls. Our results suggest that the rs6311 polymorphism seems to be the susceptibility factor in etiology of recurrent MDD. In conclusion, 5-HT2A receptor gene variants may be involved in the etiology of MDD, although the results must be verified in larger samples and different ethnicities.

The T-182C Polymorphism Enhances Promoter Activity of the Norepinephrine Transporter Gene, but may not be Associated with Antidepressant Response.

Background: Previous evidence has suggested that norepinephrine transporter (NET) gene (solute carrier family 6, member 2 [SLC6A2]) polymorphisms are involved in antidepressant response. Specifically, the polymorphism T-182C (rs2242446) located in the promoter region of SLC6A2 has been found to be associated with antidepressant response in multiple ethnic backgrounds. However, the results are inconsistent. Moreover, few studies have focused on how this T-182C polymorphism might regulate SLC6A2 promoter function. Methods: In this study, luciferase reporter assays were performed to examine the functional significance of the T-182C polymorphism. In addition, we performed a meta-analysis to explore whether this genetic variant is significantly involved in the antidepressant response. Results: We found that the -182(T) allele significantly increased promoter function compared to the C allele based on luciferase reporter assays. For the meta-analysis, six articles were identified that explored the relationship between the NET T-182C polymorphisms and antidepressant response. This study revealed no significant association between these polymorphisms and response to antidepressants (OR = 1.23, 95% CI = 0.77 - 1.97, p = 0.38 for T-182C). Conclusions: The T-182C polymorphism enhances promoter activity, but may not be associated with antidepressant response.

Predicting SSRI-Resistance: Clinical Features and tagSNPs Prediction Models Based on Support Vector Machine.

BACKGROUND: A large proportion of major depressive patients will experience recurring episodes. Many patients still do not response to available antidepressants. In order to meaningfully predict who will not respond to which antidepressant, it may be necessary to combine multiple biomarkers and clinical variables. METHODS: Eight hundred fifty-seven patients with recurrent major depressive disorder who were followed up 3-10 years involved 32 variables including socio-demographic, clinical features, and SSRIs treatment features when they received the first treatment. Also, 34 tagSNPs related to 5-HT signaling pathway, were detected by using mass spectrometry analysis. The training samples which had 12 clinical variables and four tagSNPs with statistical differences were learned repeatedly to establish prediction models based on support vector machine (SVM). RESULTS: Twelve clinical features (psychomotor retardation, psychotic symptoms, suicidality, weight loss, SSRIs average dose, first-course treatment response, sleep disturbance, residual symptoms, personality, onset age, frequency of episode, and duration) were found significantly difference (P< 0.05) between 302 SSRI-resistance and 304 SSRI non-resistance group. Ten SSRI-resistance predicting models were finally selected by using support vector machine, and our study found that mutations in tagSNPs increased the accuracy of these models to a certain degree. CONCLUSION: Using a data-driven machine learning method, we found 10 predictive models by mining existing clinical data, which might enable prospective identification of patients who are likely to resistance to SSRIs antidepressant.

The association between polymorphism of norepinephrine transporter G1287A and major depressive disorder, antidepressant response: a meta-analysis.

OBJECTIVES: Massive research has examined the cause of major depressive disorder (MDD) and accumulating evidence has revealed that the gene for the norepinephrine transporter (NET) is involved in MDDs etiology as well as the antidepressant response. The G1287A (rs5569, GRCh38, Chromosome 16, 55697923) is located in the exon 9 region of the SLC6A2 gene. It was found to be connected with MDD and antidepressant response in people of different genetic ancestries. However, the results are still inconsistent. METHODS: A meta-analysis was conducted to evaluate the overall association of rs5569 polymorphisms with MDD and the antidepressant response. RESULTS: Sixteen articles that studied the connection between the G1287A polymorphism and MDD or antidepressant response were identified, and their outcomes revealed there was a significant connection between the polymorphisms and MDD and antidepressant response. Our study indicated that the GG genotype may be a protection factor against the development of MDD [odds ratio (OR = 0.78, 95% confidence interval (CI) = 0.64-0.96, P = 0.02 for Asian population; OR = 0.79, 95% CI = 0.63-0.98, P = 0.03 for Han Chinese population] while the GG genotype had a worse antidepressant response (OR = 0.49, 95% CI = 0.25-0.94, P = 0.03). CONCLUSIONS: NET G1287A polymorphisms are involved in the etiology of MDD and antidepressant response.

A meta-analysis of selective serotonin reuptake inhibitors (SSRIs) use during prenatal depression and risk of low birth weight and small for gestational age.

BACKGROUND: Selective Serotonin Reuptake Inhibitors (SSRIs) act as the first-line antidepressants prescribed for the treatment of prenatal depression. Evidence from previous studies has suggested that the use of SSRIs treatment for prenatal depression has adversely affected fetal growth. However, these results are inconsistent and inconclusive. METHODS: In this study, we examined whether SSRIs use during pregnancy was related to low birth weight (LBW) and small for gestational age (SGA) using a meta-analysis approach. Relevant studies were retrieved by database searching and selected according to established inclusion criteria. RESULTS: Fifteen articles involved 1,977,446 subjects were identified that tested the relationship between the SSRIs use, LBW and SGA outcomes. Statistical analyses revealed a significant association between SSRIs use and suboptimal fetal growth (RR = 1.45, 95% CI = 1.18 - 1.76, Z = 3.62, p = 0.00 for SGA; RR = 1.38, 95% CI = 1.13 - 1.69, Z = 3.14, p = 0.00 for LBW). LIMITATIONS: These results must be treated with caution as we did not take the confounding factors into account (e.g., trimester SSRIs taken, specific SSRIs prescribed and maternal lifestyle during pregnancy) to elucidate their specific roles in the relationship between SSRIs use during pregnancy and fetal growth. CONCLUSION: Our findings suggested that SSRIs use for prenatal depression is associated with suboptimal fetal growth.

Treatment with escitalopram improves the attentional bias toward negative facial expressions in patients with major depressive disorders.

We hypothesized that treatment with escitalopram would improve cognitive bias and contribute to the recovery process for patients with major depressive disorder (MDD). Many previous studies have established that patients with MDD tend to pay selective attention to negative stimuli. The assessment of the level of cognitive bias is regarded as a crucial dimension of treatment outcomes for MDD. To our knowledge, no prior studies have been reported on the effects of treatment with escitalopram on attentional bias in MDD, employing a dot probe task of facial expression. We studied 25 patients with MDD and 25 controls, and used a dot probe task of facial expression to measure cognitive bias. The patients' psychopathologies were rated using the Hamilton Depression Scale (HAMD) at baseline and after 8 weeks of treatment with escitalopram. All participants performed the facial expression dot probe task. The results revealed that the 8 week escitalopram treatment decreased the HAMD scores. The patients with MDD at baseline exhibited an attentional bias towards negative faces, however, no significant bias toward either negative or happy faces were observed in the controls. After the 8 week escitalopram treatment, no significant bias toward negative faces was observed in the patient group. In conclusion, patients with MDD pay more attention to negative facial expressions, and treatment with escitalopram improves this attentional bias toward negative facial expressions. This is the first study, to our knowledge, on the effects of treatment with escitalopram on attentional bias in patients with MDD that has employed a dot probe task of facial expression.

No association between a polymorphism of the adenylate cyclase type IX gene and major depressive disorder in the Chinese Han population.

Previous studies have demonstrated that a missense single-nucleotide polymorphism variant (2316A>G; rs2230739) of the adenylate cyclase type IX gene was associated with bipolar disorder and affective disorder. We determined genotype and allele frequencies using a ligase detection reaction method in 315 patients with major depressive disorder and 278 unrelated, sex-matched healthy control subjects. We did not detect any statistically significant differences in genotype and allele frequencies between patients and healthy control subjects. Furthermore, we found no significant difference between genders in major depressive disorder, nor between patients and controls in the same gender. These results suggest that 2316A>G (rs2230739) may not be a risk factor for increasing susceptibility to major depressive disorder in the Chinese Han population.

The relationship between single nucleotide polymorphisms in 5-HT2A signal transduction-related genes and the response efficacy to selective serotonin reuptake inhibitor treatments in Chinese patients with major depressive disorder.

OBJECTIVE: To explore the possible relationship between six single nucleotide polymorphisms (SNPs) (rs6311 and rs6305 of 5-HT2A, rs5443 of Gß3, rs2230739 of ACDY9, rs1549870 of PDE1A and rs255163 of CREB1, which are all related with 5-HT2A the signal transduction pathway) and the response efficacy to selective serotonin reuptake inhibitor (SSRI) treatments in major depressive disorder (MDD) Chinese. METHODS: This study included 194 depressed patients to investigate the influence of 6 polymorphisms in 5-HT2A signal transduction-related genes on the efficacy of SSRIs assessed over 1 year. The efficacies of SSRIs on 194 MDD patients were evaluated in an 8-week open-trial study. Over 1 year, a follow-up study was completed for 174 of them to observe the long-term efficacy of SSRIs. The optimal-scaling regression analysis was used for testing the relationship between the different genotypes of five SNPs and the efficacy in MDD. RESULTS: It showed that the patients with rs5443TT and rs2230739GG have a relatively good efficacy in response to short-term SSRIs. We also found that good efficacy appeared in depressed patients with rs2230739GG in response to long-term SSRIs. CONCLUSIONS: It suggested that different genotypes of rs5443 and rs2230739 might influence the signal transduction pathways of second message and affect therapeutic efficacy.