Longitudinal alterations in mRNA expression of the BDNF neurotrophin signaling cascade in blood correlate with changes in depression scores in patients undergoing electroconvulsive therapy.

Electroconvulsive therapy (ECT) appears to be the most effective treatment for severe depression. However, its mechanisms of action are incompletely understood. Evidence suggests ECT enhances neuroplasticity and neurogenesis. While studies on ECT-induced neuroplasticity focused on brain-derived neurotrophic factor (BDNF), other factors of the BDNF/TrkB signaling cascade remain underinvestigated. We assessed longitudinal changes in depression scores, serum BDNF protein levels, and mRNA expression of BDNF/TrkB related genes (BDNF, AKT1, ERK1, CREB), NR3C1 and IGF1 in peripheral blood in 19 treatment-resistant depressed patients undergoing ECT. We also analysed DNA methylation patterns at various timepoints to explore possible epigenetic regulation of mRNA expression. Using multilevel regression, we found a negative association between depression scores and blood-based mRNA expression of BDNF/TrkB related genes and NR3C1. Expression of BDNF, ERK1 and NR3C1 increased significantly over time (BDNF: ß = 0.0295, p = 0.003; ERK1: ß = 0.0170, p = 0.034; NR3C1: ß = 0.0035, p = 0.050). For these three genes changes in mRNA expression were highly correlated (R = 0.59 - 0.88) with changes in DNA methylation for multiple CpG sites in the respective genes. Also, serum BDNF protein levels increased across the study period (ß = 0.11, p = 0.001). Our findings show that the antidepressant effects of ECT are associated with changes in expression of BDNF and its signaling molecules and that these molecular markers can be detected in peripheral blood. Alterations in DNA methylation could be a key mechanism whereby ECT influences gene expression.

COMT Val158Met-stress interaction in psychosis: role of background psychosis risk.

BACKGROUND: The interplay between the catechol-O-methyltransferase (COMT) Val158Met polymorphism and environmental stress may have etiological relevance for psychosis, but differential effects have been reported in healthy control and patient groups, suggesting that COMT Val158Met interactions with stress may be conditional on background genetic risk for psychotic disorder. METHODS: Patients with a nonaffective psychotic disorder (n = 86) and control participants (n = 109) were studied with the experience sampling method (a structured diary technique) in order to assess stress, negative affect and momentary psychotic symptoms in the flow of daily life. RESULTS: Multilevel analyses revealed significant three-way interactions between group status (patient or control), COMT genotype and stress in the model of negative affect (χ(2)(2) = 13.26, P < 0.01) as well as in the model of momentary psychotic symptoms (χ(2)(2) = 6.92, P < 0.05). Exploration of the three-way interaction revealed that in patients, COMT genotype moderated the association between stress and negative affect (χ(2)(4) = 11.50, P < 0.005), as well as the association between stress and momentary psychosis (χ(2)(4) = 12.79, P < 0.005). Met/Met genotype patients showed significantly increased psychotic and affective reactivity to stress in comparison to the Val/Met and Val/Val genotypes. In contrast, healthy controls did not display large or significant COMT Val158Met X stress interactions. CONCLUSIONS: Important differences exist in the effect of COMT Val158Met on stress reactivity, which may depend on background risk for psychotic disorder. Differential sensitivity to environmental stress occasioned by COMT Val158Met may be contingent on higher order interactions with genetic variation underlying psychotic disorder.

Meta-analysis of MTHFR gene variants in schizophrenia, bipolar disorder and unipolar depressive disorder: evidence for a common genetic vulnerability?

Past analyses examining the relationship between genetic variation in the 5, 10-methylenetetrahydrofolate reductase (MTHFR) gene and psychiatric disorders have provided mixed and largely inconclusive findings. MTHFR is involved in the one-carbon metabolic pathway which is essential for DNA biosynthesis and the epigenetic process of DNA methylation. We conducted a meta-analysis of all published case-control studies investigating associations between two common MTHFR single nucleotide polymorphisms (SNPs), MTHFR C677T (sample size 29,502) and A1298C (sample size 7934), and the major psychiatric disorders (i) schizophrenia (SZ), (ii) bipolar disorder (BPD), and (iii) unipolar depressive disorder (UDD). In order to examine possible shared genetic vulnerability, we also tested for associations between MTHFR and all of these major psychiatric disorders (SZ, BPD and UDD) combined. MTHFR C677T was significantly associated with all of the combined psychiatric disorders (SZ, BPD and UDD); random effects odds ratio (OR)=1.26 for TT versus CC genotype carriers; confidence interval (CI) 1.09-1.46); meta-regression did not suggest moderating effects of psychiatric diagnosis, sex, ethnic group or year of publication. Although MTHFR A1298C was not significantly associated with the combination of major psychiatric disorders, nor with SZ, there was evidence for diagnostic moderation indicating a significant association with BPD (random effects OR=2.03 for AA versus CC genotype carriers, CI: 1.07-3.86). Meta-analysis on UDD was not possible due to the small number of studies available. This study provides evidence for shared genetic vulnerability for SZ, BPD and UDD mediated by MTHFR 677TT genotype, which is in line with epigenetic involvement in the pathophysiology of these psychiatric disorders.

REVIEW: Genome-wide findings in schizophrenia and the role of gene-environment interplay.

The recent advent of genome-wide mass-marker technology has resulted in renewed optimism to unravel the genetic architecture of psychotic disorders. Genome-wide association studies have identified a number of common polymorphisms robustly associated with schizophrenia, in ZNF804A, transcription factor 4, major histocompatibility complex, and neurogranin. In addition, copy number variants (CNVs) in 1q21.1, 2p16.3, 15q11.2, 15q13.3, 16p11.2, and 22q11.2 were convincingly implicated in schizophrenia risk. Furthermore, these studies have suggested considerable genetic overlap with bipolar disorder (particularly for common polymorphisms) and neurodevelopmental disorders such as autism (particularly for CNVs). The influence of these risk variants on relevant intermediate phenotypes needs further study. In addition, there is a need for etiological models of psychosis integrating genetic risk with environmental factors associated with the disorder, focusing specifically on environmental impact on gene expression (epigenetics) and convergence of genes and environment on common biological pathways bringing about larger effects than those of genes or environment in isolation (gene-environment interaction). Collaborative efforts that bring together expertise in statistics, genetics, epidemiology, experimental psychiatry, brain imaging, and clinical psychiatry will be required to succeed in this challenging task.

MTHFR and risk of metabolic syndrome in patients with schizophrenia.

OBJECTIVE: Meta-analyses have implicated polymorphisms in MTHFR, encoding a critical enzyme in folate and homocysteine metabolism, in both schizophrenia and CVD. METHOD: A possible association between the C677T and A1298C polymorphisms of the MTHFR gene on the one hand, and metabolic syndrome on the other, was examined in a naturalistic cohort of 518 patients with a schizophrenia spectrum disorder screened for metabolic disturbances at the Catholic University of Louvain, Belgium. RESULTS: MTHFR A1298C, but not C677T, was associated with the metabolic syndrome, C/C genotypes having a 2.4 times higher risk compared to A/A genotypes (95% CI 1.25-4.76, p=0.009). Haplotype analysis revealed similar findings, showing greater risk for metabolic syndrome associated with the 677C/1298C haplotype compared to the reference 677C/1298A haplotype (OR 1.72, 95% CI 1.24-2.39, p=0.001). These associations were not explained by circulating folate levels. Differences between A1298C genotype groups were considerably greater in the subsample treated with clozapine or olanzapine (OR C/C versus A/A 3.87, 95% CI 1.51-9.96) than in subsample treated with any of the other antipsychotics (OR C/C versus A/A 1.30, 95% CI 0.47-3.74), although this did not formally reach statistical significance in the current cross-sectional study (gene-by-group interaction chi(2)=3.0, df=1, p=0.08). CONCLUSION: These data provide evidence supporting an association between MTHFR and risk of metabolic syndrome in patients with schizophrenia. Prospective studies evaluating the course of metabolic outcomes after initiation of antipsychotic medication are needed to evaluate possible gene-by-treatment interaction more specifically.

MTHFR genotype and differential evolution of metabolic parameters after initiation of a second generation antipsychotic: an observational study.

Most second-generation antipsychotics (SGAs) induce metabolic disturbances, but large differences exist in the degree to which individual patients develop these. Little is known about genetic factors associated with differential liability. Cross-sectional studies suggested an association between polymorphisms in 5,10-methylenetetraydrofolate reductase (MTHFR) and metabolic syndrome in patients with schizophrenia. This study aimed to assess whether the C677T (rs1801133) or A1298C (rs1801131) polymorphism in the MTHFR gene predict differential evolution of metabolic parameters over the course of a 3-month follow-up period after initiation of an SGA. One hundred and four patients with schizophrenia initiated on a SGA were measured at baseline, 6 weeks and 3 months. MTHFR A1298C, but not C677T, genotype predicted pos-baseline increases in weight [beta=2.5, standard error (SE)=0.92, P=0.006], waist circumference (beta=2.0, SE=1.0, P=0.050), fasting glucose (beta=2.8, SE=1.2, P=0.024) and glucose at 120 min during the Oral Glucose Tolerance Test (beta=10.7, SE=4.5, P=0.018) following a de novo metabolic challenge with a specific SGA. A1298C allele carriers consistently displayed the most unfavorable evolution of metabolic parameters. Thus, MTHFR A1298C genotype may explain part of the individual liability to metabolic disturbances in patients with schizophrenia.

Epigenetic regulation in the pathophysiology of Alzheimer's disease.

With the aging of the population, the growing incidence and prevalence of Alzheimer's disease (AD) increases the burden on individuals and society as a whole. To date, the pathophysiology of AD is not yet fully understood. Recent studies have suggested that epigenetic mechanisms may play a pivotal role in its course and development. The most frequently studied epigenetic mechanisms are DNA methylation and histone modifications, and investigations relevant to aging and AD are presented in this review. Various studies on human postmortem brain samples and peripheral leukocytes, as well as transgenic animal models and cell culture studies relevant to AD will be discussed. From those, it is clear that aging and AD are associated with epigenetic dysregulation at various levels. Moreover, data on e.g. twin studies in AD support the notion that epigenetic mechanisms mediate the risk for AD. Conversely, it is still not fully clear whether the observed epigenetic changes actually represent a cause or a consequence of the disease. This is mainly due to the fact that most clinical investigations on epigenetics in AD are conducted in samples of patients already in an advanced stage of the disease. Evidently, more research is needed in order to clarify the exact role of epigenetic regulation in the course and development of AD. Research on earlier stages of the disease could provide more insight into its underlying pathophysiology, possibly contributing to the establishment of early diagnosis and the development of more effective treatment strategies.