Bipolar, depression, epigenetics

Bipolar disorder is a debilitating psychiatric condition that is shaped in a concerted interplay between hereditary and triggering risk factors. Profound depression and mania define the disorder, but high clinical heterogeneity among patients complicates diagnosis as well as pharmacological intervention. Identification of peripheral biomarkers that capture the genomic response to the exposome may thus progress the development of personalized treatment. MicroRNAs (miRNAs) play a prominent role in of post-transcriptional gene regulation in the context of brain development and mental health...

We investigated gene-environment effects on structural brain endophenotype in bipolar disorder (BD) using a novel method of combining polygenic risk scores with epigenetic signatures since traditional methods of examining the family history and trauma effects have significant limitations. The study enrolled 119 subjects, including 55 BD spectrum (BDS) subjects diagnosed with BD or major depressive disorder (MDD) with subthreshold BD symptoms and 64 non-BDS subjects comprising 32 MDD subjects without BD symptoms and 32 healthy subjects...

Next-generation sequencing now enables the rapid and affordable production of reliable biological data at multiple molecular levels, collectively referred to as "omics". To maximize the potential for discovery, computational biologists have created and adapted integrative multi-omic analytical methods. When applied to diseases with traceable pathophysiology such as cancer, these new algorithms and statistical approaches have enabled the discovery of clinically relevant molecular mechanisms and biomarkers. In contrast, these methods have been much less applied to the field of molecular psychiatry, although diagnostic and prognostic biomarkers are similarly needed...

Bipolar disorder (BD) is a severe psychiatric disorder characterized by repeated conflicting manic and depressive states. In addition to genetic factors, complex gene-environment interactions, which alter the epigenetic status in the brain, contribute to the etiology and pathophysiology of BD. Here, we performed a promoter-wide DNA methylation analysis of neurons and nonneurons derived from the frontal cortices of mutant Polg1 transgenic (n = 6) and wild-type mice (n = 6). The mutant mice expressed a proofreading-deficient mitochondrial DNA (mtDNA) polymerase under the neuron-specific CamK2a promoter and showed BD-like behavioral abnormalities, such as activity changes and altered circadian rhythms...

The GABA receptors represent the main inhibitory system in the central nervous system that ensure synaptogenesis, neurogenesis, and the regulation of neuronal plasticity and learning. GABAA receptors are pentameric in structure and belong to the Cys-loop superfamily. The GABRB2 gene, located on chromosome 5q34, encodes the β2 subunit that combines with the α and γ subunits to form the major subtype of GABAA receptors, which account for 43% of all GABAA receptors in the mammalian brain. Each subunit probably consists of an extracellular N-terminal domain, four membrane-spanning segments, a large intracellular loop between TM3 and TM4, and an extracellular C-terminal domain...

The beliefs that antipsychotic drugs (APDs) are 1) effective only to treat delusions and hallucinations (positive symptoms), 2) that typical and atypical APDs differ only in ability to cause extrapyramidal side effects, and 3) that their efficacy as antipsychotics is due solely to their dopamine D2 receptor blockade are outmoded concepts that prevent clinicians from achieving optimal clinical results when prescribing an APD. Atypical APDs are often more effective than typical APDs in treating negative symptoms, cognitive impairment, and mood symptoms as well as reducing the risk for suicide and decreasing aggression...

The contemporary clinical idea of bipolar affective disorder (BD) has been shaped as an aftermath of Emil Kraepelin's thought named "manisch-depressives Irresein", put forward in 1899, with essential modifications during the last half-century. Acurrent paradigm for the etiopathogenesis of BD postulates the emergence of the illness as a result of an interaction between genetic and epigenetic factors with environmental influences.The most important for the molecular genetics of BD were the analyses of so-called candidate genes and genome-wide association studies (GWAS)...

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...

Clozapine is superior to other antipsychotics as a therapy for treatment-resistant schizophrenia and schizoaffective disorder with increased risk of suicidal behavior. This drug has also been used in the off-label treatment of bipolar disorder, major depressive disorder (MDD), and Parkinson's disease (PD). Although usually reserved for severe and treatment-refractory cases, it is interesting that electroconvulsive therapy (ECT) has also been used in the treatment of these psychiatric disorders, suggesting some common or related mechanisms...

Major Depressive Disorder (MDD) and Bipolar Disorder (BD) have a high prevalence and detrimental socio-economic consequences for the patients and the community. Furthermore, the depressive symptomatology of both disorders is essentially identical thus rendering the clinical differential diagnosis between the two significantly more difficult considering the concomitant lack of objective biomarkers. Mood disorders are multifactorial disorders the pathophysiology of which includes genetic, epigenetic, neurobiological, neuroimmunological, structural and functional brain alterations, etc...

Understanding the pathology of psychiatric disorders is challenging due to their complexity and multifactorial origin. However, development of high-throughput technologies has allowed for better insight into their molecular signatures. Advancement of sequencing methodologies have made it possible to study not only the protein-coding but also the noncoding genome. It is now clear that besides the genetic component, different epigenetic mechanisms play major roles in the onset and development of psychiatric disorders...

Dysregulated histone methylation has emerged as a recurring theme in multiple neuropsychiatric disorders. However, it is yet unclear whether the altered histone methylation is associated with aetiologic mechanisms or an outcome of disease manifestation. In this study, we examined the genomewide association studies datasets of three major psychiatric disorders, schizophrenia (SCZ), bipolar disorder (BIP), and major depression disorder (MDD), which represents a total of 231,783 cases and 425,444 controls, to clarify the relationship...

DNA methylation is a broadly-investigated epigenetic modification that has been considered as a heritable and reversible change. Previous findings have indicated that DNA methylation regulates gene expression in the central nervous system (CNS). Also, disturbance of DNA methylation patterns has been associated with destructive consequences that lead to human brain diseases such as neuropsychiatric disorders (NPDs). In this review, we comprehensively discuss the mechanism and function of DNA methylation and its most recent associations with the pathology of NPDs-including major depressive disorder (MDD), schizophrenia (SZ), autism spectrum disorder (ASD), bipolar disorder (BD), and attention/deficit hyperactivity disorder (ADHD)...

Childhood abuse (CA) is a prevalent global health concern, increasing the risk of negative mental health outcomes later in life. In the literature, CA is commonly defined as physical, sexual, and emotional abuse, as well as neglect. Several mental disorders have been associated with CA, including depression, bipolar disorder, schizophrenia, and post-traumatic stress disorder, along with an increased risk of suicide. It is thought that traumatic life events occurring during childhood and adolescence may have a significant impact on essential brain functions, which may persist throughout adulthood...

Pharmacotherapy is the most common treatment for schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD). Pharmacogenetic studies have achieved results with limited clinical utility. DNA methylation (DNAm), an epigenetic modification, has been proposed to be involved in both the pathology and drug treatment of these disorders. Emerging data indicates that DNAm could be used as a predictor of drug response for psychiatric disorders. In this study, we performed a systematic review to evaluate the reproducibility of published changes of drug response-related DNAm in SCZ, BD and MDD...

INTRODUCTION: Mood disorders are severe yet frequent psychiatric disorders worldwide, comprising major depressive disorder (MDD) and bipolar disorders (BD). Their treatment remains poorly effective. Recently, growing evidence for epigenetic mechanisms has emerged. Consequently, a great interest in a novel pharmacological class arose: RNA therapeutics. AREAS COVERED: We conducted a systematic review of RNA therapeutics -antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), short hairpin RNAs (shRNAs), and micro-RNA (miRNA) therapeutics- for the treatment of mood disorders studied in pre-clinical animal models listed in PubMed, in clinical trials registered in ClinicalTrials...

INTRODUCTION: Since the year 2000, over 413,000 service members have sustained traumatic brain injury (TBI) and may present with post-concussive sequelae including headaches, fatigue, irritability, cognitive problems, depression, insomnia, and chronic pain. Although the focus of the article is on military TBI, the usefulness of S-adenosylmethionine (SAMe) would extend to both civilian and military populations. This narrative review examines the preclinical and clinical literature of SAMe's metabolism and alterations seen in disease states such as depressive disorders, pain disorders, fatigue, cognition, dementia, use in pregnancy and peripartum, children, adolescents, and adults, to the elderly with and without dementia, stroke, and neurodegeneration, in order to highlight its potential benefit in post-concussive sequelae after TBI...

BACKGROUND: The Stanley Foundation Bipolar Treatment Outcome Network (SFBN) recruited more than 900 outpatients from 1995 to 2002 from 4 sites in the United States (US) and 3 in the Netherlands and Germany (abbreviated as Europe). When funding was discontinued, the international group of investigators continued to work together as the Bipolar Collaborative Network (BCN), publishing so far 87 peer-reviewed manuscripts. On the 25th year anniversary of its founding, publication of a brief summary of some of the major findings appeared appropriate...

Since the bipolar disorder (BD) signals identified by genome-wide association study (GWAS) often reside in the non-coding regions, understanding the biological relevance of these genetic loci has proven to be complicated. Transcriptome-wide association studies (TWAS) providing a powerful approach to identify novel disease risk genes and uncover possible causal genes at loci identified previously by GWAS. However, these methods did not consider the importance of epigenetic regulation in gene expression. Here, we developed a novel epigenetic element-based transcriptome-wide association study (ETWAS) that tested the effects of genetic variants on gene expression levels with the epigenetic features as prior and further mediated the association between predicted expression and BD...

The biological bases of bipolar disorder include aspects related, among others, to neurohormonal pathways, neurotransmission, signal transduction, regulation of gene expression, oxidative stress, neuroplasticity, and changes in the immune system. There is still a gap in understanding its complex neurobiology and, consequently, developing new treatments. Multiple factors probably interact in this complex equation of pathophysiology of bipolar disorder, such as genetic, biochemical, psychosocial, and environmental stress events, correlating with the development and severity of the bipolar disorder...