Epigenetics and Psychiatry

Psychiatric disorders including major depressive disorder, drug addiction, and schizophrenia are debilitating illnesses with a multitude of complex symptoms underlying each of these disorders. In recent years, it has become appreciated that the onset and development of these disorders goes beyond the one gene–one disease approach. Rather, the involvement of many genes is likely linked to these illnesses, and regulating the activation or silencing of gene function may play a crucial role in contributing to their pathophysiology. Epigenetic modifications such as histone acetylation and deacetylation, as well as DNA methylation can induce lasting and stable changes in gene expression, and have therefore been implicated in promoting the adaptive behavioral and neuronal changes that accompany each of these illnesses. In this review we will discuss some of the latest work implicating a potential role for epigenetics in psychiatric disorders, namely, depression, addiction, and schizophrenia as well as a possible role in treatment.

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The online version of this article (doi:10.1007/s13311-013-0213-6) contains supplementary material, which is available to authorized users.     

Endophenotypes, dimensions, risks: is psychosis analogous to common inherited medical illnesses?

Psychiatric illnesses are perceived as fundamentally different from common medical disorders, a view arising from the mind-body problem and difficulties relating the brain's emergent properties to its physiological substrates. However, schizophrenia and many common medical illnesses are heritable and result from the influence of both genetic and environmental sources. Unlike illnesses such as Huntington's disease, which are caused by a fully penetrant dominant mutation, no single "schizophrenia gene" has been identified. Instead, schizophrenia is likely caused by common variants of many genes, each contributing a subtle effect. Schizophrenia genetically resembles common medical illnesses such as type 2 diabetes, ischemic heart disease, and familial hypercholesterolemia, that have an associated genetic variant, but that are also influenced by other factors such as diet, culture and habits. Just as these illnesses operate through complex gene/environment interaction, schizophrenia is likely caused by several gene variants, neurodevelopmental processes, and learned behavioral response biases. These clinical diseases, however, represent severe forms of the phenotype for both psychiatric and medical illnesses. From a dimensional perspective, individuals possessing the same genotype could express milder forms of the clinical disorder along a spectrum of related traits. We discuss this perspective in the context of an endophenotypic and biological marker approach to understanding schizophrenia and present a research strategy to compare schizophrenia endophenotypes to risk for common medical illnesses.     

The involvement of the orbitofrontal cortex in psychiatric disorders: an update of neuroimaging findings

ObjectiveTo report structural and functional neuroimaging studies exploring the potential role of the orbitofrontal cortex (OFC) in the pathophysiology of the most prevalent psychiatric disorders (PD).MethodA non-systematic literature review was conducted by means of MEDLINE using the following terms as parameters: “orbitofrontal cortex”, “schizophrenia”, “bipolar disorder”, “major depression”, “anxiety disorders”, “personality disorders” and “drug addiction”. The electronic search was done up to July 2011.DiscussionStructural and functional OFC abnormalities have been reported in many PD, namely schizophrenia, mood disorders, anxiety disorders, personality disorders and drug addiction. Structural magnetic resonance imaging studies have reported reduced OFC volume in patients with schizophrenia, mood disorders, PTSD, panic disorder, cluster B personality disorders and drug addiction. Furthermore, functional magnetic resonance imaging studies using cognitive paradigms have shown impaired OFC activity in all PD listed above.ConclusionNeuroimaging studies have observed an important OFC involvement in a number of PD. However, future studies are clearly needed to characterize the specific role of OFC on each PD as well as understanding its role in both normal and pathological behavior, mood regulation and cognitive functioning.     

A role for Akt and glycogen synthase kinase-3 as integrators of dopamine and serotonin neurotransmission in mental health

Mental illnesses, such as bipolar disorder, attention-deficit/hyperactivity disorder, depression and schizophrenia are a major public health concern worldwide. Several pharmacologic agents acting on monoamine neurotransmission are used for the management of these disorders. However, there is still little understanding of the ultimate molecular mechanisms responsible for the therapeutic effects of these drugs or their relations with disease etiology. Here I provide an overview of recent advances on the involvement of the signalling molecules Akt and glycogen synthase kinase-3 (GSK3) in the regulation of behaviour by the monoamine neurotransmitters dopamine (DA) and serotonin (5-HT). I examine the possible participation of these signalling molecules to the effects of antidepressants, lithium and antipsychotics, as well as their possible contribution to mental disorders. Regulation of Akt and GSK3 may constitute an important signalling hub in the subcellular integration of 5-HT and DA neurotransmission. It may also provide a link between the action of these neurotransmitters and gene products, like disrupted in schizophrenia 1 (DISC1) and neuregulin (NRG), that are associated with increased risk for mental disorders. However, changes in Akt and GSK3 signalling are not restricted to a single disorder, and their contribution to specific behavioural symptoms or therapeutic effects may be modulated by broader changes in biologic contexts or signalling landscapes. Understanding these interactions may provide a better understanding of mental illnesses, leading to better efficacy of new therapeutic approaches.     

Three strategies for changing attributions about severe mental illness

The effects of three strategies for changing stigmatizing attitudes--education (which replaces myths about mental illness with accurate conceptions), contact (which challenges public attitudes about mental illness through direct interactions with persons who have these disorders), and protest (which seeks to suppress stigmatizing attitudes about mental illness)--were examined on attributions about schizophrenia and other severe mental illnesses. One hundred and fifty-two students at a community college were randomly assigned to one of the three strategies or a control condition. They completed a questionnaire about attributions toward six groups--depression, psychosis, cocaine addiction, mental retardation, cancer, and AIDS--prior to and after completing the assigned condition. As expected, results showed that education had no effect on attributions about physical disabilities but led to improved attributions in all four psychiatric groups. Contact produced positive changes that exceeded education effects in attributions about targeted psychiatric disabilities: depression and psychosis. Protest yielded no significant changes in attributions about any group. This study also examined the effects of these strategies on processing information about mental illness.     

Epigenetics and Biomarkers in the Staging of Neuropsychiatric Disorders

Epigenetics, or alterations in the phenotype or gene expression due to mechanisms other than changes in the underlying DNA sequence, reflects the sensitivity and responsiveness of human and animal brains in constantly varying circumstances regulating gene expression profiles that define the biomarkers and present the ultimate phenotypical outcomes, such as cognition and emotion. Epigenetics is associated with functionally relevant alterations to the genome in such a fashion that under the particular conditions of early, adolescent, and adult life, environmental signals may activate intracellular pathways that remodel the “epigenome,” triggering changes in gene expression and neural function. Thus, genetic influences in neuropsychiatric disorders that are subject to clinical staging, epigenetics in schizophrenia, epigenetic considerations in the expression of sensorimotor gating resulting from disease conditions, biomarkers of drug use and addiction, current notions on the role of dopamine in schizophrenia spectrum disorders, and the discrete interactions of biomarkers in persistent memory were to greater or lesser extents reflected upon. The relative contributions of endophenotypes and epistasis for mediating epigenetic phenomena and the outcomes as observed in the analysis of biomarkers appear to offer a multitude of interactive combinations to further complicate the labyrinthine machinations of diagnosis, intervention, and prognosis.     

Improving the care of individuals with schizophrenia and substance use disorders: consensus recommendations

National attention continues to focus on the need to improve care for individuals with co-occurring mental illnesses and substance use disorders, as emphasized in the 2003 President's New Freedom Commission Report on Mental Health and recent publications from the Substance Abuse and Mental Health Services Administration (SAMHSA). These reports document the need for best practice recommendations that can be translated into routine clinical care. Although efforts are underway to synthesize literature in this area, few focused recommendations are available that include expert opinion and evidence-based findings on the management of specific co-occurring disorders, such as schizophrenia and addiction. In response to the need for user-friendly recommendations on the treatment of schizophrenia and addiction, a consensus conference of experts from academic institutions and state mental health systems was organized to 1) frame the problem from clinical and systems-level perspectives; 2) identify effective and problematic psychosocial, pharmacological, and systems practices; and 3) develop a summary publication with recommendations for improving current practice. The results of the consensus meeting served as the foundation for this publication, which presents a broad set of recommendations for clinicians who treat individuals with schizophrenia. "Integrated treatment" is the new standard for evidence-based treatment for this population and recommendations are given to help clinicians implement such integrated treatment. Specific recommendations are provided concerning screening for substance use disorders in patients with schizophrenia, assessing motivation for change, managing medical conditions that commonly occur in patients with dual diagnoses (e.g., cardiovascular disease, liver complications, lung cancer, HIV, and hepatitis B or C infections) and selecting the most appropriate medications for such patients to maximize safety and minimize drug interactions, use of evidence-based psychosocial interventions for patients with dual diagnoses (e.g., Dual Recovery Therapy, modified cognitive-behavioral therapy, modified motivational enhancement therapy, and the Substance Abuse Management Module), and key pharmacotherapy principles for treating schizophrenia, substance use disorders, and comorbid anxiety, depression, and sleep problems in this population. Finally the article reviews programmatic and systemic changes needed to overcome treatment barriers and promote the best outcomes for this patient population. An algorithm summarizing the consensus recommendations is provided in an appendix.     

Parental psychiatric illness associated with schizophrenia in the siblings of schizophrenics

The diagnostic boundaries of schizophrenia remain controversial. Although there may be little disagreement about classifying process schizophrenia as schizophrenia, the inclusion of good-prognosis schizophrenia,¹ borderline syndromes, or nonpsychotic conditions has engendered more debate. The issue regarding good-prognosis schizophrenia has been clarified by a number of studies^2–6 indicating that this group has clinical and family differences from process schizophrenia. Progress in classifying borderline syndromes and nonpsychotic conditions has not been as great. As we have previously stated,⁷ the reasons seem to be difficulty in defining these disorders as well as a lack of data regarding their occurrence in the general population.Because of this impasse, we have looked for indirect ways of defining the boundaries of schizophrenia. One approach has been to compare positive family history schizophrenics with negative family history schizophrenics on the assumption that schizophrenics with a loaded family history for process schizophrenia should also have a loaded family history for other disorders that are related to schizophrenia. The frequency of other psychiatric disorders in these two groups were not significantly different;⁸ thus failing to support the extension of the concept of schizophrenia to include such nonpsychotic conditions as neuroses or personality disorder.Because there is a positive association between schizophrenia in the siblings of schizophrenics and parental schizophrenia,⁹ the present report makes the following assumption: If there are borderline or nonpsychotic psychiatric illnesses that are genetically related to schizophrenia, their occurrence in parents should be associated with schizophrenia in the siblings of schizophrenics. Conversely, if there are parental illnesses that are distinct from schizophrenia, they should be associated with other illnesses in the siblings because most mental disorders, regardless of their etiology, have been shown to run in families.¹     

Modèles de sensibilisation comportementale et troubles psychiques : aspects actuels

Behavioral sensitization is a preclinical model which can be defined as an augmentation in the behavioral effect of a psychostimulant upon re-administration. It has two phases, induction and expression. Induction refers to the transient sequence of events precipitated by psychostimulant administration that leads to the enduring changes in neural functions responsible for behavioral augmentation. Expression corresponds to the enduring neural alterations arising from the induction process that directly mediate the augmented behavorial response. These two processes are not only temporally but also anatomically and biochemically distinct. Induction seems to require the stimulation of dopamine D1 receptors in the ventral tegmental area (VTA) either directly by dopamine (DA) agonists, or indirectly via GABAergic inhibition; the stimulation of excitatory amino acid (EEA) receptor in the VTA, the amygdala and the hippocampus may also have a central role in the induction process. Contrary to its induction the expression of sensitization depends on the stimulation of the DA terminal fields and appears to be D2 mediated, whereas GABA and EEA do not seem to play a role. These processes result in an enhanced DA efflux induced by repeated exposure to stimulants. At least three different subcellular cascades have been involved in the molecular mechanisms of sensitization. Activation of these cascades induce changes in expression of neuritogenesis and synaptogenesis genes and remodelling of neural networks. First used to conceptualize various aspects of the course of affective disorders, behavioral sensitization models have been recently applied to the pathophysiology of schizophrenia, as a consequence of a better understanding of their neurobiologic underpinnings. Other psychiatric syndroms such as anxious disorders and drug addiction have been concerned too. Behavioral sensitization helps understand syndrome progression manifested by either increasing frequency, severity or spontaneity of psychiatric episodes, as well as the deteriorative course of some psychotic illnesses since sensitization, if sustained can lead to potential neurotoxic effects producing structural alterations. This model has found many applications in the psychopharmacological domain. Repeated application of stimulants either parenterally or directly into the brain may also produce a progressive increase in neural excitability, eventually producing major motor seizures in response to a previously subthreshold dose of drug. This could explain why anticonvulsants may be effective in psychiatric disorders in which behavioral sensitization is deemed to be involved. Recent data show that drugs like valproate are not only useful for treating affective illness but are also efficient in schizophrenia and anxious disorders. Contrary to lithium, valproate appears to prevent not only the induction but also the expression of behavioral sensitization in rodents. Drugs like olanzapine have, in addition to their D2 blockade effect, the capacity to block D1 receptors which may be linked to their antimanic and mood stabilising properties, considering the role of D1 receptors in the induction of sensitization phenomena. It is also possible that 5HT2 blockade play a role in this respect, as these receptors have been involved too in the development of behavioral sensitization. Finally the model allows specific predictions about the course of some psychiatric illnesses and particularly regarding the fact that treatment intervention that limit duration and number of psychiatric episodes may prevent progression of brain pathology. However such hypotheses have still to be tested through futures studies.     

The role of cerebellar genes in pathology of autism and schizophrenia

Schizophrenia and autism are neurodevelopmental diseases that have genetic as well as environmental etiologies. Both disorders have been associated with prenatal viral infection. Brain imaging and postmortem studies have found alterations in the structure of the cerebellum as well as changes in gene expression. Our laboratory has developed an animal model using prenatal infection of mice with human influenza virus that has demonstrated changes in behavior, pharmacology, structure, and gene expression in the brains of exposed offspring. In the current communication we describe altered expression of cerebellar genes associated with development of brain disorder in a mouse model for schizophrenia and autism and correlate these changes with those involved in the pathology of these two disorders.     

Absence of association of a polymorphic GGC repeat at the 5' untranslated region of the reelin gene with schizophrenia

Reelin is an extracellular matrix glycoprotein that plays an important role in guiding neuronal migration, lamination and connection during embryonic brain development. Several reports suggest that reduced reelin expression is associated with human mental illnesses such as schizophrenia, mood disorders and autism. Human reelin cDNA has been cloned and contains a polymorphic GGC repeat at the 5' untranslated region. In view of the possible regulation of reelin gene expression by this GGC polymorphism, we investigated the association of the polymorphic GGC repeat with schizophrenia in a Chinese Han population from Taiwan. We found no differences of allelic and genotypic distributions of the polymorphic GGC triplets between 162 schizophrenic patients and 176 controls in this study. Our findings do not support the involvement of the polymorphic GGC triplets of the reelin gene in the pathogenesis of schizophrenia in the population studied.     

The Metabolic Syndrome in Patients With Severe Mental Illnesses

BACKGROUND: Since the introduction of the first atypical antipsychotics in the early 1990s, this class of medication has been increasingly relied upon for the treatment of a variety of patients with psychotic and mood disorders.DATA SOURCES: The following retrospective review was derived from the MEDLINE database using the search terms metabolic syndrome, insulin resistance, obesity, diabetes, severe mental illness, schizophrenia, bipolar disorder, mood disorders, depression, unipolar depression, and prevalence from 1966 to the present. LITERATURE SYNTHESIS: Coincident with the growing usage of these agents, there have been a growing number of literature reports of changes in metabolic homeostasis among patients taking these medications. These changes have led to interest in evaluating whether there is a relationship among these mental illnesses, their psychiatric treatments, and certain physical comorbidities known collectively as the metabolic syndrome. This article reviews the existing literature around the metabolic syndrome in patients with severe mental illnesses. CONCLUSION: Patients with severe mental illnesses, particularly schizophrenia and chronic mood disorders, demonstrate a higher prevalence of metabolic syndrome or its components compared with the general population. Based upon this increased risk in these patients, baseline and periodic medical evaluations should become a standard component in ongoing clinical assessment.     

Association of DISC1 with autism and Asperger syndrome

The DISC1 gene at 1q42 has generated considerable interest in various psychiatric diseases, since a balanced translocation interrupting the gene was found to cosegregate with schizophrenia and related mental illnesses in a large Scottish pedigree. To date, linkage and association findings to this locus have been replicated in several study samples ascertained for psychotic disorders. However, the biological function of DISC1 in neuronal development would suggest a potential role for this gene also in other, early onset neuropsychiatric disorders. Here we have addressed the allelic diversity of the DISC1, DISC2 and TRAX genes, clustered in 1q42, in Finnish families ascertained for infantile autism (97 families, n(affected)=138) and Asperger syndrome (29 families, n(affected)=143). We established association between autism and a DISC1 intragenic microsatellite (D1S2709; P=0.004). In addition, evidence for association to Asperger syndrome was observed with an intragenic single nucleotide polymorphism (SNP) of DISC1 (rs1322784; P=0.0058), as well as with a three-SNP haplotype (P=0.0013) overlapping the HEP3 haplotype, that was previously observed to associate with schizophrenia in Finnish families. The strongest associations were obtained with broad diagnostic categories for both disorders and with affected males only, in agreement with the previous sex-dependent effects reported for DISC1. These results would further support the involvement of DISC1 gene also in the etiopathogenesis of early onset neuropsychiatric disorders.     

Mitochondrial dysfunction and pathology in bipolar disorder and schizophrenia

Bipolar disorder (BPD) and schizophrenia (SZ) are severe psychiatric illnesses with a combined prevalence of 4%. A disturbance of energy metabolism is frequently observed in these disorders. Several pieces of evidence point to an underlying dysfunction of mitochondria: (i) decreased mitochondrial respiration; (ii) changes in mitochondrial morphology; (iii) increases in mitochondrial DNA (mtDNA) polymorphisms and in levels of mtDNA mutations; (iv) downregulation of nuclear mRNA molecules and proteins involved in mitochondrial respiration; (v) decreased high-energy phosphates and decreased pH in the brain; and (vi) psychotic and affective symptoms, and cognitive decline in mitochondrial disorders. Furthermore, transgenic mice with mutated mitochondrial DNA polymerase show mood disorder-like phenotypes. In this review, we will discuss the genetic and physiological components of mitochondria and the evidence for mitochondrial abnormalities in BPD and SZ. We will furthermore describe the role of mitochondria during brain development and the effect of current drugs for mental illness on mitochondrial function. Understanding the role of mitochondria, both developmentally as well as in the ailing brain, is of critical importance to elucidate pathophysiological mechanisms in psychiatric disorders.     

Dual diagnosis of substance abuse in schizophrenia: prevalence and impact on outcomes

Comorbid substance abuse disorders have emerged as one of the greatest obstacles to the effective treatment of persons with schizophrenia. Estimates of the prevalence of such comorbidity vary, but as many as half of persons with schizophrenia may suffer from a comorbid drug or alcohol disorder. Younger age, male gender, and lower educational attainment are associated with greater risk for addiction. Persons with schizophrenia and comorbid addiction tend to have an earlier onset of schizophrenia than do those without comorbid addiction. Research does not support a link between specific symptoms of schizophrenia and choice of abused drugs. Rather, drug choice is correlated with the pattern of ambient drug use in the community. Comorbid substance disorders are associated with a variety of poorer outcomes, including increased psychotic symptoms, poorer treatment compliance, violence, housing instability and homelessness, medical problems (including human immunodeficiency virus infection), poor money management, and greater use of crisis-oriented services that result in higher costs of care. Considerable progress has been made over the past decade in understanding the need to integrate substance abuse treatment and mental health treatment to provide more effective care for this population.     

Association between hSKCa3 and schizophrenia not confirmed by transmission disequilibrium test in 193 offspring/parents trios.

A possible association between the small conductance calcium-regulated potassium channel gene, hSKCa3, and schizophrenia has recently been described by Chandy et al using a case-control design with patients with schizophrenia (n=141) and matched controls (n = 158). The gene may be considered as an excellent candidate gene for psychiatric disorders, since it plays a role in modulating neuronal firing patterns by regulating the slow component of after hyperpolarisation. In addition, the gene contains a highly polymorphic trinucleotide sequence (CAG) within exon 1, which encodes a polyglutamine stretch. The possible contribution of unstable trinucleotide repeats to the development of psychiatric disorders has previously been discussed. Chandy et al reported an over-representation of alleles with higher repeat number in schizophrenics as compared to controls (P = 0.0035). In an attempt to replicate these findings, we have performed a family-based study with 193 offspring/parent combinations using a sample of 49 multiplex families (two or more affected siblings with parents) and a second sample of 83 simplex families (one affected offspring with parents). No evidence for the association of longer repeats with schizophrenia was obtained when each sample was tested separately or when both samples were combined and tested for transmission disequilibrium.