The role of epigenetics in social psychiatry

Abstract

Background:

Epigenetics refers to the study of heritable changes in gene expression not involving changes in DNA sequence and is presently an active area of research in biology and medicine. There is increasing evidence that epigenetics is involved in the pathogenesis of psychiatric disorders.

Aims and Methods:

Several studies conducted to date have suggested that psychosocial factors act by modifying epigenetic mechanisms of gene expression in the brain in the pathogenesis of psychiatric disorders. Such studies have been conducted both on brain tissues and also using peripheral tissues as substitutes for brain tissues. This article reviews such studies.

Results and Conclusion:

Epigenetic mechanisms of gene expression in the brain appear to link one individual with another in the context of social psychiatry. Epigenetics appears to be of major importance to the field of social psychiatry.

Keywords

Epigenetics pathogenesis social psychiatry

Introduction

Social factors are known to influence health (Marmot, 2005), including psychiatric health (Ventriglio, Gupta, & Bhugra, 2016). Indeed, human beings are social animals, and familial or social relationships can cause many types of difficulties which could adversely affect physical and psychiatric health (Marmot, 2005; Ventriglio et al., 2016). Social factors that are known to affect health include the social gradient, stress, early life, work and social support (Marmot, 2005). For example, a meta-analysis has found that expressed emotion, a measure of the family environment that has been shown to be a reliable psychosocial predictor of relapse in schizophrenia, is a significant and robust predictor of relapse in a broad range of psychiatric disorders (Butzlaff & Hooley, 1998). Social psychiatry can be considered to be a part of social neuroscience, the study of social behaviour and social cognition (Adolphs, 2010; Insel & Fernald, 2004).

Molecular mechanisms by which social factors influence psychiatric health are thought to include genetic and immunological mechanisms (Leboyer, Oliveira, Tamouza, & Groc, 2016), the activity of neuropeptides like oxytocin and vasopressin (Insel, 2010; Insel & Fernald, 2004), increased brain-derived neurotrophic factor (BDNF) signalling in the nucleus accumbens (Krishnan et al., 2007) and the activity of neurotransmitters like serotonin and glutamate (Meyer-Lindenberg & Tost, 2012; Peterlik, Flor, & Uschold-Schmidt, 2016). Epigenetics is a new and active area of research in biomedicine, and there is increasing evidence that epigenetics plays a major role in the pathogenesis of psychiatric disorders (Abdolmaleky, Zhou, & Thiagalingam, 2015; Peedicayil, 2007). This article discusses the possible role of epigenetics in social psychiatry.

Outline of epigenetics

Epigenetics which literally means above or in addition to genetics is commonly defined as the study of heritable changes in gene expression not involving changes in DNA sequence. It involves molecular mechanisms like DNA methylation, histone modifications and non-coding RNA-mediated regulation of gene expression. Unlike the DNA sequence of genes, which is relatively hard-wired, epigenetic mechanisms of gene expression are well known to be modifiable by factors in the environment (Bird, 2007; Feil & Fraga, 2012; Thayer & Kuzawa, 2011). Heritable defects in gene expression not involving changes in DNA sequence are referred to as epimutations (Horsthemke, 2006). Epigenetics can help explain the relationship between an individual’s genetic background, the environment, ageing and disease and has been described as being at the epicentre of modern medicine (Feinberg, 2008).

Theoretical studies on the role of epigenetics in social psychiatry

The noted psychoanalyst and developmental psychologist Erik H. Erikson (1902–1994) discussed the term epigenetics in his book Childhood and Society first published in 1950. In this book, Erikson (1950) suggested a psychosocial theory of development describing important steps in an individual’s relationship with the social world. Erikson’s idea of psychosocial development took as its model epigenetics and involved eight stages during an individual’s lifetime. This theory became a highly influential theory of psychological development referred to as Erikson’s Epigenetic Principle. Erikson did not discuss the possible molecular mechanisms involved in the theory he propounded. Peedicayil (2012a) suggested that if Erikson’s Epigenetic Principle is valid and credible, then it would involve epigenetic mechanisms of gene expression. However, it must be noted that although Erikson’s observations were profound, his was an era where there was very little known about genetics and epigenetics. The term ‘epigenetics’ as we know it appeared in the medical literature in the late 1980s and 1990s (Moore, 2015).

The American psychiatric geneticist Irving Gottesman, Shields, and Hanson (1982) published an important book, Schizophrenia: The Epigenetic Puzzle. Since schizophrenia is a common genetic disorder, in this book, the authors suggested that schizophrenia is likely to be an epigenetic puzzle involving the interaction of genes and the environment. The authors suggested that both genes and environmental factors like social factors are essential for the development of the disorder, and the task ahead was to discover how genes and the environment interact to produce the disorder.

Experimental studies on the role of epigenetics in social psychiatry

The three major epigenetic mechanisms of gene expression mentioned above, DNA methylation, histone modifications and non-coding RNA-mediated regulation of gene expression, interact with each other to regulate gene expression (Allis, Caparros, Jenuwein, Lachner, & Reinberg, 2015). Studies in the fields of neuroscience, psychology and psychiatry are providing insights into how these mechanisms respond to environmental inputs and serve as biological pathways in behavioural development (McGowan & Roth, 2015). Such studies are revealing that environmental factors like psychosocial factors can become encoded within epigenetic mechanisms, leading to changes in gene expression in brain neurons and altered brain function (McGowan & Roth, 2015). Psychosocial factors are known to be able to modify all the above three epigenetic mechanisms of gene expression (McEwen et al., 2015). A recent study used positron emission tomography (PET) to show that epigenetic mechanisms of gene expression vary from one region of the brain to another in vivo in healthy individuals (Wey et al., 2016). Such studies could reveal more details in the future on how psychosocial factors modify epigenetic mechanisms in the brain leading to altered brain function in healthy and diseased individuals (Wey et al., 2016).

Experimental studies on the role of epigenetics in social psychiatry in humans were preceded by studies conducted in rodents. Such animal studies include that by Weaver et al. (2004) who showed in rats that maternal behaviour like increased pup licking and grooming and arched-back nursing caused changes in DNA methylation in the hippocampal glucocorticoid receptor (GR) gene promoter in the pups. Such changes were first seen during the first week of life, were reversed by cross fostering, persisted into adulthood and were associated with changes in histone acetylation. In another study, Tsankova et al. (2006) showed using a chronic social defeat stress model in mice that chronic social defeat induced a prolonged decrease in expression of the BDNF gene and robustly increased repressive histone methylation in promoters of this gene. Based on such animal studies, it was suggested that psychosocial factors act via epigenetic mechanisms in the pathogenesis of psychiatric disorders (Peedicayil, 2008).

The research group led by Meaney, Szyf and Turecki pioneered human studies on the role of epigenetics in social psychiatry. These workers showed that in post-mortem hippocampus obtained from suicide victims with a history of childhood neglect or abuse, the gene coding for ribosomal RNA (rRNA) was hypermethylated throughout the promoter and the 5′ regulatory region in comparison with controls who suddenly died due to unrelated causes without such a history (McGowan et al., 2008). The same group later studied epigenetic differences in a GR gene promoter between post-mortem hippocampus obtained from suicide victims with a history of neglect or abuse during childhood in comparison with suicide victims without such a history (McGowan et al., 2009). It was found that there were decreased levels of GR gene promoter messenger RNA (mRNA) and increased DNA methylation of the GR gene promoter in suicide victims with a history of childhood neglect or abuse compared to those without such a history. Other studies on the role of epigenetics in social psychiatry involving the brain have been conducted and are listed in Table 1. Peripheral samples like lymphocytes, other peripheral blood cells and buccal cells have been used for many decades in psychiatric research as substitutes for central nervous system samples. They can also potentially be used for psychiatric research involving epigenetic studies. In this regard, human studies on the role of epigenetics in social psychiatry have also been conducted on peripheral samples. Human studies conducted on DNA obtained from whole peripheral blood DNA or peripheral blood cells linking social factors with epigenetic changes are listed in Table 2. Human studies conducted on DNA obtained from other types of peripheral cells linking social factors with epigenetic changes in the body are listed in Table 3. Based on such studies of the role of epigenetics in social psychiatry, it has been suggested that epigenetics is a link between psychosocial factors and psychiatric disorders (Peedicayil, 2015).

Table 1.

Examples of studies on the role of epigenetics in social psychiatry involving the brain.

Brain tissue	Finding	Reference
Hippocampus	Early life events alter expression of many GR variants in suicide completers via effects on promoter DNA methylation	Labonté et al. (2012b)
Hippocampus	Childhood adversity alters epigenetic mechanisms in promoters of many genes	Labonté et al. (2012a)
Amygdala, fusiform and insula	High levels of oxytocin receptor gene methylation associated with face and emotion processing	Puglia, Lillard, Morris, and Connelly (2015)
Fusiform gyrus	DNA methylation of oxytocin receptor gene linked to many measures of human sociability	Haas et al. (2016)
Amygdala	Lower SES in adolescence associated with increased DNA methylation of proximal promoter of SERT gene	Swartz, Hariri, and Williamson (2016)

GR: glucocorticoid receptor; SERT: serotonin transporter; SES: socioeconomic status.

Other studies on the brain on the role of epigenetics in social psychiatry are given in the text.

Table 2.

Examples of studies on the role of epigenetics in social psychiatry involving peripheral tissues.

Tissue/cells	Finding	Reference
Whole blood DNA	Differential methylation of five genes in PTSD patients which correlated with abuse during childhood and TLS	Smith et al. (2011)
Whole blood DNA	Childhood maltreatment increases methylation of GR gene	Perroud et al. (2011)
Whole blood DNA	Dynamic changes in methylation of oxytocin receptor gene after acute psychosocial stress	Unternaehrer et al. (2012)
Lymphocytes	In PTSD patients, traumatic life events induce DNA methylation changes in GR gene promoters	Labonté, Azoulay, Yerko, Turecki, and Brunet (2014)
Whole blood DNA	Stressful life events cause DNA methylation changes in GR gene	van der Knaap et al. (2014)
Whole blood DNA	In MDD patients, DNA methylation of 5HTT gene correlates with childhood trauma	Booij et al. (2015)
Whole blood DNA	Brain function involved in processing emotional stimuli correlated with DNA methylation of 5HTT gene	Frodl et al. (2015)
Lymphocytes	GR gene methylation in normal volunteers correlates with childhood maltreatment	Radtke et al. (2015)
Leukocytes	Reduced methylation of GR gene promoter in healthy adults associated with childhood abuse	Tyrka et al. (2016)

GR: glucocorticoid receptor; MDD: major depressive disorder; 5HTT: serotonin transporter; TLS: total life stress; PTSD: post-traumatic stress disorder.

Table 3.

Examples of studies on the role of epigenetics in social psychiatry involving peripheral tissues other than blood.

Tissue/cells	Finding	Reference
Lymphoblastoid cell lines	Unresolved loss or other trauma associated with methylation of 5HTT gene	van Ijzendoorn, Caspers, Bakermans-Kranenburg, Beach, and Philibert (2010)
Lymphoblastoid cell lines	Methylation of 5HTT gene affected by childhood sex abuse	Beach, Brody, Todorov, Gunter, and Philibert (2011)
Buccal cells	Severe psychosocial deprivation in childhood associated with increased methylation of promoter of CYP2E1 gene	Kumsta et al. (2016)
Placental cells	Distress of mothers during pregnancy caused increased methylation of placental genes	Monk et al. (2016)

5HTT: serotonin transporter.

Transgenerational aspects of the role of epigenetics in social psychiatry

In mammals, the vast majority of epigenetic information appears to be reset during gametogenesis or early embryonic development (Richards, 2008). However, some epigenetic information can escape resetting and become inherited transgenerationally (Richards, 2008). Till recently, there were only data to indicate that psychiatric disorders could be inherited transgenerationally in animal models of these disorders (Franklin, 2014). However, more recently, in addition to data from animal models, there is beginning to emerge evidence for this phenomenon in human subjects as well. The American neuroscientist Rachael Yehuda has done a lot of the pioneering work on the study of transgenerational aspects of the role of epigenetics in social psychiatry, done on survivors of the Holocaust. In this regard, her group has shown that maternal post-traumatic stress disorder (PTSD) associates with greater glucocorticoid sensitivity in the offspring of such survivors (Lehrner et al., 2014). Her group has also demonstrated the influence of maternal and paternal PTSD on epigenetic regulation of the GR gene in such survivors (Yehuda et al., 2014) and that Holocaust exposure induced transgenerational effects on the methylation of the FKBP5 gene (Yehuda et al., 2016). In addition to the work of this group on this topic, Radtke et al. (2011) have demonstrated the transgenerational impact of intimate partner violence on the methylation of the promoter of the GR gene.

Role of epigenetics in psychotherapy

There is increasing evidence that psychotherapy exerts its beneficial effects in psychiatric patients by acting via epigenetic mechanisms. In this regard, psychotherapy apparently ‘undoes’ what the disease has done to patients via epigenetic mechanisms (Peedicayil, 2012b). Perroud et al. (2013) found increased methylation of the BDNF gene in patients with borderline personality disorder which was decreased by intensive dialectical behaviour therapy. The authors found that these changes in DNA methylation correlated with changes in cognitive functions. Yehuda et al. (2013), in a pilot study, found that DNA methylation of the FKBP5 gene decreased during the course of psychotherapy of war veterans with PTSD. Roberts et al. (2014) found in children with anxiety disorders that methylation of the promoter of the gene encoding the serotonin transporter (5HTT) increased in responders as compared to non-responders after the start of cognitive behaviour therapy. Roberts and co-workers (2015) found allele-specific changes in DNA methylation in the FKBP5 gene with response to cognitive behaviour therapy in children with anxiety disorders. Brückmann, Di Santo, Karle, Batra, and Nieratschker (2016) found that patients with alcohol dependence had hypomethylation of the GDAP1 gene and that this reversed during a short-term alcohol treatment programme. Ziegler et al. (2016) found that in patients with panic disorder, the monoamine oxidase (MAO) gene was hypomethylated and that this was reversed by cognitive behaviour therapy.

Role of epigenetics in the rehabilitation of psychiatric patients

Some psychiatric patients need to be rehabilitated using rehabilitation techniques. The goal of psychiatric rehabilitation is to help patients establish the emotional, social and intellectual skills necessary to live, learn and work in the community, with the least amount of professional support (Rössler, 2009). Psychiatric rehabilitation has changed how we perceive psychiatric illness. Enabling disabled individuals to live a normal life in the community causes a shift away from a focus on an illness model towards a model of functional disability (Rössler, 2006). Psychiatric rehabilitation deals with issues such as housing, meaningful work, social and intimate relationships and community life of psychiatric patients (Rössler, 2006). Since many chronically ill psychiatric patients lose close, intimate and stable relationships during the course of their illness, the therapeutic alliance between the therapist and the patient often plays a crucial role in patient care (Rössler, 2009). The principles and concepts of epigenetics like Erikson’s Epigenetic Principle can be applied during rehabilitation of psychiatric patients (Boivin, Kakooza, Warf, Davidson, & Grigorenko, 2015; Creasey & McCarthy, 1981). For example, Creasey and McCarthy (1981) designed a training programme for vocational rehabilitation counsellors who work with chronic psychiatric patients. The programme makes the emphasis that the expression and evolution of social, vocational and interpersonal abilities and disabilities can be observed and understood within a developmental context similar to that suggested by Erikson’s Epigenetic Principle.

Conclusion

The studies included in this review suggest that epigenetics plays a key role in social psychiatry and that psychosocial factors affect individuals by altering epigenetic mechanisms of gene expression. Indeed, the studies suggest that epigenetics is the basis of social psychiatry and epigenetic mechanisms of gene expression in the brain probably link one individual with another in the context of social psychiatry. However, at present, we are in the early stages of the study of the role of epigenetics in social psychiatry. In this light, many of the studies included in this review need to be replicated and corroborated.

Footnotes

Acknowledgements

The author acknowledges Dr Abraham Verghese, retired professor of psychiatry, for his comments on this manuscript.

Conflict of interest

The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship and/or publication of this article.

References

Abdolmaleky

H. M.

Zhou

J. R.

Thiagalingam

(2015). An update on the epigenetics of psychotic diseases and autism. Epigenomics, 7, 427–449.

Adolphs

(2010). Conceptual challenges and directions for social neuroscience. Neuron, 65, 752–767.

Allis

C. D.

Caparros

M.-L.

Jenuwein

Lachner

Reinberg

(2015). Overview and concepts. In Allis

C. D.

Caparros

M.-L.

Jenuwein

Reinberg

(Eds.), Epigenetics (pp. 47–115). Cold Spring Harbor, NY: Cold Spring Harbor Press.

Beach

S. R.

Brody

G. H.

Todorov

A. A.

Gunter

T. D.

Philibert

R. A.

(2011). Methylation at 5HTT mediates the impact of child sex abuse on women’s antisocial behavior: An examination of the Iowa adoptee sample. Psychosomatic Medicine, 73, 83–87.

Bird

(2007). Perceptions of epigenetics. Nature, 447, 396–398.

Boivin

M. J.

Kakooza

A. M.

Warf

B. C.

Davidson

L. L.

Grigorenko

E. L.

(2015). Reducing neurodevelopmental disorders and disability through research and interventions. Nature, 527, S155–S160.

Booij

Szyf

Carballedo

Frey

E. M.

Morris

Dymov

Frodl

(2015). DNA methylation of the serotonin transporter gene in peripheral cells and stress-related changes in hippocampal volume: A study in depressed patients and healthy controls. PLoS ONE, 10, e0119061.

Brückmann

Di Santo

Karle

K. N.

Batra

Nieratschker

(2016). Validation of differential GDAP1 DNA methylation in alcohol dependence and its potential function as a biomarker for disease severity and therapy outcome. Epigenetics, 11, 456–463.

Butzlaff

R. L.

Hooley

J. M.

(1998). Expressed emotion and psychiatric relapse: A meta-analysis. Archives of General Psychiatry, 55, 547–552.

10.

Creasey

D. E.

McCarthy

T. P.

(1981). Training vocational rehabilitation counselors who work with chronic mental patients. American Journal of Psychiatry, 138, 1102–1106.

11.

Erikson

E. H.

(1950). Childhood and society. New York, NY: W. W. Norton & Company. (Reissued in September 1993)

12.

Feil

Fraga

M. F.

(2012). Epigenetics and the environment: Emerging patterns and implications. Nature Reviews Genetics, 13, 97–109.

13.

Feinberg

A. P.

(2008). Epigenetics at the epicenter of modern medicine. JAMA, 299, 1345–1350.

14.

Franklin

T. B.

(2014). Transgenerational (heritable) epigenetics and psychiatric disorders. In Peedicayil

Grayson

D. R.

Avramopoulos

(Eds.), Epigenetics in psychiatry (pp. 577–591). Waltham, MA: Elsevier.

15.

Frodl

Szyf

Carballedo

Dymov

Vaisheva

Booij

(2015). DNA methylation of the serotonin transporter gene (SLC6A4) is associated with brain function involved in processing emotional stimuli. Journal of Psychiatry & Neuroscience, 40, 296–305.

16.

Gottesman

I. I.

Shields

Hanson

D. R.

(1982). Schizophrenia: The epigenetic puzzle. Cambridge, UK: Cambridge University Press.

17.

Haas

B. W.

Filkowski

M. M.

Cochran

R. N.

Denison

Ishak

Nishitani

Smith

A. K.

(2016). Epigenetic modification of OXT and human sociability. Proceedings of the National Academy of Sciences USA, 113, E3816–E3823.

18.

Horsthemke

(2006). Epimutations in human disease. Current Topics in Microbiology and Immunology, 310, 45–59.

19.

Insel

T. R.

(2010). The challenge of translation in social neuroscience: A review of oxytocin, vasopressin, and affiliative behavior. Neuron, 65, 768–779.

20.

Insel

T. R.

Fernald

R. D.

(2004). How the brain processes social information: Searching for the social brain. Annual Review of Neuroscience, 27, 697–722.

21.

Klengel

Pape

Binder

E. B.

Mehta

(2014). The role of DNA methylation in stress-related psychiatric disorders. Neuropharmacology, 80, 115–132.

22.

Krishnan

Han

M.-H.

Graham

D. L.

Berton

Renthal

Russo

S. J.

Nestler

E. J.

(2007). Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell, 131, 391–404.

23.

Kumsta

Marzi

S. J.

Viana

Dempster

E. L.

Crawford

Rutter

Sonuga-Barke

E. J.

(2016). Severe psychosocial deprivation in early childhood is associated with increased DNA methylation across a region spanning the transcription start site of CYP2E1. Translational Psychiatry, 6, e830.

24.

Labonté

Azoulay

Yerko

Turecki

Brunet

(2014). Epigenetic modulation of glucocorticoid receptors in posttraumatic stress disorder. Translational Psychiatry, 4, e368.

25.

Labonté

Suderman

Maussion

Navaro

Yerko

Mahar

Turecki

(2012a). Genome-wide epigenetic regulation by early-life trauma. Archives of General Psychiatry, 69, 722–731.

26.

Labonté

Yerko

Gross

Mechawar

Meaney

M. J.

Szyf

Turecki

(2012b). Differential glucocorticoid receptor exon 1(B), 1(C), and 1(H) expression and methylation in suicide completers with a history of childhood abuse. Biological Psychiatry, 72, 41–48.

27.

Leboyer

Oliveira

Tamouza

Groc

(2016). Is it time for immunopsychiatry in psychotic disorders? Psychopharmacology, 233, 1651–1660.

28.

Lehrner

Bierer

L. M.

Passarelli

Pratchett

L. C.

Flory

J. D.

Bader

Yehuda

(2014). Maternal PTSD associates with greater glucocorticoid sensitivity in offspring of Holocaust survivors. Psychoneuroendocrinology, 40, 213–220.

29.

Marmot

(2005). Social determinants of health inequalities. Lancet, 365, 1099–1104.

30.

McEwen

B. S.

Bowles

N. P.

Gray

J. D.

Hill

M. N.

Hunter

R. G.

Karatsoreos

I. N.

Nasca

(2015). Mechanisms of stress in the brain. Nature Neuroscience, 18, 1353–1361.

31.

McGowan

P. O.

Roth

T. L.

(2015). Epigenetic pathways through which experiences become linked with biology. Development and Psychopathology, 27, 637–648.

32.

McGowan

P. O.

Sasaki

D’Alessio

A. C.

Dymov

Labonté

Szyf

Meaney

M. J.

(2009). Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nature Neuroscience, 12, 342–348.

33.

McGowan

P. O.

Sasaki

Huang

T. C.

Unterberger

Suderman

Ernst

Szyf

(2008). Promoter-wide hypermethylation of the ribosomal RNA gene promoter in the suicide brain. PLoS ONE, 3, e2085.

34.

Meyer-Lindenberg

Tost

(2012). Neural mechanisms of social risk for psychiatric disorders. Nature Neuroscience, 15, 663–668.

35.

Monk

Feng

Lee

Krupska

Champagne

F. A.

Tycko

(2016). Distress during pregnancy: Epigenetic regulation of placenta glucocorticoid-related genes and fetal neurobehavior. American Journal of Psychiatry, 173, 705–713.

36.

Moore

D. S.

(2015). The developing genome: An introduction to behavioral epigenetics. New York, NY: Oxford University Press.

37.

Peedicayil

(2007). The role of epigenetics in mental disorders. Indian Journal of Medical Research, 126, 105–111.

38.

Peedicayil

(2008). Psychosocial factors may act via epigenetic mechanisms in the pathogenesis of mental disorders. Medical Hypotheses, 70, 700–701.

39.

Peedicayil

(2012a). A comparison of Erikson’s Epigenetic Principle with epigenetics. Journal of Theoretical Biology, 315, 144–145.

40.

Peedicayil

(2012b). Role of epigenetics in pharmacotherapy, psychotherapy and nutritional management of mental disorders. Journal of Clinical Pharmacy and Therapeutics, 37, 499–501.

41.

Peedicayil

(2015). Epigenetics as a link between psychosocial factors and mental disorders. Indian Journal of Psychiatry, 57, 218.

42.

Perroud

Paoloni-Giacobino

Prada

Olié

Salzmann

Nicastro

Malafosse

(2011). Increased methylation of glucocorticoid receptor gene (NR3C1) in adults with a history of childhood maltreatment: A link with the severity and type of trauma. Translational Psychiatry, 1, e59.

43.

Perroud

Salzmann

Prada

Nicastro

Hoeppli

M. E.

Furrer

Malafosse

(2013). Response to psychotherapy in borderline personality disorder and methylation status of the BDNF gene. Translational Psychiatry, 3, e207.

44.

Peterlik

Flor

P. J.

Uschold-Schmidt

(2016). The emerging role of metabotropic glutamate receptors in the pathophysiology of chronic stress-related disorders. Current Neuropharmacology, 14, 514–539.

45.

Puglia

M. H.

Lillard

T. S.

Morris

J. P.

Connelly

J. J.

(2015). Epigenetic modification of the oxytocin receptor gene influences the perception of anger and fear in the human brain. Proceedings of the National Academy of Sciences USA, 112, 3308–3313.

46.

Radtke

K. M.

Ruf

Gunter

H. M.

Dohrmann

Schauer

Meyer

Elbert

(2011). Transgenerational impact of intimate partner violence on methylation in the promoter of the glucocorticoid receptor. Translational Psychiatry, 1, e21.

47.

Radtke

K. M.

Schauer

Gunter

H. M.

Ruf-Leuschner

Sill

Meyer

Elbert

(2015). Epigenetic modifications of the glucocorticoid receptor gene are associated with the vulnerability to psychopathology in childhood maltreatment. Translational Psychiatry, 5, e571.

48.

Richards

E. J.

(2008). Population epigenetics. Current Opinion in Genetics & Development, 18, 221–226.

49.

Roberts

Keers

Lester

K. J.

Coleman

J. R.

Breen

Arendt

Wong

C. C.

(2015). HPA axis related genes and response to psychological therapies: Genetics and epigenetics. Depression and Anxiety, 32, 861–870.

50.

Roberts

Lester

K. J.

Hudson

J. L.

Rapee

R. M.

Creswell

Cooper

P. J.

Eley

T. C.

(2014). Serotonin transporter methylation and response to cognitive behaviour therapy in children with anxiety disorders. Translational Psychiatry, 4, e444.

51.

Rössler

(2006). Psychiatric rehabilitation today: An overview. World Psychiatry, 5, 151–157.

52.

Rössler

(2009). Rehabilitation techniques. In Gelder

M. G.

Andreasen

N. C.

López-Ibor

J. J.

Geddes

J. R.

(Eds.), New Oxford textbook of psychiatry (pp. 1399–1403). Oxford, UK: Oxford University Press.

53.

Smith

A. K.

Conneely

K. N.

Kilaru

Mercer

K. B.

Weiss

T. E.

Bradley

Ressler

K. J.

(2011). Differential immune system DNA methylation and cytokine regulation in post-traumatic stress disorder. American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics, 156, 700–708.

54.

Swartz

J. R.

Hariri

A. R.

Williamson

D. E.

(2016). An epigenetic mechanism links socioeconomic status to changes in depression-related brain function in high-risk adolescents. Molecular Psychiatry. Advance online publication. doi:10.1038/mp.2016.82

55.

Thayer

Z. M.

Kuzawa

C. W.

(2011). Biological memories of past environments: Epigenetic pathways to health disparities. Epigenetics, 6, 798–803.

56.

Tsankova

N. M.

Berton

Renthal

Kumar

Neve

R. L.

Nestler

E. J.

(2006). Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action. Nature Neuroscience, 9, 519–525.

57.

Tyrka

A. R.

Parade

S. H.

Welch

E. S.

Ridout

K. K.

Price

L. H.

Marsit

Carpenter

L. L.

(2016). Methylation of the leukocyte glucocorticoid receptor gene promoter in adults: Associations with early adversity and depressive, anxiety and substance-use disorders. Translational Psychiatry, 6, e848.

58.

Unternaehrer

Luers

Mill

Dempster

Meyer

A. H.

Staehli

Meinlschmidt

(2012). Dynamic changes in DNA methylation of stress-associated genes (OXTR, BDNF) after acute psychosocial stress. Translational Psychiatry, 14, E150.

59.

van der Knaap

L. J.

Riese

Hudziak

J. J.

Verbiest

M. M.

Verhulst

F. C.

Oldehinkel

A. J.

van Oort

F. V.

(2014). Glucocorticoid receptor gene (NR3C1) methylation following stressful events between birth and adolescence. The TRAILS study. Translational Psychiatry, 4, e381.

60.

van Ijzendoorn

M. H.

Caspers

Bakermans-Kranenburg

M. J.

Beach

S. R.

Philibert

(2010). Methylation matters: Interaction between methylation density and 5HTT genotype predicts unresolved loss or trauma. Biological Psychiatry, 68, 405–407.

61.

Ventriglio

Gupta

Bhugra

(2016). Why do we need a social psychiatry? British Journal of Psychiatry, 209, 1–2.

62.

Weaver

I. C.

Cervoni

Champagne

F. A.

D’Alessio

A. C.

Sharma

Seckl

J. R.

Meaney

M. J.

(2004). Epigenetic programming by maternal behavior. Nature Neuroscience, 7, 847–854.

63.

Wey

H. W.

Gilbert

T. M.

Zürcher

N. R.

She

Bhanot

Taillon

B. D.

Hooker

J. M.

(2016). Insights into neuroepigenetics through human histone deacetylase PET imaging. Science Translational Medicine, 8, 351ra106.

64.

Yehuda

Daskalakis

N. P.

Bierer

L. M.

Bader

H. N.

Klengel

Holsboer

Binder

E. B.

(2016). Holocaust exposure induced intergenerational effects on FKBP5. Biological Psychiatry, 80, 372–380.

65.

Yehuda

Daskalakis

N. P.

Desarnaud

Makotkine

Lehrner

Koch

Bierer

L. M.

(2013). Epigenetic biomarkers as predictors and correlates of symptom improvement following psychotherapy in combat veterans with PTSD. Frontiers in Psychiatry, 4, 118.

66.

Yehuda

Daskalakis

N. P.

Lehrner

Desarnaud

Bader

H. N.

Makotkine

Meaney

M. J.

(2014). Influences of maternal and paternal PTSD on epigenetic regulation of the glucocorticoid receptor gene in Holocaust survivor offspring. American Journal of Psychiatry, 171, 872–880.

67.

Ziegler

Richter

Mahr

Gajewska

Schiele

M. A.

Gehrmann

Domschke

(2016). MAOA gene hypomethylation in panic disorder – Reversibility of an epigenetic risk pattern by psychotherapy. Translational Psychiatry, 6, e773.