Epigenetics antipsychotic response

Schizophrenia is a complex condition with entwined genetic and epigenetic risk factors, posing a challenge to disentangle the intermixed pathological and therapeutic epigenetic signatures. To resolve this, we performed 850K methylome-wide and 700K genome-wide studies on the same set of schizophrenia patients by stratifying them into responders, non-responders, and drug-naïve patients. The key genes that signified the response were followed up using real-time gene expression studies to understand the effect of antipsychotics at the gene transcription level...

BACKGROUND: Environmental modification of genetic information (epigenetics) is often invoked to explain interindividual differences in the phenotype of schizophrenia. In clinical practice, such variability is most prominent in the symptom profile and the treatment response. Epigenetic regulation of immune function is of particular interest, given the therapeutic relevance of this mechanism in schizophrenia. METHODS: We analyzed the DNA methylation data of immune-relevant genes in patients with schizophrenia whose disease duration was less than 3 years, with previous lifetime antipsychotic treatment of no more than 2 weeks total...

Major depressive disorder (MDD) is a complex disorder and a leading cause of disability in 280 million people worldwide. Many environmental factors, such as microbes, drugs, and diet, are involved in the pathogenesis of depressive disorders. However, the underlying mechanisms of depression are complex and include the interaction of genetics with epigenetics and the host immune system. Modifications of the gut microbiome and its metabolites influence stress-related responses and social behavior in patients with depressive disorders by modulating the maturation of immune cells and neurogenesis in the brain mediated by epigenetic modifications...

Background & methods: Researchers have aimed to understand the mechanisms of antipsychotics through epigenetics to inform interindividual response rates. However, findings have widely varied across studies, making advancement in the field difficult. Materials & methods: A systematic review was performed to include all epigenome-wide studies of antipsychotic treatment in humans. Methylation sites were used for a pathway and enrichment map analysis was conducted. Results & conclusion: Seven studies were included and 82 methylation sites were used for the exploratory pathway meta-analysis that identified six pathway clusters...

Schizophrenia is a severe and debilitating psychiatric disorder characterized by early cognitive deficits, emotional and behavioral abnormalities resulted by a dysfunctional gene x environment interaction. Genetic and epigenetic abnormalities in cortical parvalbumin-positive GABAergic interneurons lead to alterations in glutamate-mediated excitatory neurotransmission, synaptic plasticity, and neuronal development. Epigenetic alterations during pregnancy or early phases of postnatal life are associated with schizophrenia vulnerability as well as inflammatory processes which are at the basis of brain pathology...

BACKGROUND: Choosing the appropriate antipsychotic drug (APD) treatment for patients with schizophrenia (SCZ) can be challenging, as the treatment response to APD is highly variable and difficult to predict due to the lack of effective biomarkers. Previous studies have indicated the association between treatment response and genetic and epigenetic factors, but no effective biomarkers have been identified. Hence, further research is imperative to enhance precision medicine in SCZ treatment...

The adenosine hypothesis of schizophrenia was conceptualized about two decades ago in an attempt to integrate two prominent theories of neurochemical imbalance that attribute the pathogenesis of schizophrenia to hyperfunction of the mesocorticolimbic dopamine neurotransmission and hypofunction of cortical glutamate neurotransmission. Given its unique position as an endogenous modulator of both dopamine and glutamate signaling in the brain, adenosine was postulated as a potential new drug target to achieve multiple antipsychotic actions...

Schizophrenia is regarded as a neurodevelopmental disorder with its course progressing throughout life. However, the aetiology and development of schizophrenia are still under investigation. Several data suggest that the dysfunction of epigenetic mechanisms is known to be involved in the pathomechanism of this mental disorder. The present article revised the epigenetic background of schizophrenia based on the data available in online databases (PubMed, Scopus). This paper focused on the role of epigenetic regulation, such as DNA methylation, histone modifications, and interference of non-coding RNAs, in schizophrenia development...

BACKGROUND: Antipsychotic treatment-related alterations of cortical thickness (CT) and clinical symptoms have been previously corroborated, but less is known about whether the changes are driven by gene expression and epigenetic modifications. METHODS: Utilizing a prospective design, we recruited 42 treatment-naive first-episode schizophrenia patients (FESP) and 38 healthy controls. Patients were scanned by TI weighted imaging before and after 8-week risperidone monotherapy...

Background: The choice of efficient antipsychotic therapy for schizophrenia relies on a time-consuming trial-and-error approach, whereas the social and economic burdens of the disease call for faster alternatives. Material & methods: In a search for predictive biomarkers of antipsychotic response, blood methylomes of 28 patients were analyzed before and 4 weeks into risperidone therapy. Results: Several CpGs exhibiting response-specific temporal dynamics were identified in otherwise temporally stable methylomes and noticeable global response-related differences were observed between good and bad responders...

Histone lysine specific demethylase 1 (LSD1) has been recognized as an important epigenetic target for cancer treatment. Although several LSD1 inhibitors have entered clinical trials, the discovery of novel potent LSD1 inhibitors remains a challenge. In this study, the antipsychotic drug chlorpromazine was characterized as an LSD1 inhibitor (IC50 = 5.135 μM), and a series of chlorpromazine derivatives were synthesized. Among them, compound 3s (IC50 = 0.247 μM) was the most potent one. More importantly, compound 3s inhibited LSD1 in the cellular level and downregulated the expression of programmed cell death-ligand 1 (PD-L1) in BGC-823 and MFC cells to enhance T-cell killing response...

Various studies have investigated the relationship between genetic polymorphisms of antipsychotic drug-metabolizing agents and drug response. DNA methylation is a form of epigenetic modification that regulates gene expression. Few studies have analyzed the relationship between genome-wide methylation patterns and treatment resistance schizophrenia. The primary aim of this pilot study is to investigate the association between treatment resistance status and genome-wide DNA methylation in schizophrenia patients...

BACKGROUND: Antipsychotic treatment has been conceived to alter brain connectivity, but it is unclear how the changes of network phenotypes relate to the underlying transcriptomics. Given DNA methylation (DNAm) may alter transcriptional levels, we further integrated an imaging-transcriptomic-epigenetic analysis to explore multi-omics treatment response biomarkers. METHODS: Forty-two treatment-naive first-episode schizophrenia patients were scanned by TI weighted (T1W) imaging and DTI before and after 8-week risperidone monotherapy, and their peripheral blood genomic DNAm values were examined in parallel with MRI scanning...

Treatment-resistant schizophrenia (TRS) is defined as a non-response to at least two trials of antipsychotic medication with an adequate dose and duration. We aimed to evaluate the discriminant abilities of DNA methylation probes and methylation risk score between treatment-resistant schizophrenia and non-treatment-resistant schizophrenia. This study recruited 96 schizophrenia patients (TRS and non-TRS) and 56 healthy controls (HC). Participants were divided into a discovery set and a validation set. In the discovery set, we conducted genome-wide methylation analysis (human MethylationEPIC 850K BeadChip) on the subject's blood DNA and discriminated significant methylation signatures, then verified these methylation signatures in the validation set...

Although the etiopathogenesis of mental disorders is not fully understood, accumulating evidence support that clinical symptomatology cannot be assigned to a single gene mutation, but it involves several genetic factors. More specifically, a tight association between genes and environmental risk factors, which could be mediated by epigenetic mechanisms, may play a role in the development of mental disorders. Several data suggest that epigenetic modifications such as DNA methylation, post-translational histone modification and interference of microRNA (miRNA) or long non-coding RNA (lncRNA) may modify the severity of the disease and the outcome of the therapy...

Antipsychotic-induced metabolic syndrome (APs-induced Mets) is the most common adverse drug reaction, which affects more than 60% of the psychiatric patients. Although the etiology of APs-induced Mets has been extensively investigated, there is a lack of integrated analysis of the genetic and epigenetic factors. In this study, we performed genome-wide, whole-exome sequencing (WES) and epigenome-wide association studies in schizophrenia (SCZ) patients with or without APs-induced Mets to find the underlying mechanisms, followed by in vitro and in vivo functional validations...

Background: Volumetric alterations of subcortical structures as predictors of antipsychotic treatment response have been previously corroborated, but less is known about whether their morphological covariance relates to treatment outcome and is driven by gene expression and epigenetic modifications. Methods: Subcortical volumetric covariance was analyzed by using baseline T1-weighted magnetic resonance imaging (MRI) in 38 healthy controls and 38 drug-naïve first-episode schizophrenia patients...

Hyperimmunity drives the development of Alzheimer disease (AD). The immune system is under the circadian control, and circadian abnormalities aggravate AD progress. Here, we investigate how an AD-linked mutation deregulates expression of circadian genes and induces cognitive decline using the knock-in (KI) mice heterozygous for presenilin 2 N141I mutation. This mutation causes selective overproduction of clock gene-controlled cytokines through the DNA hypermethylation-mediated repression of REV-ERBα in innate immune cells...

Interindividual variability in drug response is a major concern among patients undergoing antipsychotic drug treatment. Apart from genetic and physiological factors, this variability in drug response could also be attributed to epigenetic mechanisms. The microRNAs (miRNAs) are key epigenetic markers that play an important role in pathogenesis and drug response. Several studies have shown that miRNAs are implicated in regulating the expression of various genes involved in drug metabolism and transport. In a conventional clinical setup, it is extremely difficult to distinguish the role of miRNA in pathogenesis and drug response as it is difficult to obtain drug naïve patients...

Schizophrenia (SCZ) is a severe psychiatric disorder with several clinical manifestations that include cognitive dysfunction, decline in motivation, and psychosis. Current standards of care treatment with antipsychotic agents are often ineffective in controlling the disease, as only one-third of SCZ patients respond to medications. The mechanisms underlying the pathogenesis of SCZ remain elusive. It is believed that inflammatory processes may play a role as contributing factors to the etiology of SCZ. Galectins are a family of β-galactoside-binding lectins that contribute to the regulation of immune and inflammatory responses, and previous reports have shown their role in the maintenance of central nervous system (CNS) homeostasis and neuroinflammation...