Global hypomethylation in schizophrenia

Epigenetic aberrations in leukocytes of patients with schizophrenia: association of global DNA methylation with antipsychotic drug treatment and disease onset

Philippe A. Melas, Maria Rogdaki, Urban Ösby, Martin Schalling, Catharina Lavebratt, Tomas J. Ekström

Abstract

Even though schizophrenia has a strong hereditary component, departures from simple genetic transmission are prominent. DNA methylation has emerged as an epigenetic explanatory candidate of schizophrenia’s nonmendelian characteristics. To investigate this assumption, we examined genome-wide (global) and gene-specific DNA methylation levels, which are associated with genomic stability and gene expression activity, respectively. Analyses were conducted using DNA from leukocytes of patients with schizophrenia and controls. Global methylation results revealed a highly significant hypomethylation in patients with schizophrenia (P<2.0×10-6) and linear regression among patients generated a model in which antipsychotic treatment and disease onset explained 11% of the global methylation variance (adjusted R2=0.11, ANOVA P>0.001). Specifically, haloperidol was associated with higher (“control-like”) methylation (P=0.001), and early onset (a putative marker of schizophrenia severity) was associated with lower methylation (P=0.002). With regard to the gene-specific methylation analyses, and in accordance with the dopamine hypothesis of psychosis, we found that the analyzed region of S-COMT was hypermethylated in patients with schizophrenia (P=0.004). In summary, these data support the notion of a dysregulated epigenome in schizophrenia, which, at least globally, is more pronounced in early-onset patients and can be partly rescued by antipsychotic medication. In addition, blood DNA-methylation signatures show promise of serving as a schizophrenia biomarker in the future.—Melas, P. A., Rogdaki, M., Ösby, U., Schalling, M., Lavebratt, C., Ekström, T. J. Epigenetic aberrations in leukocytes of patients with schizophrenia: association of global DNA methylation with antipsychotic drug treatment and disease onset. FASEB J. 26, 2712-2718 (2012). www.fasebj.org

DNA (cytosine-5) methyltransferase inhibitors: a therapeutic agent for schizophrenia?

I think increasing DNA demethylation by increasing activity of TET enzymes, which demethylate DNA, would be much safer. Cancers are associated with a global hypomethylation in what are called seas as opposed to CpG islands which are hypermethylated

DNA methyltransferase inhibitors coordinately induce expression of the human reelin and glutamic acid decarboxylase 67 genes

Marija Kundakovic  1 Ying ChenErminio CostaDennis R Grayson Affiliations

Abstract

Reelin and glutamic acid decarboxylase 67 (GAD67) mRNAs and protein levels are substantially reduced in postmortem brains of patients with schizophrenia. Increasing evidence suggests that the observed down-regulation of reelin and GAD67 gene expression may be caused by dysfunction of the epigenetic regulatory mechanisms operative in cortical GABAergic interneurons. To explore whether human reelin and GAD67 mRNAs are coordinately regulated through DNA methylation-dependent mechanisms, we studied the effects of DNA methyltransferase inhibitors on reelin and GAD67 expression in NT-2 neuronal precursor cells. Competitive reverse transcription-polymerase chain reaction with internal standards was used to quantitate mRNA levels. The data showed that reelin and GAD67 mRNAs are induced in the same dose- and time-dependent manners. We further demonstrated that the activation of these two genes correlated with a reduction in DNA methyl-transferase activity and DNA methyltransferase 1 (DNMT1) protein levels. Time course Western blot analysis showed that DNMT1 protein down-regulation occurs temporally before the reelin and GAD67 mRNA increase. In addition, chromatin immunoprecipitation assays demonstrated that the activation of the reelin gene correlates with the dissociation of DNMT1 and methyl-CpG binding protein 2 (MeCP2) from the promoter, and an increased acetylation of histones H3 in the region. Together, our data strongly imply that human reelin and GAD67 genes are coordinately regulated through epigenetic mechanisms that include the action of DNMT1. Our study also suggests that negative regulation of the reelin gene involves methylation-dependent recruitment of DNMT1, MeCP2, and certain histone deacetylases, which most likely reduce the activity of the promoter by shifting the surrounding chromatin into a more compact state.

MCT oil is a disaster for individuals with schizophrenia

Any palmitic acid/stearic acid combination purchased must be very high quality and food grade otherwise shorter chain fatty acids could be mixed in which would cause very large difficulties. No stearic acid manufactured in Malaysia should be purchased.

Shorter Chain Triglycerides Are Negatively Associated with Symptom Improvement in Schizophrenia

Anna Tkachev,1,*Elena Stekolshchikova,1Nickolay Anikanov,1Svetlana Zozulya,2Aleksandra Barkhatova,2Tatiana Klyushnik,2 and Daria Petrova1Cecilia M. P. Rodrigues,

Abstract

Schizophrenia is a serious mental disorder requiring lifelong treatment. While medications are available that are effective in treating some patients, individual treatment responses can vary, with some patients exhibiting resistance to one or multiple drugs. Currently, little is known about the causes of the difference in treatment response observed among individuals with schizophrenia, and satisfactory markers of poor response are not available for clinical practice. Here, we studied the changes in the levels of 322 blood plasma lipids between two time points assessed in 92 individuals diagnosed with schizophrenia during their inpatient treatment and their association with the extent of symptom improvement. We found 20 triglyceride species increased in individuals with the least improvement in Positive and Negative Syndrome Scale (PANSS) scores, but not in those with the largest reduction in PANSS scores. These triglyceride species were distinct from the rest of the triglyceride species present in blood plasma. They contained a relatively low number of carbons in their fatty acid residues and were relatively low in abundance compared to the principal triglyceride species of blood plasma.

Low sphingomyelin in schizophrenia

The takeaway – ‘Sphingomyelin (SM) percentage was the lipid abnormality most robustly associated with a schizophrenia diagnosis.’

Membrane lipidomics in schizophrenia patients: a correlational study with clinical and cognitive manifestations

C Tessier  1   2 K Sweers  3 A Frajerman  2 H Bergaoui  2 F Ferreri  2 C Delva  4 N Lapidus  5   6 A Lamaziere  1   7 J P Roiser  8 M De Hert  3 P Nuss  1   2   7

Abstract

Schizophrenia is a severe mental condition in which several lipid abnormalities-either structural or metabolic-have been described. We tested the hypothesis that an abnormality in membrane lipid composition may contribute to aberrant dopamine signaling, and thereby symptoms and cognitive impairment, in schizophrenia (SCZ) patients. Antipsychotic-medicated and clinically stable SCZ outpatients (n=74) were compared with matched healthy subjects (HC, n=40). A lipidomic analysis was performed in red blood cell (RBC) membranes examining the major phospholipid (PL) classes and their associated fatty acids (FAs). Clinical manifestations were examined using the positive and negative syndrome scale (PANSS). Cognitive function was assessed using the Continuous Performance Test, Salience Attribution Test and Wisconsin Card Sorting Test. Sphingomyelin (SM) percentage was the lipid abnormality most robustly associated with a schizophrenia diagnosis. Two groups of patients were defined. The first group (SCZ c/SM-) is characterized by a low SM membrane content. In this group, all other PL classes, plasmalogen and key polyunsaturated FAs known to be involved in brain function, were significantly modified, identifying a very specific membrane lipid cluster. The second patient group (SCZ c/SM+) was similar to HCs in terms of RBC membrane SM composition. Compared with SCZ c/SM+, SCZ c/SM- patients were characterized by significantly more severe PANSS total, positive, disorganized/cognitive and excited psychopathology. Cognitive performance was also significantly poorer in this subgroup. These data show that a specific RBC membrane lipid cluster is associated with clinical and cognitive manifestations of dopamine dysfunction in schizophrenia patients. We speculate that this membrane lipid abnormality influences presynaptic dopamine signaling.

Epigenetics, schizophrenia and identical twins discordant for schizophrenia

Studies on identical twins where one twin has schizophrenia and the other twin does not show that schizophrenia is due to epigenetic changes. Where one identical twin has schizophrenia the probability of the other identical twin having schizophrenia is 40%. DNA and/or histones of the ill twin must be hypermethylated as the illness is not in the genes as one twin with the very same genes is not ill. That genes are all determinative is a sort of religious belief rather than a scientific viewpoint.

Life expectancy among persons with schizophrenia or bipolar affective disorder

Life-expectancy was 18.7 years shorter for schizophrenic men compared to men in the general population. Corresponding numbers for schizophrenic women was 16.3 years, for bipolar men 13.6 years, and for bipolar women 12.1 years,.’ With DNA demethylating mechanisms going awry in schizophrenia, due to dysregulation of TET enzymes and JumjC domain-containing proteins, all kinds of illnesses in individuals with schizophrenia can develop shortening life spans.

Why cocoa butter is not an option.

Unfortunately, no

Cocoa butter has high levels of stearic acid and palmitic acid but cocoa butter also has high levels of oleic acid. Oleic acid is a disaster in terms of mental health or at least olive oil is. Olive oil has very high levels of oleic acid. Chocolate is made from cocoa butter. Eating chocolate to ameliorate depression has attractions but due to the high oleic acid content of chocolate, chocolate does not work.

In schizophrenia desaturation from saturated fatty acids to monounsaturated fatty acids was enhanced as estimated by the ratios of products to precursors. Alternatively saturated fatty acids could be decreased compared to monosaturated fats due to saturated fats not being synthesized. A goal in terms of treatment of schizophrenia is to decrease the ratio of monounsatrutated fats to saturated fats by supplementing with a high quality food grade stearic acid/palmitic acid combination. Supplemental vitamin B6 would be required. Cholesterol and glucose levels would need to be checked. .

The case for autism being biochemically similar to schizophrenia and Alzheimer’s disease

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Aconitase activity was significantly decreased in cerebellums of individuals who had autism. Glutathione levels were decreased in individuals with autism. Glutathione peroxidase activity is decreased in individuals with autism. Homocysteine levels are increased in children with autism. Vitamin D levels are decreased in individuals with autism. Individuals with autism have reduced bone mineral density. Taurine levels are low in a subset of individuals with autism. There are low levels of biotin in patients with autism. Iron deficiency is very common in autism.

See my papers Treatment-resistant schizophrenia: focus on the transsulfuration pathway. and A disease-modifying treatment for Alzheimer’s disease: focus on the trans-sulfuration pathway as to how similar biochemical abnormalities are also present in schizophrenia and Alzheimer’s disease. Other posts on this blog are also relevant to biochemical abnormalities found in schizophrenia.

Autism, schizophrenia and Alzheimer’s disease are epigenetic illnesses. Despite various biochemical commonalities between autism, schizophrenia and Alzheimer’s disease there are epigenenetic differences with these epigenetic differences channeling the illnesses in divergent directions. However, with autism, schizophrenia and Alzheimer’s disease being fundamentally similar treatments for autism, schizophrenia and Alzheimer’s disease could be very similar. As there are now no biological treatments for autism treatments currently used in autism and which are partially effective can not now be clearly hooked up to a treatment for schizophrenia.

Social skills interventions is individuals with autism aged 6-21 have shown limited and equivocal effectiveness. Biological treatments for autism are needed.

Opioids can result in euphoria so opioid antagonists would be perfect for individuals with schizophrenia

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Samidorphan is an opioid antagonist. Samidorphan supposedly reduces weight gain that very frequently occurs with olanzapine. ALKERMES INC, a pharmaceutical corporation, concluded that individuals with schizophrenia could benefit from less than normal opioid agonism, which fits right in with the history of the treatment of schizophrenia. Some terrible treatment is somehow or other a boon to individuals with schizophrenia. Olanzapine/samidorphan, with olanzapine being the antipsychotic and samidorphan being the opioid antagonist, combines two pleasure killing drugs in one pill so, of course, olanzapine/samidorphan is a treatment advance for individuals with schizophrenia. Metabolic parameters did not vary between olanzapine and olanzapine/samidorphan and individuals on olanzapine/samidorphan still gain weight. Also a meta-analysis indicates that olanzapine/samidorphan is not effective in reducing weight gain due to olanzapine. LYBALVI, an olanzapine/samidorphan combination, was recently approved by the FDA for the treatment of schizophrenia and bipolar 1 disorder.