Tricyclics vs SSRIs for postpartum depression

Summary Background: We investigated whether differential responsivity to tricyclics (TCA) compared to serotonin specific reuptake inhibitors (SSRI) occurred in our clinical population of women with postpartum depression. Method: Sequential records (N = 35) of women with non-psychotic, non-bipolar, postpartum-onset major depression were reviewed to determine drug response. Response was defined as 50% reduction in the initial depression score by week 8 of treatment. Results: The response rate was 67% for TCA was 79% for SSRI. The five nonresponders to TCA were treated with an SSRI, and four (80%) were effectively treated. Discussion: This naturalistic data obtained from our clinic supports that SSRI are superior to TCA for the treatment of postpartum major depression. The difference in percent response (12%) is similar to that of other studies in which TCA were compared to SSRI for treatment depression in women.     

Gender differences in response to antidepressant treatment prescribed in primary care. Does menopause make a difference?

BACKGROUND: Epidemiological surveys have consistently reported that the prevalence of major depression in women is almost twice as high as it is in men. While it seems that no major gender differences have been observed in the severity and symptomatology of depression, results regarding differences in antidepressant treatment response are controversial, especially when considering menopause in treatment response. METHODS: A total of 242 women (95 in their menopause), and 59 men beginning antidepressant treatment with a selective serotonin reuptake inhibitor (SSRI; Citalopram, Fluoxetine, Paroxetine or Sertraline) from 16 primary care (PC) centres were followed up during 6 months. Menopause effect and gender differences in antidepressant treatment response were evaluated. Additionally, severity and symptomatology of depression were compared among genders. RESULTS: Overall results suggest that menopause is related to a worse treatment response and to a poorer self-evaluation of global health status. No gender differences were observed in treatment response, depression severity, and symptomatology. LIMITATIONS: Since our sample included PC participants, a wide spectrum of depression severity was considered. Additionally, menopause was assessed by means of participants' self-report. CONCLUSIONS: Menopause seems to negatively affect SSRI treatment response of depressed women treated in PC.     

乳腺癌中印记基因SLC22A18/TSSC5/BWR1A启动子区甲基化及mRNA表达的研究

目的： 研究印记基因SLC22A18启动子区甲基化对乳腺侵润性导管癌组织中的SLC22A18 mRNA表达的影响，探讨其与临床病理特征之间的关系。方法：实时荧光定量逆转录聚合酶链反应（real-time quantitative RT-PCR）方法检测40例乳腺侵润性导管癌及其癌旁组织中SLC22A18 mRNA的表达，甲基化特异性聚合酶链反应(MSP)检测SLC22A18基因启动子区的甲基化状态。检测DNA甲基转移酶抑制剂5-氮杂-2′-脱氧胞苷（5-aza-2′-deoxycytidine，5-aza-dc）和组蛋白去乙酰化酶抑制剂曲古霉素A（TSA）作用于乳腺癌细胞株MDA-MB-231后，对SLC22A18基因启动子区DNA甲基化和mRNA表达的影响。结果：SLC22A18在40例乳腺侵润性导管癌中mRNA表达量低于癌旁组织（0.12±0.10 vs 0.69±1.05，P＜0.01）；40例乳腺侵润性导管癌及对应癌旁组织中，SLC22A18启动子区的甲基化发生率分别为75％和37.5%，差异有统计学意义（P＜0.01）；在40例乳腺侵润性导管癌组织中，甲基化组SLC22A18 mRNA表达量低于非甲基化组（0.11±0.08 vs 0.24±0.18，P＜0.01）。5-aza-dc和5-aza-dc/TSA能不同程度逆转乳腺癌细胞株MDA-MB-231中SLC22A18基因的甲基化状态，并上调SLC22A18基因表达。结论：SLC22A18基因甲基化与乳腺癌发生有一定的关联，SLC22A18基因表达下调与其启动子区CpG岛异常甲基化相关。     

Maternal depression and anxiety are associated with altered gene expression in the human placenta without modification by antidepressant use: implications for fetal programming

We sought to determine if maternal depression, anxiety, and/or treatment with selective serotonin reuptake inhibitors (SSRIs) affect placental human serotonin transporter (SLC6A4), norepinephrine transporter (SLC6A2), and 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) gene expression. Relative mRNA expression was compared among placental samples (n = 164) from healthy women, women with untreated depression and/or anxiety symptoms during pregnancy, and women who used SSRIs. SLC6A4 expression was significantly increased in placentas from women with untreated mood disorders and from women treated with SSRIs, compared to controls. SLC6A2 and 11β-HSD2 expression was increased in noncontrol groups, though the differences were not significant. SLC6A4, SLC6A2, and 11β-HSD2 expression levels were positively correlated. The finding that maternal depression/anxiety affects gene expression of placental SLC6A4 suggests a possible mechanism for the effect(s) of maternal mood on fetal neurodevelopmental programming. SSRI treatment does not further alter the elevated SLC6A4 expression levels observed with exposure to maternal depression or anxiety.     

Response to antidepressants in major depressive disorder with melancholic features: the CRESCEND study

BackgroundThis study aimed to determine whether major depressive disorders with melancholic and without melancholic features differ with respect to their responses to treatment with antidepressants.MethodsFrom a nationwide sample of 18 hospitals in South Korea, 559 presenting patients with major depressive disorder were recruited. The DSM-IV based Structured Clinical Interview was administered for confirmatory diagnoses and depression subtypes with/without melancholic features. After baseline evaluation, they received naturalistic clinician-determined antidepressant interventions. Assessment scales for evaluating depression (HAMD), anxiety (HAMA), global severity (CGI-s), and functioning (SOFAS) were administered at baseline and re-evaluated at 1, 2, 4, 8, and 12 weeks later.ResultsAt baseline, the 243 (43.5%) participants with melancholic features were more likely to have a previous history of depression, and had higher HAMA and lower SOFAS scores. After adjustment for baseline status, participants with melancholic features were more likely to achieve and to experience shorter times to CGI-s remission and associated with an enhanced global symptomatic remission with any antidepressant treatment. They were more likely to achieve and to experience shorter times to CGI-s remission and this difference was strongest in those receiving selective serotonin reuptake inhibitor (SSRI) antidepressants treatment.LimitationsThe study was observational, and the treatment modality was naturalistic.ConclusionsThese findings suggest a faster and more evident global response to pharmacotherapy in melancholia compared to other depressive syndromes, particularly where SSRI agents are used.     

Preeclampsia is Associated with Decreased Methylation of the GNA12 Promoter

Preeclampsia, characterized by high blood pressure, albuminuria and other systemic disorders, is a serious complication during pregnancy. It has been reported that GNA12 is overexpressed during preeclampsia. In this study, we investigated the potential association between the methylation of the GNA12 promoter and preeclampsia. The methylation level at eight CpG sites of the GNA12 promoter was analyzed by MassARRAY in placenta and peripheral blood DNA samples from 50 preeclampsia patients and 50 normal pregnant women. In the placenta DNA samples, the methylation level at three CpG sites of the GNA12 promoter was significantly lower in the preeclampsia patients than in the controls. The difference was also significant at two of the three CpG sites in the peripheral blood DNA samples. The mRNA expression level of GNA12 in placenta was analyzed by real‐time quantitative PCR in 20 cases and 20 controls. Consistent with the decreased methylation level, the mRNA expression level of GNA12 was higher in preeclampsia patients than in controls. Our results showed that preeclampsia is associated with decreased methylation of the GNA12 promoter, which can be detected in both the placenta and the peripheral blood of the pregnant women.     

Refined mapping of the human serotonin transporter (SLC6A4) gene within 17q11 adjacent to the CPD and NF1 genes

The SLC6A4 gene encodes the serotonin transporter, the target of an important class of antidepressant drugs (serotonin selective reuptake inhibitors). Polymorphisms in the SLC6A4 gene have been reported to be associated with susceptibility to depression and other psychiatric disorders. We have constructed a 1 Mb YAC and PAC contig which harbours both the SLC6A4 and the carboxypeptidase D (CPD) genes. The order of loci within the contig was cen-D17S975-D17S1549-24R-D17S1294-SLC6A4-28L+ ++-(CPD, D17S2009, D17S2004)-D17S2120-ter. Both genes were deleted in one of 17 neurofibromatosis type 1 (NF1) patients carrying submicroscopic NF1 contiguous gene deletions.     

DNA methylation of FKBP5 and response to exposure‐based psychological therapy

Differential DNA methylation of the hypothalamic‐pituitary‐adrenal axis related gene FKBP5 has recently been shown to be associated with varying response to environmental influences and may play a role in how well people respond to psychological treatments. Participants (n = 111) received exposure‐based cognitive behavioural therapy (CBT) for agoraphobia with or without panic disorder, or specific phobias. Percentage DNA methylation levels were measured for the promoter region and intron 7 of FKBP5. The association between percentage reduction in clinical severity and change in DNA methylation was tested using linear mixed models. The effect of genotype (rs1360780) was tested by the inclusion of an interaction term. The association between change in DNA methylation and FKBP5 expression was examined. Change in percentage DNA methylation at one CpG site of intron 7 was associated with percentage reduction in severity (β = ?4.26, p = 3.90 × 10^?4), where a decrease in DNA methylation was associated with greater response to therapy. An interaction was detected between rs1360780 and changes in DNA methylation in the promoter region of FKBP5 on treatment outcome (p = .045) but did not survive correction for multiple testing. Changes in DNA methylation were not associated with FKBP5 expression. Decreasing DNA methylation at one CpG site of intron 7 of FKBP5 was strongly associated with decreasing anxiety severity following exposure‐based CBT. In addition, there was suggestive evidence that allele‐specific methylation at the promoter region may also be associated with treatment response. The results of this study add to the growing literature demonstrating the role of biological processes such as DNA methylation in response to environmental influences.     

DYNC1H1 gene methylation correlates with severity of spinal muscular atrophy

Methylation profiles of CpG islands within the SLC23A2, CDK2AP1, and DYNC1H1 genes and their association with spinal muscular atrophy (SMA) severity were studied. High clinical heterogeneity of SMA suggests the existence of different factors modifying SMA phenotype with gene methylation as a plausible one. The genes picked up in our earlier genome‐wide methylation studies of SMA patients demonstrated obvious differences in their methylation patterns, thus suggesting the likely involvement of their protein products in SMA development. Significantly decreased methylation of CpG islands within exon 37 of the DYNC1H1 gene was observed in patients with a severe SMA manifestation (type I) compared to mildly affected SMA patients (types III–IV). This finding provides new information on peculiarities of methylation in clinically different types of SMA patients and gives a clue for identification of new SMA modifiers.     

Harm avoidance moderates the influence of serotonin transporter gene variants on treatment outcome in bipolar patients

Response to pharmacological treatments is moderated by both genetic and environmental factors. The contribution of such factors is relatively small and complex interactions are likely to be involved. Serotonin transporter gene (SLC6A4) is a major candidate gene associated to response to antidepressant treatment. Moreover, the 5-HTTLPR polymorphism has been associated with anxiety-related traits such as neuroticism and harm avoidance (HA), which are known to influence the risk to develop mood disorders and response to treatments. In the present study we aimed to investigate the interaction between 3 SLC6A4 variants and HA on medium term antidepressant response in a sample of depressed bipolar-spectrum patients followed for 12 months. Contrary to expectations, SLC6A4 variants did significantly influence neither the course of depressive symptoms nor HA scores. However, a significant interaction was observed between HA and 5-HTTLPR genotype. Indeed, a high HA impaired outcome in patients carrying the L_G/S or the S/S genotype more than in L_A/L_A patients. Though a number of limitations characterize the present study, our results indicate HA as a potential moderator of the effect of 5-HTTLPR on the outcome of depression. Given that many factors may influence response to pharmacological treatments, studies that consider personality and other individual characteristics are warranted also in pharmacogenetic investigations.     

CpG island methylation,response to combination chemotherapy,and patient survival in advanced microsatellite stable colorectal carcinoma

The CpG island methylator phenotype (CIMP) is a distinct epigenetic phenotype in colorectal carcinoma with concordant methylation in multiple promoter CpG islands. The relationship between CpG island methylation and clinical outcomes among colorectal cancer patients treated with chemotherapy has been a controversial subject. Utilizing real-time polymerase chain reaction (PCR; MethyLight technology), we quantified DNA methylation in 13 CpG island loci (CACNA1G, CDKN2A, CRABP1, IGF2, MLH1, NEUROG1, RUNX3, SOCS1, MINT1, MINT31, IGFBP3, MGMT, and WRN) in 30 metastatic microsatellite stable colorectal carcinomas in phase I/II clinical trials of combination chemotherapy (5-fluorouracil, irinotecan, leucovorin, and gefitinib). Tumor response was assessed by CT scans performed at baseline and every 6 weeks thereafter. Overall CIMP-high status (either ≥9/13 or ≥7/13 methylated markers; identifying 3 or 5 CIMP-high tumors, respectively) and methylation in CACNA1G, IGF2, MLH1, NEUROG1, RUNX3, MINT31, and WRN were associated with worse survival (all p < 0.01). Although not statistically significant, there was a trend toward resistance to chemotherapy among tumors with CpG island methylation. In conclusion, CpG island methylation may predict poor survival in metastatic microsatellite stable colorectal carcinoma treated with chemotherapy. Additional studies are necessary to examine the role of DNA methylation in treatment efficacy.     

Alteration of the affective modulation of the startle reflex during antidepressant treatment

Whereas the amplitude of the startle reflex varies with stimulus valence in the normal population, a lack of this affective modulation has been reported in patients with major depressive disorder. The present study sought to clarify blunted startle modulation as a feature of depression by comparing 16 patients diagnosed with major depression prior to and after 2 weeks of SSRI treatment, and 16 healthy controls. The affect‐modulated startle reflex paradigm and the Self‐Assessment Manikin were used to probe affective reactivity. In addition, a preliminary analysis of change in affective reactivity pattern was performed with depressed patients who could be assessed in the eighth week of treatment (n = 13). The control group showed a linear trend in response across valence categories, which was stable over sessions. Blunted affective reactivity was observed only in the patients and persisted after 2 weeks of treatment. Nevertheless, a linear trend could be detected in the eighth week of treatment. These findings confirm that the affective reactivity is blunted in depression and provide initial evidence for the lack of change in the early phase of SSRI antidepressant treatment. Nevertheless, in a small group, the emergence of a linear trend in response was evident later with treatment. Large‐scale studies are required to assess the relation between the treatment response and the change in affective modulation of the startle reflex, as a potential biomarker.     

Aberrant methylation impairs low density lipoprotein receptor‐related protein 1B tumor suppressor function in gastric cancer

DNA methylation plays a significant role in tumor progression. In this study, we used CpG microarray and differential methylation hybridization approaches to identify low density lipoprotein receptor‐related protein 1B (LRP1B) as a novel epigenetic target in gastric cancer. LRP1B was hypermethylated in four gastric cancer cell lines, and low LRP1B mRNA expression was associated with high methylation levels in gastric cancer cell lines. Addition of a DNA methylation inhibitor (5‐Aza‐dC) restored the mRNA expression of LRP1B in these cell lines, indicating that DNA methylation is involved in regulating LRP1B expression. In 45 out of 74 (61%) clinical samples, LRP1B was highly methylated; LRP1B mRNA expression was significantly lower in 15 out of 19 (79%, P < 0.001) gastric tumor tissues than in corresponding adjacent normal tissues. In addition, ectopic expression of mLRP1B4 in gastric cancer cell lines suppressed cell growth, colony formation and tumor formation in nude mice. These results collectively indicate that LRP1B is a functional tumor suppressor gene in gastric cancer and that is regulated by DNA methylation. © 2010 Wiley‐Liss,Inc.     

Serotonin receptor 1A −1019C/G variant: Impact on antidepressant pharmacoresponse in melancholic depression?

Previous studies on the effects of serotonin receptor 1A (5-HT1A) gene variation on treatment response in depression revealed inconsistent results with studies pointing towards a detrimental influence of the 5-HT1A −1019G allele on antidepressant treatment response, while others did not discern any involvement of 5-HT1A variants. In order to further delineate the impact of 5-HT1A gene variation on pharmacoresponse in depression over 6 weeks of antidepressant treatment, the influence of the 5-HT1A −1019C/G (rs6295) polymorphism was investigated in 340 Caucasian patients with a Major Depressive Episode (DSM-IV) with particular attention to the subtype of depression (major depression and melancholic depression). Antidepressant treatment response across 5-HT1A −1019C/G genotype groups showed no differences in either Major Depressive Episode or major depression between genotype groups, whereas stratification for the melancholic subtype of depression revealed a significantly worse treatment response as conferred by the −1019CC genotype (p = 0.02). The poorer treatment response in melancholic depression could first be detected in week 2 (p = 0.03), continuing until week 6 and showing a maximum effect in week 3 (p = 0.01). The present study adds to the clarification of the role of 5-HT1A variation in treatment response in major depression by providing preliminary support for poor treatment response mediated by the 5-HT1A −1019C allele repressing 5-HT1A activity specifically in the melancholic subtype of depression.     

Review of evidence for genetic testing for CYP450 polymorphisms in management of patients with nonpsychotic depression with selective serotonin reuptake inhibitors

PurposeCytochrome P450 (CYP450) enzymes metabolize selective serotonin reuptake inhibitor (SSRI) drugs used in treatment of depression. Variants in these genes may impact treatment efficacy and tolerability. The purpose of this study was 2-fold: to systematically review the literature for evidence supporting CYP450 genotyping to guide SSRI treatment for major depression, and, where evidence is inadequate, to suggest future research.MethodsWe searched MEDLINE® and other databases for studies addressing five key questions suggested by the Evaluation of Genomic Applications in Practice and Prevention Working Group. Eligibility criteria were defined, and studies were reviewed independently by paired researchers. A conceptual model was developed to guide future research.ResultsReview of 1200 abstracts led to the final inclusion of 37 articles. The evidence indicates relatively high analytic sensitivity and specificity of tests detecting a subset of polymorphisms of CYP2D6, 2C19, 2C8, 2C9, and 1A1. We found marginal evidence regarding a clinical association between CYP450 variants and SSRI metabolism, efficacy, and tolerability in the treatment of depression.ConclusionsCurrent evidence does not support the use of CYP450 genotyping to guide SSRI treatment of patients with depression. Studies are proposed that will effectively guide decision-making in the area of CYP450 testing in depression, and genetic testing more generally.     

Depression and Antidepressant Use in Gastrointestinal Carcinoid Cancer Patients1

Although mood disturbance is a common manifestation in all cancers that require clinical attention, very little is known regarding the psychiatric management of depression in patients with gastrointestinal carcinoid tumors. The goal of this study was to evaluate the degree of depression among patients with gastrointestinal carcinoid tumors, determine the prevalence of selective serotonin reuptake inhibitor (SSRI) use among these patients, and determine whether SSRI users differed from nonusers on demographic and general medical variables. Approximately 22% of the respondents in this study met screening criteria for clinically elevated or borderline depression. Moreover, 7% of respondents were following an SSRI regimen, whereas 7% were following a non‐SSRI antidepressant regimen. Analyses revealed no differences on demographic or general medical indicators between SSRI users and nonusers.     

Large-scale methylation analysis of human genomic DNA reveals tissue-specific differences between the methylation profiles of genes and pseudogenes

Cytosine in CpG dinucleotides is frequently found to be methylated in the DNA of higher eukaryotes and differential methylation has been proposed to be a key element in the organization of gene expression in man. To address this question systematically, we used bisulfite genomic sequencing to study the methylation patterns of three X-linked genes and one autosomal pseudogene in two adult individuals and across nine different tissues. Two of the genes, SLC6A8 and MSSK1, are tissue-specifically expressed. CDM is expressed ubiquitously. The pseudogene, psi SLC6A8, is exclusively expressed in the testis. The promoter regions of the SLC6A8, MSSK1 and CDM genes were found to be essentially unmethylated in all tissues, regardless of their relative expression level. In contrast, the pseudogene psi SLC6A8 shows high methylation of the CpG islands in all somatic tissues but complete demethylation in testis. Methylation profiles in different tissues are similar in shape but not identical. The data for the two investigated individuals suggest that methylation profiles of individual genes are tissue specific. Taken together, our findings support a model in which the bodies of the genes are predominantly methylated and thus insulated from the interaction with DNA-binding proteins. Only unmethylated promoter regions are accessible for binding and interaction. Based on this model we propose to use DNA methylation studies in conjunction with large-scale sequencing approaches as a tool for the prediction of cis-acting genomic regions, for the identification of cryptic and potentially active CpG islands and for the preliminary distinction of genes and pseudogenes.     

Prognostic CpG Methylation Biomarkers Identified by Methylation Array in Esophageal Squamous Cell Carcinoma Patients

Background: Esophageal squamous cell carcinoma (ESCC) is an aggressive cancer with poor prognosis. We aimed to identify a panel of CpG methylation biomarkers for prognosis prediction of ESCC patients.Methods: Illumina''s GoldenGate methylation array, supervised principal components, Kaplan-Meier survival analyses and Cox regression model were conducted on dissected tumor tissues from a training cohort of 40 ESCC patients to identify potential CpG methylation biomarkers. Pyrosequencing quantitative methylation assay were performed to validate prognostic CpG methylation biomarkers in 61 ESCC patients. The correlation between DNA methylation and RNA expression of a validated marker, SOX17, was examined in a validation cohort of 61 ESCC patients.Results: We identified a panel of nine CpG methylation probes located at promoter or exon1 region of eight genes including DDIT3, FES, FLT3, NTRK3, SEPT5, SEPT9, SOX1, and SOX17, for prognosis prediction in ESCC patients. Risk score calculated using the eight-gene panel statistically predicted poor outcome for patients with high risk score. These eight-gene also showed a significantly higher methylation level in tumor tissues than their corresponding normal samples in all patients analyzed. In addition, we also detected an inverse correlation between CpG hypermethylation and the mRNA expression level of SOX17 gene in ESCC patients, indicating that DNA hypermethylation was responsible for decreased expression of SOX17.Conclusions: This study established a proof-of-concept CpG methylation biomarker panel for ESCC prognosis that can be further validated by multiple cohort studies. Functional characterization of the eight prognostic methylation genes in our biomarker panel could help to dissect the mechanism of ESCC tumorigenesis.