Genetics and Epigenetics of Schizophrenia

Schizophrenia (SCZ) is a complex mental disorder, with a longstanding history of neurobiological investigation. It is more common in those persons who are genetically predisposed to the disorder. Since Kraepelin, psychiatrists were aware that the SCZ tended to run in families. Its heritability is up to 85%. Although the etiology of SCZ is unknown, it is now thought to be multifactorial, with multiple susceptibility genes interacting with environmental and developmental factors. There is a huge amount of genetic studies, including polymorphisms, expression, methylation, microRNAs, and epigenomics. However, identifying genes for SCZ using traditional genetic approaches has thus far proven quite difficult. Reasons for this include the complexity, heterogeneity, and comorbidity of this disorder, and also the poor definition of the clinical phenotype. Important approaches to find the relation between genotype and phenotype and may be causal genetic factors are endophenotypes and pathway analysis. However, genetic researchers need to consider carefully the models of causality they choose. There is a pathophysiological pathway that extends from genes, through proteins, neurons, neural circuits, neural regions, mental functions, external behaviors, and symptoms of SCZ. In this chapter, the genetics and epigenetics of SCZ are briefly discussed

The Role of Epigenetics in Psychosis

Epigenetics (genome - environment interaction) is the study of mitotically heritable, but reversible changes in gene expression without any change in DNA modifications and the chromatin structure. Transition to psychosis is a complex and longitudinal process during which epigenetic changes have been hypothesized and investigated. This process is especially important in individuals at high/ultrahigh risk for psychosis, before the development of full-blown psychosis. Psychoses is a range of complex disorders, where genetic variants explain only a portion of risk. Neuro-epigenetic mechanisms may explain the remaining share of risk, as well as the transition from susceptibility to the actual disease. There is a need for computational model of psychosis integrating genetic risk with environmental factors (epigenetic) associated with the disorder to discover its pathophysiological pathways. Epigenetic dysregulation of many genes has been widely speculated that are important factors involved in etiology, pathophysiology, and course of the psychoses, such as schizophrenia, and mood disorders with psychotic features. In addition, the role of epigenetic changes, including histone and DNA modifications and also targeting microRNAs in the treatment of psychoses is a new field of investigations

Longitudinal Effects of Bumetanide on Neuro-Cognitive Functioning in Drug-Resistant Epilepsy

Antiepileptic drugs (AEDs) have repeatedly shown inconsistent and almost contradictory effects on the neurocognitive system, from substantial impairments in processing speed to the noticeable improvement in working memory and executive functioning. Previous studies have provided a novel insight into the cognitive improvement by bumetanide as a potential antiepileptic drug. Through the current investigation, we evaluated the longitudinal effects of bumetanide, an NKCC1 co-transporter antagonist, on the brain microstructural organization as a probable underlying component for cognitive performance. Microstructure assessment was completed using SPM for the whole brain assay and Freesurfer/TRACULA for the automatic probabilistic tractography analysis. Primary cognitive operations including selective attention and processing speed, working memory capacity and spatial memory were evaluated in 12 patients with a confirmed diagnosis of refractory epilepsy. Participants treated with bumetanide (2 mg/ day) in two divided doses as an adjuvant therapy to their regular AEDs for 6 months, which followed by the re-assessment of their cognitive functions and microstructural organizations. Seizure frequency reduced in eight patients which accompanied by white matter reconstruction; fractional anisotropy (FA) increased in the cingulum-cingulate gyrus (CCG), anterior thalamic radiation (ATR), and temporal part of the superior longitudinal fasciculus (SLFt) in correlation with the clinical response. The voxel-based analysis in responder patients revealed increased FA in the left hippocampus, right cerebellum, and right medial temporal lobe, while mean diffusivity (MD) values reduced in the right occipital lobe and cerebellum. Microstructural changes in SLFt and ATR accompanied by a reduction in the error rate in the spatial memory test. These primary results have provided preliminary evidence for the effect of bumetanide on cognitive functioning through microstructural changes in patients with drug-resistant epilepsy

Comparing the effects of fluoxetine and imipramine on total cholesterol, triglyceride, and weight in patients with major depression

<p>Abstract</p> <p>Background</p> <p>There are some reports on the effects of antidepressants on metabolic syndrome. However, our search in the previously published literature showed a lack of information on the comparison of the effects of different classes of antidepressants on lipid profile. Therefore, this study was aimed to compare the effects of fluoxetine and imipramine on serum total cholesterol (TC) and triglyceride (TG) as well as body weight (BW) in patients with major depressive disorder.</p> <p>Methods</p> <p>Fifty one patients, 18 to 70 years of age, with major depressive disorder complied with the criteria of this preliminary, open-label clinical trial. Subjects received either imipramine (75–200 mg/day) or fluoxetine (20–40 mg/day) for 8 weeks. Total cholesterol and TG levels, as well as BW were compared at baseline with those at weeks 4 and 8. Data was analyzed by SPSS software version 16.0.</p> <p>Results</p> <p>In the fluoxetine group, TC levels decreased from 165.71 mg/dL to 156.71 mg/dL at week 4 (P = 0.07), and to 143.94 mg/dL at week 8 (P = 0.16); TG levels decreased from 129.35 mg/dL to 115.88 mg/dL at week 4 (P <0.001), and to 110.41 mg/dL at week 8 (P = 0.56). In the imipramine group, TC levels increased from 169.10 mg/dL to 178.69 mg/dL at week 4 (P = 0.07), and to 208.69 mg/dL at week 8 (P < 0.001) while TG levels increased from 111.73 mg/dL to 128.83 mg/dL at week 4 (P = 0.005), and to 160.90 mg/dL at week 8 (P < 0.001). BW was significantly increased in the imipramine group at weeks 4 and 8. In the fluoxetine group, BW was non-significantly decreased from 75.69 ± 7.97 Kg (baseline) to 75.67 ± 8.01 Kg at week 4 (P = 0.88), and to 75.22 ± 8.67 Kg at week 8 (P = 0.20), while in the imipramine group, BW had significant increases from 72.53 ± 8.55 Kg (baseline) to 73.95 ± 8.61 mg/dL at week 4 (P < 0.001), and to 75.13 ± 8.34 mg/dL at week 8 (P < 0.001).</p> <p>Repeated measures ANOVA showed significant effects on both TC and TG levels as well as on BW in all patients receiving imipramine. However, in patients on fluoxetine, repeated measures ANOVA showed significant effects of this medication only on TC levels in males.</p> <p>Conclusions</p> <p>Monitoring TC and TG and BW is recommended before starting imipramine in depressed patients with increased risk for cardiovascular disease. Fluoxetine may be the preferred agent in those with high or borderline high lipid levels.</p

Epidemiology of Major Depressive Disorder in Iran: a Systematic Review and Meta-Analysis

Objectives: There are a large number of primary researches on the prevalence of major depressive disorder (MDD) in Iran; however, their findings are varied considerably. A systematic review was performed in order to summarize the findings.Methods: Electronic and manual searches in international and Iranian journals were conducted to find relevant studies reporting MDD pre-valence. To maximize the sensitivity of the search, the references of relevant papers were also explored. We explored the potential sources of heterogeneity such as diagnostic tools, gender and other characteristics using meta-regression model. The com-bined mean prevalence rates were calculated for genders, studies using each type of instruments and for each province using meta-analysis method.Results: From 44 articles included in the systematic review, 24 reported current prevalence and 20 reported lifetime prevalence of MDD. The overall estimation of current prevalence of MDD was 4.1% (95% CI: 3.1-5.1). Women were 1.95 (95% CI: 1.55-2.45) times more likely to have MDD. The current prevalence of MDD in urban inhabitants was not significantly different from rural inhabitants. The analysis identified the variations in diagnostic tools as an important source of heterogeneity.Conclusions: Although there is not adequate information on MDD prevalence in some areas of Iran, the overall current prevalence of MDD in the country is high and females are at the greater risk of disease

Association between Neuregulin-1 Gene Variant ‎‎(rs2439272) and Schizophrenia and its Negative ‎Symptoms in an Iranian Population

Objective: Although the etiology of schizophrenia is unknown, it has a significant genetic component. ‎A number of studies have indicated that neuregulin-1 (NRG1) gene may play a role in the ‎pathogenesis of schizophrenia. In this study, we examined whether the rs2439272 of NRG1 ‎is associated with schizophrenia and its negative symptoms in an Iranian population.‎ Method: Rs2439272 was genotyped in 469 participants including 276 unrelated patients with schizophrenia and 193 healthy controls. The association of genetic risk with PANSS, and negative ‎symptoms was examined in the total, male and female samples. COCAPHASE and ‎CLUMP22 programs were used to compare the allele and genotype frequencies, and ‎general linear regression was used to analyze the quantitative dependent variables by the ‎selected variant.‎ Results: In this study, it was revealed that the G allele of rs2439272 might be an allele with the ‎increased risk of developing schizophrenia, especially in the male participants. In addition, ‎significant differences were found between the G allele and GG genotype frequencies and ‎PANSS, and negative symptoms in the total and male participants.‎ Conclusion: Our results supported the association between rs2439272 in NRG1 gene and risk of ‎schizophrenia and its negative symptoms in an Iranian population