Epigenetics, broadly defined as the regulation of gene expression without alteration of the genome, has become a field of tremendous interest in neuroscience, neurology, and psychiatry. This research has rapidly changed the way researchers think about brain function. Exciting epigenetic discoveries have been found in addiction, early life stress, neurodegeneration, post-traumatic stress disorder, and depression. As researchers more precisely define the epigenetic landscape that regulates disease progression in each of these cases, therapeutics can be designed to specifically target the molecules that mediate these epigenetic processes. Further, epigenetics may lead, to the identification of novel biomarkers for diagnosis and for the monitoring of treatment. Epigenetic profiling is likely to become a routine tool for the diagnosis of neurological and psychiatric disorders in the near future.
addiction; biomarker; epigenetics; therapeutics; PTSD; neurodegeneration
Psychiatric disorders are complex multifactorial disorders involving chronic alterations in neural circuit structure and function. While genetic factors play a role in the etiology of disorders such as depression, addiction, and schizophrenia, relatively high rates of discordance among identical twins clearly point to the importance of additional factors. Environmental factors, such as stress, play a major role in the psychiatric disorders by inducing stable changes in gene expression, neural circuit function, and ultimately behavior. Insults at the developmental stage and in adulthood appear to induce distinct maladaptations. Increasing evidence indicates that these sustained abnormalities are maintained by epigenetic modifications in specific brain regions. Indeed, transcriptional dysregulation and associated aberrant epigenetic regulation is a unifying theme in psychiatric disorders. Aspects of depression can be modeled in animals by inducing disease-like states through environmental manipulations, and these studies can provide a more general understanding of epigenetic mechanisms in psychiatric disorders. Understanding how environmental factors recruit the epigenetic machinery in animal models is providing new insights into disease mechanisms in humans.
acetylation; animal model; depression; early life; epigenetic; histone; methylation; stress
The transgenerational epigenetic programming involved in the passage of environmental exposures to stressful periods from one generation to the next has been examined in human populations, and mechanistically in animal models. Epidemiological studies suggest that gestational exposures to environmental factors including stress are strongly associated with an increased risk of neurodevelopmental disorders, including attention deficit-hyperactivity disorder, schizophrenia, and autism spectrum disorders. Both maternal and paternal life experiences with stress can be passed on to offspring directly during pregnancy or through epigenetic marks in the germ cell. Animal models of parental stress have examined relevant offspring phenotypes and transgenerational outcomes, and provided unique insight into the germ cell epigenetic changes associated with disruptions in neurodevelopment. Understanding germline susceptibility to exogenous signals during stress exposure and the identification of the types of epigenetic marks is critical for defining mechanisms underlying disease risk.
development; fetal; germline; histone; maternal; methylation; microRNA; paternal; sperm
Obesity is now epidemic worldwide. Beyond associated diseases such as diabetes, obesity is linked to neuropsychiatric disorders such as depression. Alarmingly maternal obesity and high-fat diet consumption during gestation/lactation may “program” offspring longterm for increased obesity themselves, along with increased vulnerability to mood disorders. We review the evidence that programming of brain and behavior by perinatal diet is propagated by inflammatory mechanisms, as obesity and high-fat diets are independently associated with exaggerated systemic levels of inflammatory mediators. Due to the recognized dual role of these immune molecules (eg, interleukin [IL]-6, 11-1β) in placental function and brain development, any disruption of their delicate balance with growth factors or neurotransmitters (eg, serotonin) by inflammation early in life can permanently alter the trajectory of fetal brain development. Finally, epigenetic regulation of inflammatory pathways is a likely candidate for persistent changes in metabolic and brain function as a consequence of the perinatal environment.
anxiety; cognition; epigenetics; maternal high-fat diet; maternal obesity; microglia; neuroinflammation; perinatal programming; placenta
We review studies with human and nonhuman species that examine the hypothesis that epigenetic mechanisms, particularly those affecting the expression of genes implicated in stress responses, mediate the association between early childhood adversity and later risk of depression. The resulting studies provide evidence consistent with the idea that social adversity, particularly that involving parent-offspring interactions, alters the epigenetic state and expression of a wide range of genes, the products of which regulate hypothalamic-pituitary-adrenal function. We also address the challenges for future studies, including that of the translation of epigenetic studies towards improvements in treatments.
chromatin; DNA methylation; epigenetics; glucocorticoid receptor; hypothalamic-pituitary-adrenal axis; maternal care
Drug addiction is characterized by uncontrolled drug consumption and high rates of relapse to drug taking during periods of attempted abstinence. Addiction is now largely considered a disorder of experience-dependent neuroplasticity, driven by remodeling of synapses in reward and motivation relevant brain circuits in response to a history of prolonged drug intake. Alterations in gene expression play a central role in addiction-relevant neuroplasticity, but the mechanisms by which additive drugs remodel brain motivation circuits remains unclear. MicroRNAs (miRNAs) are a class of noncoding RNA that can regulate the expression of large numbers of protein-coding mRNA transcripts by binding to the 3' untranslated region (3' UTR) of target transcripts and blocking their translation into the encoded protein or triggering their destabilization and degradation. Emerging evidence has implicated miRNAs in regulating addiction-relevant neuroplasticity in the brain, and in controlling the motivational properties of cocaine and other drugs of abuse. Here, the role for miRNAs in regulating basic aspects of neuronal function is reviewed. The involvement of miRNAs in controlling the motivational properties of addictive drugs is also summarized. Finally, mechanisms by which miRNAs exert their actions on drug intake, when known, are considered.
addiction; cocaine; nicotine; opiate; amphetamine; MeCP2; BDNF; miR-212
Cellular processes that control transcription of genetic information are critical for cellular function, and are often implicated in psychiatric and neurological disease states. Among the most critical of these processes are epigenetic mechanisms, which serve to link the cellular environment with genomic material. Until recently our understanding of epigenetic mechanisms has been limited by the lack of tools that can selectively manipulate the epigenome with genetic, cellular, and temporal precision, which in turn diminishes the potential impact of epigenetic processes as therapeutic targets. This review highlights an emerging suite of tools that enable robust yet selective interrogation of the epigenome. In addition to allowing site-specific epigenetic editing, these tools can be paired with optogenetic approaches to provide temporal control over epigenetic processes, allowing unparalleled insight into the function of these mechanisms. This improved control promises to revolutionize our understanding of epigenetic modifications in human health and disease states.
cognitive disorder; DNA methylation; epigenetics; epigenome editing; histone modification; neuroepigenetics; neuropharmacology; optoepigenetics; psychiatry
Dynamic regulation of chromatin structure in postmitotic neurons plays an important role in learning and memory. Methylation of cytosine nucleotides has historically been considered the strongest and least modifiable of epigenetic marks. Accumulating recent data suggest that rapid and dynamic methylation and demethylation of specific genes in the brain may play a fundamental role in learning, memory formation, and behavioral plasticity. The current review focuses on the emergence of data that support the role of DNA methylation and demethylation, and its molecular mediators in memory formation.
behavior; epigenetics; learning; synaptic plasticity
Early-onset, familial Alzheimer's disease (AD) is rare and may be attributed to disease-causinq mutations. By contrast, late onset, sporadic (non-Mendelian) AD is far more prevalent and reflects the interaction of multiple genetic and environmental risk factors, together with the disruption of epigenetic mechanisms controlling gene expression. Accordingly, abnormal patterns of histone acetylation and methylation, as well as anomalies in global and promoter-specific DNA methylation, have been documented in AD patients, together with a deregulation of noncoding RNA. In transgenic mouse models for AD, epigenetic dysfunction is likewise apparent in cerebral tissue, and it has been directly linked to cognitive and behavioral deficits in functional studies. Importantly, epigenetic deregulation interfaces with core pathophysiological processes underlying AD: excess production of Aβ42, aberrant post-translational modification of tau, deficient neurotoxic protein clearance, axonal-synaptic dysfunction, mitochondrial-dependent apoptosis, and cell cycle re-entry. Reciprocally, DNA methylation, histone marks and the levels of diverse species of microRNA are modulated by Aβ42, oxidative stress and neuroinflammation. In conclusion, epigenetic mechanisms are broadly deregulated in AD mainly upstream, but also downstream, of key pathophysiological processes. While some epigenetic shifts oppose the evolution of AD, most appear to drive its progression. Epigenetic changes are of irrefutable importance for AD, but they await further elucidation from the perspectives of pathogenesis, biomarkers and potential treatment.
acetylation; apoptosis; Bcl2; beta-amyloid methylation; cell cycle re-entry; HDAC; histone; inflammation; microRNA; microtubule; miR; miRNA; oxidative stress; phosphorylation; tau; secretase
Epigenetic modifications control chromatin structure and function, and thus mediate changes in gene expression, ultimately influencing protein levels. Recent research indicates that environmental events can induce epigenetic changes and, by this, contribute to long-term changes in neural circuits and endocrine systems associated with altered risk for stress-related psychiatric disorders such as major depression. In this review, we describe recent approaches investigating epigenetic modifications associated with altered risk for major depression or response to antidepressant drugs, both on the candidate gene levels as well as the genome-wide level. In this review we focus on DNA methylation, as this is the most investigated epigenetic change in depression research.
acetylation; antidepressant; epigenetics; epigenome-wide association study; EWAS; histone modification; major depression; methylation
Schizophrenia is a major psychiatric disorder that lacks a unifying neuropathology, while currently available pharmacological treatments provide only limited benefits to many patients. This review will discuss how the field of neuroepigenetics could contribute to advancements of the existing knowledge on the neurobiology and treatment of psychosis. Genome-scale mapping of DMA methylation, histone modifications and variants, and chromosomal loopings for promoter-enhancer interactions and other epigenetic determinants of genome organization and function are likely to provide important clues about mechanisms contributing to dysregulated expression of synaptic and metabolic genes in schizophrenia brain, including the potential links to the underlying genetic risk architecture and environmental exposures. In addition, studies in animal models are providing a rapidly increasing list of chromatin-regulatory mechanisms with significant effects on cognition and complex behaviors, thereby pointing to the therapeutic potential of epigenetic drug targets in the nervous system.
epigenome; DNA methylation; epigenetic drug target; histone modification; psychosis; prefrontal cortex
Schizophrenia (SZ) and bipolar disorder (BPD) patients show a downregulation of GAD67, reelin (RELN), brain-derived neurotrophic factor (BDNF), and other genes expressed in telencephalic GABAergic and glutamatergic neurons. This downregulation is associated with the enrichment of 5-methylcytosine and 5-hydroxymethylcytosine proximally at gene regulatory domains at the respective genes. A pharmacological strategy to reduce promoter hypermethylation and to induce a more permissive chromatin conformation is to administer drugs, such as the histone deacetylase (HDAC) inhibitor valproate (VPA), that facilitate chromatin remodeling. Studies in mouse models of SZ indicate that clozapine induces DNA demethylation at relevant promoters, and that this action is potentiated by VPA. By activating DNA demethylation, clozapine or its derivatives with VPA or other more potent and selective HDAC inhibitors may be a promising treatment strategy to correct the gene expression deficits detected in postmortem brain of SZ and BPD patients.
bipolar; chromatin remodeling; clozapine epigenetics; histone deacetylase inhibitor; neuroleptic; psychosis; schizophrenia
Clinical studies find that childhood adversity and stress-ful life events in adulthood increase the risk for major depression and for suicide. The predispositions to either major depression or suicide are thought to depend on genetic risk factors or epigenetic effects. We investigated DNA methylation signatures postmortem in brains of suicides with diagnosis of major depressive disorder. DNA methylation levels were determined at single C-phosphate-G (CpG) resolution sites within ventral prefrontal cortex of 53 suicides and nonpsychiatric controls, aged 16 to 89 years. We found that DNA methylation increases throughout the lifespan. Suicides showed an 8-fold greater number of methylated CpG sites relative to controls (P<2.2x10-16), with greater DNA methylation changes over and above the increased methylation observed in normal aging. This increased DNA methylation may be a significant contributor to the neuropathology and psychopathology underlying the risk of suicide in depression.
aging; depression; DNA methylation; epigenetics; mood disorder; suicide
The recent trend for recognizing the need that patients actively participate in the assessment of the outcome of treatment is a welcome development, not only because it adds valuable data, but also because its recognition of the partnership role that the patients should have in research on outcome of mental illness.
patient-reported outcome; psychiatry; mental health; patient report
Health-related quality of life (HRQoL) is a multidimensional concept that includes subjective reports of symptoms, side effects, functioning in multiple life domains, and general perceptions of life satisfaction and quality. Rather than estimating it from external observations, interview, or clinical assessment, it is best measured by direct query. Due to a perception that respondents may not be reliable or credible, there has been some reluctance to use self-report outcomes in psychiatry. More recently, and increasingly, HRQoL assessment through direct patient query has become common when evaluating a range of psychiatric, psychological, and social therapies. With few exceptions, psychiatric patients are credible and reliable reporters of this information. This article summarizes studies that highlight the development, validation, and application of HRQoL measures in psychiatry. Thoughtful application of these tools in psychiatric research can provide a much-needed patient perspective in the future of comparative effectiveness research, patient-centered outcomes research, and clinical care.
health-related quality of life; quality of life; psychiatric outcome; psychiatric symptom; patient-reported outcome
Assessing quality of life (QoL) as a patient-reported outcome in adult psychiatry poses challenges in terms of concepts, methods, and applications in research and practice. This review will outline conceptually the construct of QoL, its dimensionality, and its representation across patient groups. Methodological challenges are examined, along with principles of QoL instrument development and testing, as well as across cultures. Application of instruments in epidemiological, clinical health economics, and health services research is reviewed based on pertinent literature. Validated measures for depression, psychosis, and anxiety disorders are available in adult psychiatry, and are increasingly used in research. Still, targeted measures are lacking for many mental health conditions and only rarely are tools applied in the practice context. Progress has been made in the development of instruments that are now ready for implementation. The information to be gained is valuable for identifying patient-reported needs for and benefits of treatment.
adult; instrument; mental health; patient report; quality of life
This article provides an overview of the conceptual foundations of measuring health-related quality of life (HRQoL) in children and adolescents in child and adolescent psychiatry, and of the current state of research in this field. The available procedures for determining quality of life are presented according to their areas of use and their psychometric characteristics. The internationally available generic instruments for measuring HRQoL in children are identified and assessed in terms of their strengths and weaknesses with regard to selected criteria. As a result, seven generic HRQoL instruments and two utility procedures have been identified which satísfy the following criteria: (i) psychometric qualíty; (ii) age-appropriate measurement; (iii) versions for self-reporting and external rating; and (iv) cross-cultural measurement. The identified instruments satisfy the individual criteria to different degrees. They are increasingly being used in health services research, treatment studies, and epidemiological research; however, they are not yet widely used as part of the clinical routine in child and adolescent psychiatrics.
quality of life; child; adolescent; (generic) instrument
Patient-reported outcomes (PROs) are increasingly important in health care and mental health research. Furthermore, caregivers become partners in care for patients with mental disorders, and health workers are more attentive to the expectations and needs of caregivers. A number of outcomes for caregivers are measured and used in daily practice in order to promote actions to improve health care systems and progress in research on the impact of mental disorders on their caregivers. This paper proposes an inventory of the different outcomes and different measurement tools used to assess the impact of disorders, raising a number of methodological and conceptual issues that limit the relevance of measurement tools and complicate their use. Finally, we propose some recommendations promoting the development of relevant outcome measures for caregivers and their integration into current systems of care.
burden; caregiver; clinical and social outcome; mental health; patient-reported outcome; psychometrics
Patient reported outcomes (PROs) of quality of life (QoL), functioning, and depressive symptom severity are important in assessing the burden of illness of major depressive disorder (MDD) and to evaluate the impact of treatment. We sought to provide a detailed analysis of PROs before and after treatment of MDD from the large Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. This analysis examines PROs before and after treatment in the second level of STAR*D. The complete data on QoL, functioning, and depressive symptom severity, were analyzed for each STAR*D level 2 treatment. PROs of QoL, functioning, and depressive symptom severity showed substantial impairments after failing a selective serotonin reuptake inhibitor trial using citalopram (level 1). The seven therapeutic options in level 2 had positive statistically (P values) and clinically (Cohen's standardized differences [Cohen's d]) significant impact on QoL, functioning, depressive symptom severity, and reduction in calculated burden of illness. There were no statistically significant differences between the interventions. However, a substantial proportion of patients still suffered from patient-reported QoL and functioning impairment after treatment, an effect that was more pronounced in nonremitters. PROs are crucial in understanding the impact of MDD and in examining the effects of treatment interventions, both in research and clinical settings.
major depressive disorder; quality of life; functioning; individual burden of illness; STAR*D
The aim of the present article is to review QoL scales used in studies investigating patients with schizophrenia over the past 5 years, and to summarize the results of QoL assessment in clinical practice in these patients. Literature available from January 2009 to December 2013 was identified in a PubMed search using the key words “quality of life” and “schizophrenia” and in a cross-reference search for articles that were particularly relevant. A total of n=432 studies used 35 different standardized generic and specific QoL scales in patients with schizophrenia. Affective symptoms were major obstacles for QoL improvement in patients with schizophrenia. Though positive symptoms, negative symptoms, and cognitive functioning may be seen as largely independent parameters from subjective QoL, especially in cross-sectional trials, long-term studies confirmed a critical impact of early QoL improvement on long-term symptomatic and functional remission, as well as of early symptomatic response on long-term QoL. Results of the present review suggest that QoL is a valid and useful outcome criterion in patients with schizophrenia. As such, it should be consistently applied in clinical trials. Understanding the relationship between symptoms and functioning with QoL is important because interventions that focus on symptoms of psychosis or functioning alone may fail to improve subjective QoL to the same level. However, the lack of consensus on QoL scales hampers research on its predictive validity. Future research needs to find a consensus on the concept and measures of QoL and to test whether QoL predicts better outcomes with respect to remission and recovery under consideration of different treatment approaches in patients with schizophrenia.
antipsychotic; assertive community treatment; integrative care; quality of life; remission; schizophrenia; symptom
Patient self-reported symptoms are of crucial importance to identify anxiety disorders, as well as to monitor their treatment in clinical practice and research. Thus, for evidence-based medicine, a precise, reliable, and valid (ie, “objective”) assessment of the patient's reported “subjective” symptoms is warranted. There is a plethora of instruments available, which can provide psychometrically sound assessments of anxiety, but there are several limitations of current tools that need to be carefully considered for their successful use. Nevertheless, the empirical assessment of mental health status is not as accepted in medicine as is the assessment of biomarkers. One reason for this may be that different instruments assessing the same psychological construct use different scales. In this paper we present some new developments that promise to provide one common metric for the assessment of anxiety, to facilitate the general acceptance of mental health assessments in the future.
anxiety; computerized adaptive test; item response theory; measurement; patient-reported outcome; questionnaire
Since 2000, patient reports have contributed significantly to the widening diagnostic criteria for post-traumatic stress disorder, notably with the inclusion of complex, repeated, and indirect threat to people who develop symptoms. This paper describes and explains why patient reports matter, through worldwide mental health users' movements and the human rights movement. It looks at 46 recent patient-reported outcomes of preferred psychological treatments in clinical research and practice, and compares them with clinician-reported outcomes, using rating scales that diagnose and measure therapeutic gains. Attention is given to one qualitative study of survivors of the London bombings as an example of patients' personal traumatic experiences. Understanding patients' views and their limitations can help increase success in trauma-focused therapy outcomes, particularly where patients fail to engage with or complete treatment, where they doubt the validity of the treatment, or do not see it as culturally appropriate, or fear of revisiting the past. Specific recommendations are made for a more collaborative approach with patients in psychiatric and community care and clinical research.
PTSD diagnosis; patient report; trauma-focused CBT; engagement; attrition; EMDR; NET; users' movement; traumatic memory; London bombings survivors
The purpose of the article was to provide an overview of patient-reported outcomes (PROs) and related measures that have been examined in the context of obsessive-compulsive disorder (OCD). The current review focused on patient-reported outcome measures (PROMs) that evaluated three broad outcome domains: functioning, health-related quality of life (HRQoL), and OCD-related symptoms. The present review ultimately included a total of 155 unique articles and 22 PROMs. An examination of the PROs revealed that OCD patients tend to suffer from significant functional disability, and report lower HRQoL than controls. OCD patients report greater symptom severity than patients with other mental disorders and evidence indicates that PROMs are sensitive to change and may be even better than clinician-rated measures at predicting treatment outcomes. Nonetheless, it should be noted that the measures reviewed lacked patient input in their development. Future research on PROMs must involve patient perspectives and include rigorous psychometric evaluation of these measures.
patient-reported outcome; obsessive-compulsive disorder; functioning; health-related quality of life; symptom
Patient-reported outcome (PRO) refers to measures that emphasize the subjective view of patients about their health-related conditions and behaviors. Typically, PROs include self-report questionnaires and clinical interviews. Defining PROs for borderline personality disorder (BPD) is particularly challenging given the disorder's high symptomatic heterogeneity, high comorbidity with other psychiatric conditions, highly fluctuating symptoms, weak correlations between symptoms and functional outcomes, and lack of valid and reliable experimental measures to complement self-report data. Here, we provide an overview of currently used BPD outcome measures and discuss them from clinical, psychometric, experimental, and patient perspectives. In addition, we review the most promising leads to improve BPD PROs, including the DSM-5 Section III, the Recovery Approach, Ecological Momentary Assessments, and novel experimental measures of social functioning that are associated with functional and social outcomes.
recovery; DSM-5; Ecological Momentary Assessments; behavioral economics; game theory; comorbidity; quantitative trait psychology
Post-traumatic stress disorder (PTSD) may be associated with long-lasting psychological suffering, distressing psychosocial disability, markedly reduced health-related quality of life, and increased morbidity and mortality in a subgroup of individuals in the aftermath of serious traumatic events. Both etiopathogenesis and treatment modalities of PTSD are best conceptualized within a biopsychosotial model. Pharmacotherapy may lay claim to a major role in the multimodal treatment approaches. Here we outline two different pharmacotherapeutic trends that aim to modify the encoding, consolidation, and rehearsal of traumatic memory in order to reduce the risk of PTSD immediately after trauma exposure on the one hand, and that endeavor to treat the clinical state of PTSD on the other. The theoretical rationales of both pharmacological strategies are the complex neurobiological underpinnings that characterize traumatic memory organization and clinical PTSD. Meanwhile, promising data from randomized controlled trials have been obtained for both approaches. Empirical evidence may inform clinicians in their clinical efforts for this special group of patients. The efficacy of several classes of drugs that have been investigated within a context of research should be evaluated critically and still have to stand the test of effectiveness in daily clinical practice. From a patient perspective, empirical results may serve as a psychoeducative guideline to what pharmacotherapeutic approaches may realistically achieve, what their risks and benefits are, and what their limits are in contributing to reducing the often major chronic suffering caused by serious traumatic events. Ethical issues have to be considered, particularly in the context of pharmacological strategies projected to prevent PTSD in the aftermath of traumatic exposure.
trauma; trauma memory; PTSD; pharmacotherapy; prevention