Clinical Psychology Review 77 (2020) 101830

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Clinical Psychology Review

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The applied implications of epigenetics in anxiety, affective and stress- T

related disorders - A review and synthesis on psychosocial stress,
psychotherapy and prevention
Miriam A. Schielea, Michael G. Gottschalka, Katharina Domschkea,b,⁎
a
Department of Psychiatry and Psychotherapy, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Hauptstrasse 5, D-79104 Freiburg,
Germany
b
Center for Basics in NeuroModulation, Faculty of Medicine, University of Freiburg, Breisacher Straße 64, D-79106 Freiburg, Germany

HIGHLIGHTS

• Epigenetic mechanisms are biochemical DNA modifications governing gene function.

• Epigenetic alterations arise following stressful or beneficial environmental input.
• Candidate genes of a diverse range of biological processes have been evaluated.
• Epigenetic alterations are modifiable/reversible by various forms of psychotherapy.
• Prospectively, epigenetic profiles may represent trait and therapy response markers.

ARTICLE INFO ABSTRACT

Keywords: Mental disorders are highly complex and multifactorial in origin, comprising an elaborate interplay of genetic
Epigenetics and environmental factors. Epigenetic mechanisms such as DNA modifications (e.g. CpG methylation), histone
Methylation modifications (e.g. acetylation) and microRNAs function as a translator between genes and the environment.
Histone modification Indeed, environmental influences such as exposure to stress shape epigenetic patterns, and lifetime experiences
Psychiatry
continue to alter the function of the genome throughout the lifespan. Here, we summarize the recently bur-
Psychotherapy
Resilience
geoning body of research regarding the involvement of aberrant epigenetic signatures in mediating an increased
vulnerability to a wide range of mental disorders. We review the current knowledge of epigenetic changes to
constitute useful markers predicting the clinical response to psychotherapeutic interventions, and of psy-
chotherapy to alter – and potentially reverse – epigenetic risk patterns. Given first evidence pointing to a
transgenerational transmission of epigenetic information, epigenetic alterations arising from successful psy-
chotherapy might be transferred to future generations and thus contribute to the prevention of mental disorders.
Findings are integrated into a multi-level framework highlighting challenges pertaining to the mechanisms of
action and clinical implications of epigenetic research. Promising future directions regarding the prediction,
prevention, and personalized treatment of mental disorders in line with a ‘precision medicine’ approach are
discussed.

“Psychological mechanisms […] parallel their epigenetic biological and
non-biological determinants” Louis Kaywin (1960)
1. Introduction
Within the classical ”nature” and ”nurture”, i.e. biological vs. non-
biological vulnerability-stress-model of mental disorders, there has
been a conceptual dichotomy of biological risk factors and pharmaco-
logical treatments on one hand and psychological mechanisms as well
as psychotherapeutic interventions on the other hand. Recent neuro-
biological research, however, provides evidence for a convergence and
integration of biological and psychological mechanisms on an epige-
netic level as foreshadowed by the psychoanalyst Louis Kaywin as early
as in 1960: “Psychological mechanisms […] parallel their epigenetic
biological and non-biological determinants” (Kaywin, 1960).

⁎
Corresponding author at: Department of Psychiatry and Psychotherapy, University of Freiburg, Hauptstrasse 5, D-79104 Freiburg, Germany.
E-mail address: katharina.domschke@uniklinik-freiburg.de (K. Domschke).

https://doi.org/10.1016/j.cpr.2020.101830
Received 11 September 2019; Received in revised form 16 January 2020; Accepted 20 January 2020
Available online 04 February 2020
0272-7358/ © 2020 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/BY-NC-ND/4.0/).
M.A. Schiele, et al.
Family, twin and adoption studies point to a substantial contribu-
tion of genetic factors to the pathogenesis of mental disorders.
Heritability rates are estimated to be moderate to high for most mental
disorders, varying between ~40–80% (Gratten, Wray, Keller, &
Visscher, 2014), with the remaining variance being attributed to non-
genetic influences. Molecular genetic studies have identified chromo-
somal loci and genetic variants to be associated with disorder risk. For
instance, linkage studies based on family and twin data have provided
evidence for several putative chromosomal risk loci that co-segregate
with mental disorders (e.g. schizophrenia: Riley & Kendler, 2006; de-
pression: Levinson, 2006; anxiety disorders: Hamilton, 2009), yet, the
loci in question often span large chromosomal regions containing many
potential vulnerability genes, and replication findings regarding the
susceptibility loci described so far are scarce. In hypothesis-driven
candidate gene and hypothesis-generating genome-wide association
studies (GWAS), a wide range of single nucleotide polymorphisms
(SNPs) has been investigated in efforts to elucidate the genetic under-
pinnings of mental disorders. Several variants in putative risk genes
covering a plethora of biological processes in e.g. neurotransmitter,
neuropeptide, neuroimmune or neuroendocrine signaling systems have
been related, though not unequivocally, to different disease entities.
These findings emphasize the complex, highly polygenic and partly
overlapping genetic architecture of mental disorders (see for example
Hoehe and Morris-Rosendahl, 2018 or Smoller, 2016).
In addition to genetic influences, a number of environmental factors
such as childhood adversity or prolonged exposure to psychosocial
stressors (Peedicayil, 2004; Rutten et al., 2013; Teicher & Samson,
2013) contribute to mental disorder risk. By contrast, positive en-
vironmental influences including functional coping strategies or social
support can increase resilience against mental disorders (Rutten et al.,
2013). Yet, genetic and environmental factors – both detrimental and
beneficial – do not act in isolation but rather interactively with one
another in conferring mental disorder risk or resilience, respectively. A
number of gene-environment interactions (G × E) underlying mental
disorders have been reported, although not all G × E have been re-
producible (Uher, 2014), which might be due to the influence of epi-
static effects, additional mitigating environmental factors and/or epi-
genetic mechanisms (Schiele et al., 2016).
Epigenetic mechanisms – etymologically derived from the Greek
prefix “epi”, meaning “over” or “above” genetics – possess a central
function at the interface between genetics and environmental influ-
ences. They modulate gene function, are involved in cellular differ-
entiation, respond to environmental triggers, are temporally dynamic,
are modifiable – and potentially reversible – by (psycho-)pharmacolo-
gical interventions, and thus may carry great therapeutic potential
(Boks et al., 2012; Szyf & Bick, 2013).
Epigenetic alterations have been associated with various mental
disorders; however, an exhaustive review of epigenetic changes on a
categorical phenotype level is beyond the scope of this article. For
comprehensive reviews detailing epigenetic mental disorder associa-
tions studies, the reader is referred elsewhere (Abdolmaleky, Zhou, &
Thiagalingam, 2015; Berkel & Pandey, 2017; Gottschalk & Domschke,
2016; Klengel, Pape, Binder, & Mehta, 2014; Millan, 2014; Nestler,
Pena, Kundakovic, Mitchell, & Akbarian, 2016; Park et al., 2019;
Schiele & Domschke, 2018). Here, we place a special focus on the role
of epigenetics as a mediator or mechanism of psychosocial stress and
psychotherapeutic interventions, thus conferring risk or resilience to-
wards anxiety, affective and stress-related disorders by maladaptively
or adaptively responding to environmental influences. An improved
understanding of the possibly heritable role of epigenetics in the com-
plex pathogenesis of anxiety, affective and stress-related disorders and
the elucidation of epigenetic mechanisms of psychotherapy may prove
useful in the development of novel preventive measures and in the
optimization of psychotherapy in a field with a currently still high rate
of non-remission and treatment resistance. While the exhaustive lit-
erature state of rodent studies related to the (epi)genetics of stress and
2
Clinical Psychology Review 77 (2020) 101830
resilience has been reviewed elsewhere (Jimenez et al., 2018; Miller,
2017; Szyf, 2015), here we will exclusively focus on human studies.
2. Prologue: epigenetic mechanisms
Epigenetic mechanisms such as DNA modifications, histone mod-
ifications and microRNAs are defined as biochemical alterations at the
level of the DNA, its 3-D structure or of regulatory small non-coding
RNA sequences governing gene transcription and translation, without,
however, entailing a change in the DNA sequence itself. A key feature of
epigenetic modifications is their capacity of dynamic reversibility.
Compared to the epigenetic modifications expanded upon in this sec-
tion, genetic alterations of the DNA strand (that is of the very sequence
of base pairs itself) as caused by mutation, transposition and re-
combination, are seldom if ever completely reversible within a given
cellular system. In other words, genetic modifications can be viewed as
comparably slow, rare and permanent, while certain epigenetic mod-
ifications occur fast, commonly and dynamically in response to ex-
trinsic or intrinsic biological signals and have a capacity for complete
reversal. Nevertheless, at this point it should be noted that epigenetics
and genetics share an inseparable interdependence, insomuch as epi-
genetic modifications influence the probability of regional mutations,
and mutations themselves can alter the entire cellular epigenetic sig-
nature in return (Gibbs et al., 2010; Sweder & Hanawalt, 1993). For an
in-depth review of mental disorder epigenetics with a special focus on
pathophysiology and treatment options refer to Schuebel, Gitik,
Domschke, & Goldman (2016).
2.1. DNA modifications
The classical set of epigenetic DNA modifications includes me-
thylation (addition of a CH3 group) and hydroxymethylation (addition
of a CH2OH group) primarily targeting carbon atoms of cytosine bases
of cytosine-guanine pairs often located in so-called CpG-islands
(chromosomal locations rich in cytosine-guanine pairs; the “p” de-
notes the phosphate group between any two given DNA bases) (for
examples see Fig. 1). Various other forms of DNA base modifications
have been described, yet they are far less well understood in their
cellular function and occur considerably less often. CpG methylation is
conferred by DNA-methyltransferases (DNMTs). Demethylation is in-
duced indirectly by enzymes of the growth arrest and DNA damage 45
(Gadd45) family, which replace the methylated by an unmethylated
cytosine base via base excision repair (BER), or ten-eleven-transloca-
tion (TET) proteins, which induce hydroxymethylation followed by
BER (see Fig. 1). On a functional level, the transcriptomic effect of a
given epigenetic modification is crucially influenced by its location
within the gene structure, which is composed of regulatory elements
and the gene body itself, i.e. the protein-coding exons interspersed
with non-coding introns. For example, CpG methylation in promoters,
enhancers and transcription start sites generally results in a silencing
(reduction) of transcription of the respective gene, while reciprocally
a reduced methylation (i.e. hypomethylation) of the same region
would result in a comparably increased transcription rate (Suzuki &
Bird, 2008). This rule of thumb is reversed as soon as intragenic, e.g.
exonic and intronic regions are investigated; here, increased levels of
methylation (i.e. hypermethylation) result in a proportionally in-
creased transcription rate and vice versa hypomethylation leads to
reduced transcription levels (Suzuki & Bird, 2008). The functional
consequences of epigenetic DNA modifications other than methylation
are not as well understood. CpG hydroxymethylation for example has
been hypothesized to functionally overwrite the effect of local CpG
methylation, and at the same time CpG-methylation-independent ef-
fects have been described. CpG methylation to date is the most well
researched epigenetic modification and therefore constitutes a major
focus of this review, whereas other epigenetic modifications remain a
central topic for future investigations.
M.A. Schiele, et al. Clinical Psychology Review 77 (2020) 101830

Figure 1. Epigenetic mechanisms.

Ac=Acetylation; Ph=Phosphorylation; Me=Methylation; H2A=Histone H2A; H2B=Histone H2B; H3=Histone H3; H4=Histone H4; HDAC=Histone deacetylase;
HAT=Histone acetyltransferase; C=Cytosine; G=Guanine; A=Adenine; T=Thymine; C2,5,6=carbon atoms at positions 2, 5 and 6 in pyrimidine heterocycle;
N1,3,4=nitrogen atoms at positions 1, 3 and 4 in pyrimidine heterocycle; DNMT=DNA methyltransferase; CH3=methyl group; TET proteins=Ten-eleven-trans-
location proteins; Gadd45 proteins=Growth arrest and DNA damage 45 proteins; CH2OH=Hydroxymethyl group; BER=base excision repair

2.2. Histone modifications [HDAC]) (see Fig. 1).

The packaging density of DNA around histone protein (H2A, H2B,
H3, H4) octamers (together referred to as nucleosomes) can vary: ac-
tively transcribed genes are more likely to be found in “euchromatin”,
i.e. “open chromatin”, with genes being arranged like beads on a string
and thus accessible to the transcription machinery, while higher con-
densed states of nucleosomes (i.e. “closed” or “heterochromatin”) ra-
ther impede transcription and thus lead to silencing of the respective
genes involved. The packaging density is crucially determined by the
so-called “histone code” consisting of the sum of all covalent histone
modifications including but not limited to methylation, acetylation,
phosphorylation, ubiquitination, sumoylation and ADP-ribosylation
(Jenuwein & Allis, 2001) of amino acid residues in the histones’ tail
regions (see Fig. 1). This effect is mainly driven by affecting the elec-
tronic charge of amino acid residues in the tail regions of histones, in
return altering the histone-DNA-binding affinity and the interaction of
histones with other proteins involved in the silencing and activation of
genes, e.g. via promoting chromatin condensation or unfolding. Despite
still constituting an extensive transcriptomic research topic, basic
principles of the histone code have been established. As outlined above
for epigenetic DNA modifications, covalent histone alterations are
conferred by various protein classes building a tripartite system, one
protein to induce the histone alteration (e.g. a histone acetyltransferase
[HAT]), one protein to convey the transcriptional effect (e.g. a protein
with a bromodomain, targeted at binding to acetylated histones and
affecting DNA accessibility and/or transcription regulation), and finally
a protein reversing the histone alteration (e.g. a histone deacetylase
2.3. MicroRNAs (miRNAs)
Further to covalent changes to DNA and histones, recent advances in
our understanding of transcriptome regulation have suggested small
non-coding RNAs, so called microRNAs (miRNAs), as an additional
player influencing RNA stability and translation of entire gene net-
works. Spread throughout the genome, miRNA genes do not code for a
specific protein, but exert important effects on the post-translational
regulation of gene expression (Bartel, 2004). In brief, the primary
miRNA is processed by nuclear RNases (a protein class cleaving RNA
molecules) into a pre-miRNA (Gregory et al., 2004), which is exported
into the cytosol, where further RNase processing occurs, until it is
turned into a targeting sequence and integrated into a RNA-multi-
protein-complex (Gregory, Chendrimada, Cooch, & Shiekhattar, 2005)
aimed at the 3’-untranslated region (3’-UTR) of messenger RNAs
(mRNAs) of specific genes, thereby downregulating their translation
(Lim et al., 2005).
3. Epigenetic “scars” of psychosocial stress
Considerable evidence for a lasting impact of stress-associated ex-
periences on gene expression and behavior via epigenetic programming
emerges from a plethora of studies in preclinical models of mental
disorders (Alyamani & Murgatroyd, 2018; Kundakovic & Champagne,
2015; Provencal & Binder, 2015). Here, we focus exclusively on human
studies, exemplarily compiling results from investigations of various

3
 Table 1
Primary findings of epigenetic studies related to psychosocial stress
Study Sample
Hypothalamic–pituitary–adrenal (HPA) axis system
McGowan et al., 2009 Suicide victims (n=24)
Healthy probands (n=12)
Tyrka et al., 2012 Healthy probands (n=99)
Parent et al., 2017 Preschoolers (n=260)
Farrell et al., 2018 MDD patients (n=33)
Healthy probands (n=34)
Perroud et al., 2011 BPD patients (n=101)
MDD patients (n=99)
Radtke et al., 2015 Healthy probands (n=46)
Oberlander et al., 2008 Newborns (n=85)
Klengel et al., 2013 Healthy probands (n=76)
Monk et al., 2016 Healthy probands (n=61)
Tozzi et al., 2018 MDD patients (n=56)
Klinger-Konig et al., 2019 Community sample (n=3,965)
Monoaminergic and GABA-ergic systems
van IJzendoorn et al., 2010 Healthy probands (n=143)
4
Beach et al., 2011 Healthy probands (n=155)
Ouellet-Morin et al., 2013 Healthy monozygotic twin pairs (n=28)
Domschke et al., 2012 PD patients (n=44)
Healthy probands (n=44)
Domschke et al., 2013 PD patients (n=65)
Healthy probands (n=65)
Neuropeptide and neurotrophic factor systems
Unternaehrer et al., 2016 Healthy infants (n=39)
Smearman et al., 2016 Healthy probands (n=393)
Unternaehrer et al., 2015 Healthy probands (n=85)
MicroRNAs (miRNAs)
Wiegand et al., 2018 Healthy probands (n=24)
Epigenome-wide association studies (EWAS)
Yang et al., 2013 Maltreated children (n=96)
Non-maltreated children (n=96)
Mehta et al., 2013 PTSD patients with adverse childhood
events (n=32)
PTSD patients without adverse childhood
events (n=29)
Healthy probands with trauma exposure
outside of childhood (n=108)
Weder et al., 2014 Maltreated children (n=94)
Non-traumatized children (n=96)
Psychosocial stressor
Childhood maltreatment
Childhood maltreatment
Childhood maltreatment over past
six months
Childhood maltreatment
Childhood maltreatment
Childhood adversities
Prenatal maternal depression and
anxiety symptoms
Childhood trauma
Perceived stress during second
trimester
Childhood trauma
Childhood maltreatment
Unresolved loss and trauma
Sexual abuse
Bullying experiences
Life events during the past year
Life events during the past year
Stressful life events during the two
years prior to birth
Childhood abuse
Maternal care during childhood
Trier Social Stress Test
Childhood maltreatment
Adverse childhood events
Childhood trauma
Gene Primary findings
M.A. Schiele, et al.
NR3C1 ↑ NR3C1 methylation in suicide victims with maltreatment history
NR3C1 ↑ NR3C1 methylation associated with increased childhood maltreatment
NR3C1 ↑ NR3C1 methylation associated with increased childhood maltreatment over past six
months
↓ NR3C1 methylation change associated with increased childhood maltreatment at six-
month follow-up
NR3C1 ↑ NR3C1 methylation associated with increased childhood emotional abuse in MDD
patients
NR3C1 ↑ NR3C1 methylation associated with increased childhood maltreatment in BPD patients
(high degree of childhood trauma) compared to MDD patients (low degree of childhood
trauma)
NR3C1 ↑ NR3C1 methylation associated with increased number of childhood adversities
NR3C1 ↑ NR3C1 methylation associated with increased prenatal maternal depression and
anxiety symptoms
FKBP5 ↓ FKBP5 methylation associated with increased childhood trauma
FKBP5 ↑ FKBP5 methylation associated with increased perceived stress
FKBP5 ↓ FKBP5 methylation associated with increased childhood trauma
FKBP5 No significant interaction of FKBP5 methylation and childhood maltreatment on lifetime
MDD diagnoses
SLC6A4 ↑ SLC6A4 methylation associated with lower levels of unresolved loss and trauma
SLC6A4 ↑ SLC6A4 methylation associated with degree of sexual abuse
SLC6A4 ↑ SLC6A4 methylation associated with degree of bullying
MAOA ↓ MAOA methylation associated with increased negative life events
↑ MAOA methylation associated with increased positive life events
GAD1 ↓ GAD1 methylation associated with increased negative life events
OXTR ↓ OXTR methylation associated with increased stressful life events
OXTR ↑ OXTR methylation in interaction with increased childhood abuse predicted higher
ratings of anxiety and depression
OXTR ↑ OXTR methylation associated with lower maternal care
BDNF ↑ BDNF methylation associated with lower maternal care
- miR 21 correlated with experienced stress
EWAS 2,868 significantly differentially methylated CpGs, mainly in neoplasm-related genes
EWAS Significant differently methylated CpGs in genes related to development, adhesion and
migration of cells independent of adverse childhood events in PTSD, unique changes in
CpGs related to nervous system development in PTSD with adverse childhood events
EWAS ↓ Methylation in ID3, GRIN1 and TPPP related to increased depression scores,
independent of childhood maltreatment
(continued on next page)
Clinical Psychology Review 77 (2020) 101830
M.A. Schiele, et al. Clinical Psychology Review 77 (2020) 101830

MDD=major depressive disorder; PD=panic disorder; PTSD=post-traumatic stress disorder; BPD=borderline personality disorder; NR3C1=glucocorticoid receptor gene; FKBP5=FK506 binding protein 51 gene;
SLC6A4=serotonin transporter gene; MAOA=monoamine oxidase A gene; GAD1=glutamate decarboxylase 67 gene; OXTR=oxytocin receptor gene; BDNF=brain derived neurotrophic factor gene; ID3=DNA-binding
protein inhibitor ID-3 gene; GRIN1=glutamate receptor NMDA type subunit 1 gene; TPPP=tubulin polymerization promoting protein gene; SPDEF=SAM pointed domain-containing Ets transcription factor gene;
representations of psychosocial stress associated with epigenetic al-

↓ Methylation at miR124-3 CpG site associated with increased childhood maltreatment

Post-hoc significant association of a SPDEF CpG site with the frequency of negative life
terations. In particular, we will summarize investigations of DNA me-
mainly in genes related to morphology and development and DNA and transcription

No significant epigenome-wide findings, yet top hits were primarily associated with
491 significantly differentially methylated CpGs predictive of depressive symptoms,
thylation involved in several biological systems such as the hypotha-
lamic-pituitary-adrenal (HPA) axis, a primary stress-related connection

Cumulative lifetime stress was associated with accelerated epigenetic aging

Degree of combat trauma was associated with accelerated epigenetic aging

between the CNS and the periphery, and within neurotransmitter-re-
lated signaling pathways including the monoaminergic and GABA-ergic
systems, often connected with the mechanisms of action of several
clinically available psychopharmacological compounds. Furthermore,
neuropeptide or neurotrophic factor systems, involved in inter-neuronal
and brain-body communication, as well as hypothesis-generating ap-
proaches on an epigenome-wide level will be expanded upon. Finally,
findings regarding miRNA expression and epigenetic aging associated
with psychosocial stress will be presented. For an overview of epige-
netic effects associated with psychosocial stressors, see Table 1.

3.1. Hypothalamic–pituitary–adrenal (HPA) axis system

The neuroendocrine integration provided by the HPA axis allows

methyltransferase activity

CpG=chromosomal location rich in cytosine-guanine pairs; EWAS=epigenome-wide association study; ↑=increased methylation; ↓=decreased methylation.
the body to react to various perceived forms of internal or external
stressors, regulating complex processes such as affectivity, immune
Primary findings

response and energy metabolism.

factor binding

The glucocorticoid receptor is a crucial effector of the HPA axis and

the central key component of the negative feedback loop regulating
events

cortisol secretion. The gene coding for the glucocorticoid receptor

(NR3C1; chromosomal location 5q31.3) consists of 11 exons, with the
untranslated exon 1 displaying nine identified variants, each accom-
DNA methylation-based predictor

DNA methylation-based predictor

panied by its own promoter region (1A, I, D, J, E, B, F, C, H). Most studies

focused on the promoter region of exon 1F, a particularly interesting
of age (“epigenetic clock”)

of age (“epigenetic clock”)

genomic region since it includes binding sites for the nerve growth
factor-inducible protein A (NGFI-A), which regulate NR3C1 gene ex-
pression (Weaver et al., 2007). In a seminal study, McGowan et al.
reported reduced hippocampal NR3C1 expression in an all-male post-
mortem investigation comparing 12 suicide victims with a history of
EWAS

EWAS

EWAS

EWAS

childhood abuse to 12 suicide victims without a history of childhood

Gene

abuse as well as to 12 healthy control subjects (McGowan et al., 2009).

Reduced expression was linked to increased hippocampal NR3C1 1F
Combat trauma during deployment
Stressful negative life events in the

promoter CpG methylation in suicide victims with maltreatment his-

Early life parental separation

tory. On a functional level, in vitro patch methylation mimicking this

epigenetic state resulted in decreased NGFI-A binding and corre-
Childhood maltreatment

Prenatal maternal stress

spondingly reduced NGFI-A-induced gene transcription (McGowan

Psychosocial stressor

et al., 2009). Accordingly, an investigation of the epigenetic modulation

Lifetime stressors

of NR3C1 1F promoter methylation in leukocytes of healthy probands

(n=99) revealed positive correlations between the degree of methyla-
past year

tion with relevance to NGFI-A binding and reported childhood mal-

treatment, parental loss and childhood adversity (Tyrka, Price, Marsit,
Walters, & Carpenter, 2012). Respectively, a negative correlation with
Individuals without early life separation

regard to the amount of total secreted cortisol following a dex-

EWAS meta-analysis (total n=1,740)
Individuals with early life separation

amethasone/corticotrophin-releasing hormone challenge has been de-

MDD patients with low childhood
BPD patients with high childhood

scribed (Tyrka et al., 2012). The complex nature of epigenetic mod-

Healthy adolescents (n=1,287)

ifications during early development was emphasized by a study

Healthy probands (n=392)
from their parents (n=83)

from their parents (n=83)

measuring NR3C1 promoter methylation in saliva of preschoolers

Military soldiers (n=96)
maltreatment (n=96)

maltreatment (n=93)

(n=260), who had experienced maltreatment in the past six months, at

two time points set six months apart (Parent et al., 2017). The mean
methylation of the promoter 1D region positively predicted childhood
maltreatment at baseline (also evaluated over a six month period), but
Sample

negatively predicted the change in methylation and maltreatment at

follow-up. Promoter 1F methylation predicted childhood adversity at
baseline, and methylation at CpG sites directly downstream of the
NGFI-A binding sites negatively predicted methylation change and
Rijlaarsdam et al., 2016

maltreatment at follow-up, suggesting that maltreated children display

Table 1 (continued)

increased NR3C1 promoter methylation after trauma and decreased

Khulan et al., 2014

Zannas et al., 2015

Prados et al., 2015

Epigenetic aging

Boks et al., 2015

promoter methylation at later follow-up stages (Parent et al., 2017).

Tay et al., 2019

Nevertheless, several studies have supported the notion that increased

NR3C1 methylation is associated with an increased risk of psycho-
Study

pathology, often in combination with G × E effects relating to negative

emotional experiences. DNA methylation of the NR3C1 1F promoter in

5
M.A. Schiele, et al.
whole blood samples was significantly higher in depressed individuals
(n=33) compared to healthy probands (n=34), and mean exon 1F
methylation and NGFI-A binding site methylation positively correlated
with increased levels of morning cortisol levels and average morning
cortisol output in depressed patients (Farrell et al., 2018). Furthermore,
increased NGFI-A binding site methylation was linked to the severity of
experienced emotional abuse, but not physical abuse and/or emo-
tional/physical neglect during childhood exclusively in depressed in-
dividuals, but not in healthy probands (Farrell et al., 2018). Within a
mixed mental disorder cohort of 101 patients with borderline person-
ality disorder (BPD) and a high degree of childhood trauma and of 99
patients with major depressive disorder (MDD) and a low degree of
childhood trauma, a significant link between higher peripheral blood
NR3C1 exon 1F methylation and experiences of sexual abuse, and a
linear trend between the severity of sexual abuse and the extent of
methylation have been reported (Perroud et al., 2011). Similar asso-
ciations of higher NR3C1 exon 1F methylation levels with increased
severity of childhood trauma were reported for physical abuse, physical
neglect, emotional abuse and emotional neglect as well for the total
number of different types of childhood trauma (Perroud et al., 2011).
These results were further supported by an analysis of the effects of
methylation sites across NR3C1 exons 1 and 2 in 46 volunteers, high-
lighting a CpG island in exon 1F as the only genomic region with a
significant positive correlation between the degree of methylation and
the number of childhood adversities on the one hand and with BPD and
MDD symptoms on the other hand (Radtke et al., 2015). When eval-
uated in a prediction model of future psychopathology, the number of
experienced childhood adversities, a combined principal component of
NR3C1 exon 1 and 2 methylation and their interaction, all had sig-
nificant predictive potential, yet interestingly, when evaluating the ef-
fect of childhood adversity and exon 1F methylation alone on the de-
velopment of BPD symptoms, only significant main effects, yet no
interaction effect, were found, emphasizing the complex nature of the
underlying epigenetic mechanisms (Radtke et al., 2015). Notably,
higher NR3C1 methylation in neonatal mononuclear cells extracted
from cord blood (n=85 newborns) at different exon 1F CpG sites was
associated with increased prenatal maternal depression and anxiety
symptoms in the second, mid-third and third trimester (Oberlander
et al., 2008). Yet, only the heightened methylation of a CpG island co-
localizing with the NGFI-A binding site in newborns predicted infant
HPA reactivity in form of an elevated cortisol release during a stress
challenge at three months of age, hinting at the epigenetic impact of
prenatal stress exposure (Oberlander et al., 2008).
Another important player of functional HPA axis regulation is coded
for by the peptidyl-prolyl cis-trans isomerase FKBP5 gene (chromo-
somal location 6p21.31). FKBP5 lowers the affinity of cortisol for its
receptor and hinders the translocation of the receptor-ligand-complex
into the nucleus, while at the same time partaking in an intracellular
ultra-short negative feedback loop downregulating NR3C1 activity
(Wochnik et al., 2005). Transcription of FKBP5 is regulated by mainly
intronic glucocorticoid-response elements (GRE) dependent on NR3C1
binding, showcasing an intricate interplay affected by epigenetic
modifications (Jaaskelainen, Makkonen, & Palvimo, 2011). A sig-
nificant interaction effect of FKBP5 rs1360780 A alleles (leading to an
amplified transcription due to enabling a three-dimensional interaction
of distal GRE enhancer elements in FKBP5 intron 2 with the core pro-
moter site, hypothesized to convey increased post-traumatic stress
disorder [PTSD] risk) and early childhood trauma, independent of
adulthood trauma, has been reported for decreased peripheral blood
methylation of GREs in intron 7 in 76 adults (Klengel et al., 2013). In
turn, dexamethasone exposure of proliferating, but not of differ-
entiated, human hippocampal progenitor cells resulted in a stable de-
methylation of CpG sites in FKPB5 intron 7. This suggests a distinct
window of vulnerability for relevant epigenetic modifications of the
functional GREs, resulting in increased FKBP5 transcription due to
NR3C1 binding, hence an overreaction of the ultra-short feedback loop
6
Clinical Psychology Review 77 (2020) 101830
resulting in heightened systemic glucocorticoid resistance (Klengel
et al., 2013). Moreover, an evaluation of blood mRNA expression
guided by GREs indicated that FKBP5 rs1360780 A allele carriers with
childhood abuse, but not without childhood abuse, displayed gluco-
corticoid receptor resistance in transcripts representative of immune
and inflammatory signaling pathways, potentially reflecting a periph-
eral phenotype promoting the vulnerability towards or development of
stress-related disorders (Klengel et al., 2013). Placental hypermethyla-
tion across NR3C1 and FKBP5 has been associated with higher second
trimester perceived stress and increased anxious and depressive symp-
toms, in case of FKBP5 in 61 women (Monk et al., 2016). Based on
mediation analyses, perceived stress was associated with increased
FKBP5 methylation which in turn was associated with lower third tri-
mester fetal coupling (correlation of fetal movement and heart rate;
indicative of CNS maturation), denoting an epigenetic link between
pregnancy stress and fetal development (Monk et al., 2016). Moreover,
in 56 MDD patients, higher severity of childhood trauma has been
linked to decreased whole blood FKBP5 methylation in the CpG island
covering the third GRE in intron 7, in carriers of the FKBP5 rs1360780
A risk allele (Tozzi et al., 2018). Furthermore, lower FKBP5 intron 7
methylation was associated with reduced bilateral inferior orbitofrontal
gyrus (a cortical area implicated in response inhibition; particularly
modulation and reappraisal of negative emotion) grey matter volume in
MDD patients (n=56) and controls (n=50), and with increased neu-
ronal activation during valence recognition of emotional faces in MDD
patients exclusively, linking FKBP5 demethylation with a neuronal
network potentially involved in the expression of affective clinical
symptoms (Tozzi et al., 2018). However, it should be noted that despite
a recent replication of reduced whole blood FKBP5 intron 7 methylation
in rs1360780 A/A genotype carriers and in comparably more depressed
individuals in a large community sample (n=3,965), main and inter-
action effects in combination with childhood maltreatment on lifetime
MDD were not successfully re-established (Klinger-Konig et al., 2019),
thus blurring the picture of FKBP5 methylation merging with early life
experiences as a reliable predictive biomarker of negative affective
spectrum symptoms.
Taken together, genes related to HPA axis regulation, especially
NR3C1, are among the most promising epigenetic biomarkers, which
are currently explored regarding their predictive potential at identi-
fying individuals susceptible to maladaptive responses to psychological
stressors, and could also serve as surrogate markers of HPA axis ac-
tivity, when comparing different treatment modalities (Zannas & West,
2014).
3.2. Monoaminergic and GABA-ergic systems
Amongst the most commonly investigated neurotransmitter sys-
tems, especially due to its relation to affective and anxiety spectrum
disorders, the monoaminergic system has been a common point of focus
for epigenetic studies. The (transcriptionally) more active long allele (l)
of the serotonin transporter linked polymorphic region (5-HTTLPR), a
part of the gene coding for the serotonin transporter (SLC6A4; chro-
mosomal location 17q11.2; regulates serotonergic signaling in the CNS
by sodium-dependent reuptake of serotonin from the synaptic cleft into
the pre-synapse, therefore reducing neurotransmitter availability to
pre- and post-synaptic serotonin receptors), has been implicated as a
protective factor against MDD due to exposure to various lifetime
stressors. On an epigenetic level, higher degrees of promoter methyla-
tion have been related to increased experiences of unresolved loss or
trauma in l/l genotype carriers (van IJzendoorn, Caspers, Bakermans-
Kranenburg, Beach, & Philibert, 2010). In homozygote carriers of the
less active short allele (s) - usually, but not unequivocally, implicated in
an increased susceptibility for affective and anxiety-related traits -
higher SLC6A4 promoter methylation was associated with lower levels
of unresolved loss and trauma, indicating different molecular forms of
adjustment in risk allele carriers in 143 participants (van IJzendoorn,
M.A. Schiele, et al.
et al., 2010). Contrarily, an all-female study (n=155) found greater
levels of SLC6A4 promoter methylation in individuals who suffered
from sexual abuse and significant positive correlations between 5-
HTTLPR genotypes and hypermethylation with regard to antisocial
personality disorder symptoms, with higher degrees of correlation with
an increasing number of s alleles (Beach, Brody, Todorov, Gunter, &
Philibert, 2011). A longitudinal study of 28 monozygotic twin pairs
showed that bullied twins had higher SLC6A4 promoter methylation
levels at age ten than non-bullied twins, while notably prior to any
bullying experience at age five methylation levels were indistinguish-
able, as were child-specific family environments and individual risk
factors prior to or concomitant to bullying (Ouellet-Morin et al., 2013).
Overall methylation changes between the ages of five and ten were
exclusively based on a single CpG island, at which methylation levels
also displayed a negative correlation with the cortisol response to a
psychological stress challenge, supporting the hypothesis that the ser-
otonergic and HPA systems display a functional epigenetic connection
(Ouellet-Morin et al., 2013).
However, attention has not solely been focused on the SLC6A4; the
monoamine oxidase A gene (MAOA, chromosomal location Xp11.3),
whose protein product catalyzes the oxidative deamination of amines
(e.g. 5-hydroxytryptamine, norepinephrine and epinephrine) and is
therefore important in the metabolism of neuro- and vaso-active
amines, has also been evaluated epigenetically. The MAOA gene is
commonly investigated for a functional genetic variation in its pro-
moter region, i.e. the upstream variable number of tandem repeats
(uVNTR) consisting of “protective” short (transcriptionally less active)
and “risk” long (transcriptionally more active) alleles predisposing for
instance to panic-related phenotypes (Howe et al., 2016; Reif et al.,
2012). The epigenetic signature of MAOA, in particular of CpG islands
flanking the uVNTR and covering the first exon, has also been in-
vestigated with respect to stress-associated experiences. Comparing 44
female patients with panic disorder with 44 mentally healthy control
probands showed a significantly lower average MAOA methylation in
panic disorder, principally in CpG islands downstream of the uVNTR
and within the first exon (Domschke et al., 2012). While methylation
was not affected by age, smoking status or selective serotonin-reuptake
inhibitor (SSRI) medication, the long uVNTR variants were associated
with increased overall methylation in healthy controls (Domschke
et al., 2012). Most strikingly, across female panic disorder patients and
controls the proportion of negative life events during the past year was
significantly negatively correlated with CpG island methylation down-
stream of the uVNTR and within the first MAOA exon (Domschke et al.,
2012). The proportion of positive recent life events was significantly
positively correlated with methylation at both genomic sites, pointing
towards a role of MAOA hypomethylation as an epigenetic correlate of
susceptibility-increasing environmental experiences in the etiology of
panic disorder (Domschke et al., 2012).
Notably, the majority of findings relating to the epigenetics of
psychosocial stressors and monoaminergic neurotransmission point
towards a hypermethylation of SLC6A4 and a hypomethylation of
MAOA, mirroring the results observed in categorical analyses of MDD
patients (Bakusic, Schaufeli, Claes, & Godderis, 2017; Schiele et al.,
2019), further stressing the need for longitudinal study designs evalu-
ating methylation states over the disease course of affective disorders.
Besides the accumulating evidence for epigenetic changes in ser-
otonin signaling and metabolism, other neurotransmitter systems have
been implicated in mediating the influence of external stressors on the
underlying pathophysiology of mental disorders. For example, average
methylation across CpG islands in the promoter region and the second
intron of the GAD1 gene (chromosomal location 2q31.1) coding for the
glutamate decarboxylase 67, which catalyzes the pyridoxal phosphate-
dependent decarboxylation of glutamate to GABA, was found to be
lower in panic disorder patients compared to healthy controls (n=65
each), with a particularly strong effect in the promoter region
(Domschke et al., 2013). This GAD1 promoter hypomethylation was
7
Clinical Psychology Review 77 (2020) 101830
significantly negatively correlated with the proportion of exposure to
negative life events during the past year in patients and controls, pri-
marily in females, and was hypothesized to convey a compensatory
mechanism in the face of adverse environmental stimuli by raising the
availability of the inhibitory neurotransmitter GABA following stressful
experiences (Domschke et al., 2013).
3.3. Neuropeptide and neurotrophic factor systems
The nonapeptide oxytocin, which is released by the neurohypo-
physis, regulates smooth muscle tonus during parturition and lactation,
and has been shown to influence complex social cognition and affilia-
tive behavior with a high relevance to anxiety-related phenotypes (for
review see Gottschalk & Domschke, 2018).
Methylation of the transcription-regulating exon 3 of the oxytocin
receptor gene (OXTR, chromosomal location 3p25.3) in cord blood of
39 infants was negatively associated with the occurrence of stressful life
events during the two years prior to birth, postpartum depression in-
tensity, and maternal cortisol awaking response and diurnal cortisol
profile during the second trimester of pregnancy, independent of po-
tentially confounding sociodemographic and birth-related factors
(Unternaehrer et al., 2016). This suggests that prenatal adversity might
trigger an epigenetic adaption in a gene with known relevance for
childbirth and mother-child bonding via increased expression of OXTR
(Unternaehrer et al., 2016). Moreover, it has been described that ex-
periences of childhood abuse lead to increased methylation down-
stream of exon 3, supporting the notion of differential effects of pre-
and postnatal stressors, while only an interaction of environmental
trauma and methylation downstream of exon 3 and within exon 1
predicted adult psychopathological symptoms in 393 adult participants
(Smearman et al., 2016). Hypomethylation within exon 1 and hy-
permethylation downstream of exon 3 in combination with severe
childhood abuse was associated with higher adult ratings of anxiety and
depression symptoms (Smearman et al., 2016). In line with these
findings on negative post-natal experiences, increased OXTR exon 3
methylation was furthermore linked to low reported maternal care
during childhood, especially in males, as was hypermethylation of exon
6 of the brain derived neurotrophic factor gene (BDNF, chromosomal
location 11p14.1) (Unternaehrer et al., 2015). BDNF is a member of the
nerve growth factor family that binds to membrane-bound tyrosine
receptor kinases and promotes differentiation and survival of peripheral
and central neuronal cell populations, influences axonal and dendritic
growth and morphology, and regulates synaptic transmission and
plasticity.
In synopsis, these findings point towards early life stress to be ac-
companied by widespread epigenetic modifications across different
neuropeptide and neurotrophic factor systems. Interestingly, psycho-
social stress has been demonstrated to significantly increase whole
blood methylation of OXTR exon 3 in an acute post-stress phase (15
minutespast challenge) and to significantly decrease methylation, even
below the point of pre-stress baseline methylation, in a follow-up phase
(90 minutespast challenge) in 76 adults (Unternaehrer et al., 2012). No
such changes were detectable for BDNF exon 6 methylation, high-
lighting the importance to evaluate the short-term and long-term tem-
poral dynamics of epigenetic modifications in light of potentially ad-
verse environmental influences (Unternaehrer et al., 2012).
3.4. MicroRNAs (miRNAs)
Moreover, a recent investigation of stress-associated miRNAs in
saliva found significant changes in miR 20b, miR 21 and miR 26b be-
fore, during and after a psychosocial stress challenge (Trier Social Stress
Test) in 24 healthy participants (Wiegand et al., 2018).: Concentrations
of miR 21 correlated positively with experienced stress over the course
of the challenge, while miR 21 and miR 26b concentrations correlated
positively with the secreted amount of the salivary stress marker alpha-
M.A. Schiele, et al.
amylase, suggesting an integration of miRNA-related processes into
sympathetic stress regulation and offering a non-invasive way to de-
termine a dynamic acute stress indicator (Wiegand et al., 2018).
3.5. Epigenome-wide association studies (EWAS)
Similar to the non-hypothesis driven approach followed in genome-
wide association studies (GWAS), epigenome-wide association studies
(EWAS) utilize high-throughput methylation profiling techniques, al-
lowing for the evaluation of thousands of CpG sites simultaneously in
discovery approaches with ever-growing sample sizes aimed at the
identification of novel epigenetic hotspots in relation to various phe-
notypes of interest.
An EWAS comparing maltreated children (n=96) removed from
their parents by protective services with demographically matched
children (n=96) found 2,868 significantly differentially methylated
saliva CpG sites mainly situated in promoter regions and gene bodies.
When comparing the results to a pathway database of disorder-asso-
ciated biomarkers, authors discerned a significant enrichment for epi-
genetic changes in genes related to a diverse range of neoplasms in-
cluding lung cancer, colorectal cancer and breast cancer (Yang et al.,
2013). A unique experimental design accessing gene expression and
EWAS data from PTSD patients with (n=32) and without (n=29) ad-
verse childhood events compared to controls with trauma exposure
outside of their childhood (n=108) found that gene expression profiles
differed widely for both disorder groups (2% overlap) indicating dis-
tinct PTSD profiles in the presence or absence of childhood trauma
(Mehta et al., 2013). For 94% of the loci, the direction of the change
predicted by differences in methylation agreed with the change ob-
served in gene expression, i.e. methylated CpGs close to the transcrip-
tion start site predicted reduced transcription. Furthermore, about two
thirds of transcripts representative of PTSD with childhood abuse dis-
played methylation changes, but only one third of transcripts was re-
presentative of PTSD without childhood abuse, indicating that changes
in gene expression are more prominently linked to changes in corre-
sponding DNA methylation in the presence rather than the absence of
childhood abuse in PTSD (Mehta et al., 2013). Remarkably, evaluation
of the associated biological processes affected by methylation indicated
an overlap related to the development, adhesion and migration of cells,
whereas in PTSD with childhood abuse unique nervous system devel-
opment processes were overrepresented. Conversely, PTSD without
abuse history distinctly displayed apoptosis processes, possibly re-
flecting differences in PTSD pathophysiology based on past experiences
of maltreatment (Mehta et al., 2013).
An EWAS in maltreated (n=94) vs. non-traumatized children
(n=96) analyzing DNA methylation as a predictor of dimensional de-
pression ratings discovered three significant CpG sites within the genes
coding for the DNA-binding protein inhibitor ID-3 (ID3, chromosomal
location 1p36.12), the inotropic glutamate receptor NMDA type subunit
1 (GRIN1, chromosomal location 9q34.3), and the tubulin poly-
merization promoting protein (TPPP, chromosomal location 5p15.33),
with lower methylation correlating with increased depression scores
(Weder et al., 2014). All three CpG sites were predictors independent of
interaction effects with childhood maltreatment, yet the ID3 CpG site
showed an interaction effect with childhood maltreatment on cortisol
secretion, with increased methylation predicting decreased diurnal
cortisol secretion in controls, yet increased cortisol secretion in mal-
treated children (Weder et al., 2014).
Comparing 83 males exposed to early life stress in form of separa-
tion from their parents to 83 non-separated controls, no epigenome-
wide changes were detected. However, when evaluating the develop-
ment of depressive symptoms over a 5-10 year period significant as-
sociations for 491 CpG probes in 351 different genes were discovered
(Khulan et al., 2014). Among the most significant findings were hy-
pomethylations in the genes coding for the leucine-rich glioma-
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Clinical Psychology Review 77 (2020) 101830
inactivated protein 1 (LGI1, chromosomal location 10q23.33) and 2
(LGI2, chromosomal location 4p15.2) in addition to other genes related
to brain functioning. Pathway analysis revealed an overrepresentation
of hypomethylated genes representing biological processes related to
morphology and development, as well as DNA and transcription factor
binding (Khulan et al., 2014).
A surprising result arose from an EWAS investigation comparing an
all-female set of patients with BPD (n=96) and a history of high
childhood adversity to patients with MDD (n=93) reporting low rates
of childhood maltreatment: comparison of BPD to MDD and low to high
childhood trauma severity in multi- and univariate analyses highlighted
a CpG site close to miR 124-3, where hypomethylation was linked to
BPD and increased childhood trauma (Prados et al., 2015). This result
was validated via pyrosequencing and hypothesized to reflect the cri-
tical role of neuronal development and HPA axis regulation under
epigenetic control, given that miR 124-3 targets NR3C1 and the mi-
neralocorticoid receptor (NR3C2) (Prados et al., 2015).
Strikingly, a meta-analysis of two large EWAS sample sets (total
n=1,740) found no epigenome-wide significant CpG methylation hit in
cord blood extracted DNA associated with prenatal maternal stress
(Rijlaarsdam et al., 2016). A follow-up analysis of the top EWAS meta-
analysis hits (p<.0001) in pathway databases indicated methyl-
transferase activity as the single most overrepresented molecular
function. A clustering approach aimed at identifying differentially
methylated regions found no Bonferroni-corrected cluster associated
with prenatal maternal stress, underscoring the clinical need for larger
sample sizes in order to reach the statistical power to detect robust
EWAS results (Rijlaarsdam et al., 2016).
A large EWAS in 1,287 adolescents found post-hoc significant po-
sitive correlation of a CpG island within the promoter of the SAM
pointed domain-containing Ets transcription factor (SPDEF, chromo-
somal location 6p21.31) with the frequency of negative stressful life
events in the past year (Tay et al., 2019). Moreover, a significant in-
teraction effect between the frequency of stressful life events in the past
year and increased methylation was discerned to result in an higher
incidence of lifetime binge drinking behavior. A methylation-expression
quantitative trait loci (eQTL) analysis suggested that methylation would
lead to expression changes in multiple trans-genes enriched for genes
previously linked to opioid-related disorders, alcoholism and tobacco
use, providing converging evidence for a novel epigenetic risk marker
of adolescent substance abuse integrating the molecular effects of
psychosocial stress (Tay et al., 2019).
Due to small effect sizes more recent approaches with samples in the
thousands can be expected to return epigenome-wide significant find-
ings related to psychosocial stressors which prove robust to replication
attempts. Additionally, novel hits are expected to emerge with advances
in throughput and sequencing techniques. EWAS constitute a promising
field for future studies, especially given that they produce a quantitative
outcome measure, which makes them particularly attractive for statis-
tical approaches in combination with dimensional phenotypes.
3.6. Epigenetic aging
Composite epigenomic markers such as a DNA methylation-based
predictor of age (“epigenetic clock”; Horvath, 2013) have attracted
great interest with regard to both stress and mental health. Accelerated
epigenetic aging has been shown to be conferred by cumulative, par-
ticularly personal lifetime stress in a cohort of highly traumatized
African-Americans (Zannas et al., 2015), and 6-month exposure of male
soldiers to combat deployment in Afghanistan (Boks et al., 2015). In-
creased epigenetic aging has also found to be associated with the ca-
tegorical phenotype of major depression (Han et al., 2018). These
findings suggest epigenetic aging as a possible mechanistic link be-
tween the experience of psychosocial stress and aging-related disease
phenotypes (see Zannas, 2016).
M.A. Schiele, et al.
4. Transgenerational transmisson of stress via epigenetic
mechanisms?
Preclinical studies suggest a potential intergenerational transmis-
sion of epigenetic information as an engram of environmental experi-
ences via multiple mechanisms conferred by paternal sperm and ma-
ternal germline to shape endocrine programming, brain development
and the behavioral phenotype in the offspring (Babenko, Kovalchuk, &
Metz, 2015; Bale, 2014; Dias & Ressler, 2014; Franklin et al., 2010;
Klengel, Dias, & Ressler, 2016; Nagy & Turecki, 2015; Rodgers, Morgan,
Bronson, Revello, & Bale, 2013; Stenz, Schechter, Serpa, & Paoloni-
Giacobino, 2018; Yeshurun & Hannan, 2019). It has to be noted,
however, that to date evidence from human studies is merely correla-
tional as detailed below.
In a study examining 25 women exposed to the Tutsi genocide in
Rwanda during pregnancy and their children in comparison with 25
non-exposed Rwandan control mothers and their offspring, Perroud
et al. (2014) observed higher rates of PTSD and depression symptoms in
mothers exposed to the genocide as well as in their children. In addi-
tion, methylation of the NR3C1 exon 1F promoter region was increased
in exposed compared to non-exposed mothers. Likewise, higher NR3C1
methylation was also observed in children of genocide-exposed mothers
relative to control children. In a retrospective study in 25 mothers ex-
posed to intimate partner violence during pregnancy and their children
(n=25), NR3C1 promoter methylation in children as assessed during
adolescence was positively associated with maternal exposure to vio-
lence during pregnancy (Radtke et al., 2011). In 32 Holocaust survivors
and their 22 adult offspring compared to eight non-exposed control
parents and their nine children, parental Holocaust exposure was found
to predict FKBP5 intron 7 methylation in offspring. Of note, increased
whole blood CpG methylation was observed in the third (of a total of
three) GRE of FKBP5 intron 7 in Holocaust survivors compared to
contemporary Jewish controls, while children of Holocaust survivors
were characterized by decreased methylation compared to control
children, which may possibly reflect a biological adaptation in response
to altered glucocorticoid levels (Yehuda et al., 2016). Furthermore,
offspring carrying the FKBP5 rs1360780 A risk allele showed a sig-
nificant negative correlation between the degree of physical and sexual
childhood abuse and CpG methylation across the first GRE in intron 7,
while G/G genotype carriers displayed a positive correlation, sug-
gesting a potential site-specific epigenetic response based on either
personal childhood or parental trauma (Yehuda et al., 2016). Methy-
lation of the third GRE in intron 7 was further positively correlated with
methylation at the same site in their offspring and overall average
methylation of intron 7 was negatively correlated with wake-up cor-
tisol, indicating a potential functional relevance to HPA axis regulation
(Yehuda et al., 2016).
In 21 families with school-age children, parental psychological
distress severity was found to be predictive of methylation status at
three CpG sites located in the dopamine transporter (DAT; chromo-
somal location 5p15.33) promotor region in their children. Paternal –
but not maternal – methylation at three CpG sites were associated with
methylation at three, albeit different, CpG sites in children (Cimino
et al., 2017).
While the familiality of mental disorders has been well established
and associations between the exposure to stressful experiences and
trauma with epigenetic alterations have been described extensively in
the literature (see above), it has yet to be conclusively established if –
and how – stress-induced epigenetic alterations can be passed on to
subsequent generations (Jawaid, Roszkowski, & Mansuy, 2018;
Youssef, Lockwood, Su, Hao, & Rutten, 2018).
5. Epigenetics: markers and mechanisms of psychotherapy and
prevention?
In light of the dynamic nature of epigenetic modifications and their
9
Clinical Psychology Review 77 (2020) 101830
responsiveness to environmental input as outlined above, recent re-
search has begun to place a particular focus on epigenetic changes in
relation to the effects of psychotherapy by examining the potential of
epigenetic patterns in predicting the therapeutic outcome, as well as
temporal modifications as possible mechanistic correlates of clinical
changes occurring over the course of psychotherapeutic or – to a lesser
extent – also preventive interventions. For an overview of epigenetic
effects accompanying treatment response, see Table 2.
5.1. Hypothalamic–pituitary–adrenal (HPA) axis system
In 16 patients with PTSD, higher NR3C1 exon 1F methylation levels
prior to a 12-week prolonged exposure intervention were found to be
predictive of improved treatment response (greater changes in clin-
ician-rated and self-reported symptom severity from pre- to post-
treatment) and lower post-treatment symptoms as well as of lower self-
reported (but not clinician-rated) symptom severity at follow-up
(Yehuda et al., 2013).
In a total of 16 combat veterans with PTSD, FKBP5 exon 1 promoter
methylation – although not predictive of treatment outcome per se –
was found to decrease in responders to a 12-week prolonged exposure
psychotherapy (n=8) during the recovery period from post-treatment
to follow-up (Yehuda et al., 2013). In another study, following mind-
fulness-based stress reduction in 22 patients with PTSD, treatment re-
sponders (n=11) were characterized by a decrease in FKBP5 intron 7
methylation, whereas methylation increased in non-responders. Fur-
thermore, changes in PTSD symptoms from pre- to post-therapy were
inversely correlated with methylation change in the investigated region
(Bishop et al., 2018).
In a sample of 111 adult patients diagnosed with agoraphobia with/
without panic disorder or specific phobia treated with disorder-specific
cognitive behavioral therapy (CBT), pre- to post-treatment percentage
changes in FKBP5 methylation at a single CpG site in intron 7 was in-
versely related to changes in clinical severity observed at follow-up. The
pre- to post-methylation change at one CpG site in the promoter region
was furthermore nominally significantly associated with post-treat-
ment, but not follow-up, symptom severity. Moreover, a trend for an
allele-specific methylation change from pre- to post-therapy at one CpG
site located in the promoter region to be positively related to outcome
at follow-up emerged in FKBP5 rs1360780 A risk allele carriers (Roberts
et al., 2019). Enhanced treatment response has also been associated
with nominal increases in FKBP5 exon 1 methylation changes from pre-
to post-CBT at one CpG site in 98 children and adolescents with mixed
anxiety disorders, but again only in FKBP5 rs1360780 A risk allele
carriers (Roberts et al., 2015).
5.2. Monoaminergic and GABA-ergic systems
In 116 children with mixed anxiety disorders following CBT, treat-
ment non-responders were characterized by a decrease in methylation
as driven by a single CpG site in the promoter region of the SLC6A4
gene post-treatment, while in turn, treatment responders – although not
statistically significant – displayed a small increase in methylation at
the same site on a descriptive level. Of note, patients who showed
continued symptom improvement six months after psychotherapy ces-
sation were characterized by a significant increase in average SLC6A4
promoter methylation relative to those who did not improve or wor-
sened at follow-up (Roberts et al., 2014).
A recent study on the effect of a mindfulness-based preventive in-
tervention in medical students preparing for a stressful exam, however,
the effectiveness of the preventive measure, i.e. stress reduction, went
along with a decrease in SLC6A4 methylation (Stoffel et al., 2019).
In 28 female patients with panic disorder in comparison to matched
healthy controls, DNA methylation in a region spanning exon 1/intron
1 of the MAOA gene was shown to significantly increase in treatment
responders following a six-week exposure-based CBT, whereas
M.A. Schiele, et al. Clinical Psychology Review 77 (2020) 101830

Table 2
Primary findings of psychotherapyepigenetic studies
Study Diagnosis Cases Therapy form Therapy duration Gene Primary findings

Yehuda et al., 2013 PTSD n=16 PE 12 weeks NR3C1 ↑ NR3C1 baseline methylation in responders (n=8) post-PE
3-month FU FKBP5 ↓ FKBP5 methylation in responders (n=8) at FU
↑ FKBP5 methylation in non-responders (n=8) at FU
Bishop et al., 2018 PTSD n=22 MBSR 9 weeks FKBP5 ↓ Methylation in responders (n=11) post-MBSR
↑ Methylation in non-responders (n=11) post-MBSR
Roberts et al., 2019 AG, AG+PD, n=111 CBT Variable/not FKBP5 ↓ Methylation associated with higher symptom improvement post-
SpP specified CBT
6-month FU
Roberts et al., 2015 Mixed AD n=98 CBT Variable/not FKBP5 ↓ Methylation associated with greater reduction in symptom severity
specified at FU in FKBP5 rs1360780 T allele carriers
6-month FU
Roberts et al., 2014 Mixed AD n=116 CBT Variable/not SLC6A4 ↓ Methylation in non-responders post-CBT
specified ↑ Methylation in responders at FU
6-month FU
Ziegler et al., 2016 PD n=28 CBT 6 weeks MAOA ↑ Methylation in responders (n=11) post-CBT
Schiele et al., 2018 SpP n=28 CBT (VR) 2 weeks MAOA ↑ Methylation post-CBT
Perroud et al., 2013 BPD n=167 DBT 4 weeks BDNF ↓ Methylation in responders (n=115) post-DBT
↑ Methylation in non-responders (n=52) post-DBT
Thomas et al., 2018 BPD n=26 DBT 12 weeks BDNF ↓ Methylation post-DBT
Knoblich et al., 2018 BPD n=24 DBT 12 weeks APBA3 No methylation change post-DBT
MCF2 ↑ Baseline methylation in responders (n=7)
Kahl et al., 2016 MDD n=37 CBT 6 weeks SLC2A1 ↓ Methylation in remitters (n=18)
Ziegler et al., 2019 PD n=47 CBT 6 weeks EWAS ↑ IL1R1 methylation post-CBT
Vinkers et al., 2019 PTSD n=44 tfCBT (partially with 6-8-month FU EWAS Changes in 12 DMRs
EMDR) ↑ ZFP57 methylation in responders (n=11) at FU

PTSD=post-traumatic stress disorder; AG=agoraphobia; PD=panic disorder; SpP=specific phobia; AD=anxiety disorder; BPD=borderline personality disorder;
MDD=major depressive disorder; PE=prolonged exposure therapy; CBT=cognitive behavioral therapy; VR=virtual reality; MBSR=mindfulness-based stress re-
duction; DBT=dialectic behavioral therapy; tfCBT=trauma-focused psychotherapeutic intervention; FU=follow-up; NR3C1=glucocorticoid receptor gene;
FKBP5=FK506 binding protein 51 gene; SLC6A4=serotonin transporter gene; MAOA=monoamine oxidase A gene; BDNF=brain derived neurotrophic factor gene;
APBA3=amyloid beta precursor protein binding family A member 3 gene; MCF2=MCF.2 cell line derived transforming sequence gene; SLC2A1=solute carrier
family 2 member 1 gene; IL1R1=interleukin 1 receptor type 1 gene; ZFP57=zinc-finger protein 57 gene; EWAS=epigenome-wide association study;
DMR=differentially methylated region; ↑=increased methylation; ↓=decreased methylation.

methylation levels remained unchanged or even decreased in non-re-
sponders. Of note, following therapy DNA methylation levels in CBT
responders no longer differed from those in healthy controls (Ziegler
et al., 2016). Similarly, in 28 female patients with acrophobia, sig-
nificant increases in average MAOA methylation as well as at four single
CpG sites - conferring decreased MAOA expression in luciferase-based
reporter gene assays - were observed following a two-session exposure-
based treatment in virtual reality, and to correlate with improvements
in clinical symptoms (Schiele et al., 2018).
– was significantly related to favorable response to DBT in 24 patients
with BPD (Knoblich et al., 2018).
Hypermethylation of the solute carrier family 2 member 1
(SLC2A1, chromosomal location 1p34.2) promoter region in 37 patients
with MDD was found to decrease in treatment remitters compared to
non-remitters after six weeks of inpatient treatment with CBT (Kahl
et al., 2016).
5.5. Epigenome-wide association studies (EWAS)

5.3. Neuropeptide and neurotrophic factor systems
In 115 patients with BPD, following a four-week course of intensive
dialectic behavior therapy (I-DBT) treatment non-responders were
found to increase in methylation at BDNF exons 1 and 4, while, in turn,
treatment responders decreased in methylation. Alterations in methy-
lation were furthermore found to be related to changes in depressive
symptom severity, hopelessness and impulsivity (Perroud et al., 2013).
In 41 patients with BPD, BDNF exon 4 hypermethylation was discerned
in saliva, but not in blood, as compared to healthy controls. BDNF
methylation in saliva was found to decrease following a 12-week dia-
lectic behavioral therapy (DBT) program in a subsample of 26 BPD
patients, although changes in methylation did not correlate with
symptom improvement (Thomas et al., 2018).
A longitudinal epigenome-wide study assessed changes on the DNA
methylome level corresponding to clinical effects of manualized six-
week CBT in panic disorder using the Illumina MethylationEPIC
BeadChip. Suggestive evidence was discerned for an increase in me-
thylation directly after CBT at cg06943668 in the interleukin 1 receptor
type 1 (IL1R1) gene in treatment responders suggesting a potentially
immunomodulatory effect of successful CBT (Ziegler et al., 2019). In
PTSD patients, response to trauma-focused CBT partially supplemented
by Eye Movement Desensitization and Reprocessing (EMDR) has been
observed to be accompanied by dynamic alterations in 12 differentially
methylated genomic regions (DMRs) six to eight months after treat-
ment, with most consistent evidence for increasing methylation of the
zinc-finger protein 57 (ZFP57) genomic region along with successful
treatment (Vinkers et al., 2019).

5.4. Candidate genes related to other biological systems 5.6. Epigenetic aging

Pre-treatment increased methylation of the amyloid beta precursor
protein binding family A member 3 (APBA3, chromosomal location
19p13.3) and the MCF.2 cell line derived transforming sequence
(MCF2, chromosomal location Xq27.1) genes – both previously asso-
ciated with BPD in an epigenome-wide approach (Teschler et al., 2013)
The effects of stress on the composite epigenetic marker of “epige-
netic aging” as reviewed above might be preventable by targeted be-
havioral interventions or resilience-increasing environments: While
depressive symptoms of parents living in the rural southeastern United
States, scored when their children were 11 years old, were found to be

10
M.A. Schiele, et al.
predictive of accelerated epigenetic aging in the offspring at age 20,
participation in a family-centered prevention training (Strong African
American Families [SAAF] program) seems to have prevented such
alterations in youths. This protective effect on epigenetic aging in the
intervention group could be attributed to reductions in harsh parenting
from age 11 to age 16 (Brody, Yu, Chen, Beach, & Miller, 2016). Also,
while exposure to higher levels of racial discrimination in African
American youth from rural Georgia, USA, was associated with increased
epigenetic aging, supportive family environments prevented ac-
celerated epigenetic aging despite exposure to racial discrimination
(Brody, Miller, Yu, Beach, & Chen, 2016).
6. Discussion and future directions
6.1. Epigenetics at the interface between genes and environment in mental
disorders
Mental disorders are highly complex and multifactorial in origin,
comprising an elaborate interplay of genetic and environmental (G ×
E) factors that act on a number of biological systems, and thus require a
framework that includes multiple levels of analysis. Epigenetic me-
chanisms function as a translator between genes and the environment
and add yet another level of intricacy in the discussion of differential
susceptibility rather than vulnerability. The “differential susceptibility
hypothesis” (Belsky & Pluess, 2009) entails a conceptualization of
plasticity genes rather than risk genes insofar as a given genotype
promotes increased sensitivity to environmental conditions in general
and, depending on the nature of the environment, can result in bene-
ficial or detrimental outcomes. Accordingly, experiences of stress and
adversity do not necessarily result in a heightened susceptibility for
mental disorders and, eventually, manifest pathology, but can convey
resilience. This phenomenon might be conferred by epigenetic me-
chanisms governing the functionality of putative “risk” genes de-
pending on environmental constellations.
In this context, it is important to note that “environmental influ-
ences” should be understood as an umbrella term encompassing any
and all input present in and arising from the environment and are not
limited to the repercussions of explicitly adverse environmental insults.
Rather, environmental input equally entails the presence of beneficial
factors, for example related to interpersonal aspects (e.g. attachment,
social support, friendship/relationship quality and stability). Moreover,
psychosocial factors (e.g. financial status) and lifestyle aspects such as
bodily activity and exercise, diet, smoking behavior, or substance abuse
have been linked to mental disorders one the one hand, and epigenetic
changes on the other. Finally, various characteristics of the surrounding
physical environment such as exposure to radiation, toxins, climate and
seasonal change are capable of inducing a wide range of epigenetic
modifications (see Kanherkar, Bhatia-Dey, & Csoka, 2014).
From an evolutionary perspective, adaptability to psychosocial
stressors and the environment as a whole might – apart from random
mutations, chromosomal and DNA sequence alterations generating
phenotypic variation and thus contributing to natural selection as as-
sumed in a neo-Darwinian model – also be conferred by epigenetic
mechanisms. By promoting genetic mutations and by transitioning into
the germline during development, environmentally induced epigenetic
marks are suggested to contribute to an ‘inheritance of acquired traits’
and thus promote natural selection in a neo-Lamarckian way potentially
facilitating neo-Darwinian evolution (Guerrero-Bosagna, 2019; Skinner,
2015). Along these lines, epigenetic adaptive plasticity is considered to
affect speciation (for review see Hernando-Herraez, Garcia-Perez,
Sharp, & Marques-Bonet, 2015). However, the general conservation and
divergence of DNA methylation patterns across species, with particular
regard to traits related to mental disorders, remain to be elucidated in a
systematic comparative epigenomics fashion. In a first pilot study,
Sipahi et al. (2014) have traced and characterized the evolution of
genomic sites associated with the development of PTSD and found that
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Clinical Psychology Review 77 (2020) 101830
the majority of PTSD-associated CpG sites are shared by all primates,
while PTSD-associated CpG sites proximal to immune system-related
genes may have disproportionately evolved during the more recent
evolutionary history.
6.2. Epigenetics as a switch between risk and resilience?
Regarding the role of epigenetic mechanisms in contributing to a
risk-increasing status towards mental disorders, there is no doubt that
environmental influences such as early, even prenatal trauma shape
epigenetic patterns and that life experience continues to alter the
function of the genome throughout the lifespan (see Fig. 2). As re-
viewed above (see section 3, ’Epigenetic ”scars“ of psychosocial stress’),
epigenetic changes in candidate genes including NR3C1, FKBP5,
SLC6A4 and BDNF have repeatedly been associated with stress experi-
ences and may thus constitute the most promising dynamic markers of
stress to date.
The biochemical mechanisms translating input from, broadly, the
environment into epigenetic changes are not yet completely under-
stood, however, one lead points to a process involving glucocorticoids
as markers of HPA axis activation following stress exposure to bind to
glucocorticoid receptors (GRs) in the cell, which then function as
transcription factors in the nucleus and initiate a host of transcriptomic
modifications resulting in enduring change of the epigenetic machinery
(Zannas & Chrousos, 2017). However, given the complex-genetic nature
of mental disorders, the exact mechanisms brokering the modulation of
epigenetic signatures and their downstream consequences in response
to environmental influences towards an increased risk for mental dis-
orders are yet to be conclusively determined and likely involve the
intricate interplay between different neurotransmitter (e.g. mono-
aminergic and GABA-ergic, see above), neuropeptide, neurotrophic and
other systems.
Although research has mostly focused on the negative consequences
of stress exposure, changes in epigenetic signatures are suggested to
equally reflect the biological impact of not only detrimental but also
beneficial environmental influences, thus possibly contributing to an
increased resilience towards mental disorders (see Fig. 2). For instance,
augmented maternal care has been shown to exert a preventive effect
by increasing resilience via epigenetic changes in rodents, resulting in
reduced depression- and anxiety-related behaviors in response to stress
(Singh-Taylor et al., 2018) (for a review of animal models of epigenetic
mechanisms conferring resilience towards mental disorders see Dudley,
Li, Kobor, Kippin, & Bredy, 2011). Accordingly, secure attachment as
compared to disorganized attachment in human infants accounted for
11.9% of the variation in genome-wide DNA methylation, which might
contribute to differential resilience against mental disorders (Garg
et al., 2018). In particular, lower DNA methylation levels of the gene
coding for the oxytocin prepropeptide (OXT) have been linked to more
secure attachment styles along with a superior ability to correctly re-
cognize emotional facial expressions and thus potentially mediate
higher resilience against mental disorders characterized by various
forms of decreased social functioning (Haas et al., 2016). This notion
was further supported by a study reporting decreased OXTR methyla-
tion to be associated with lower ratings of self-reported attachment
anxiety in young probands (Ebner et al., 2019). As mentioned above,
human MAOA methylation has been found to be positively correlated
with the percentage of recently experienced positive life events, while
relative hypomethylation has been associated with the experience of
negative life events (Domschke et al., 2012) and a number of mental
disorders including panic disorder, depression and substance abuse (for
review, see Ziegler & Domschke, 2018). The classical vulnerability-
stress model of mental disorders, arguably one of the most influential
models of disorder development, as well as conceptually similar ap-
proaches such as the “allostatic load”, “double-hit” or “three-hit” hy-
potheses predominantly focus on risk-increasing factors that, assuming
a cumulative effect, will lead to manifestation of disease (Bayer, Falkai,
M.A. Schiele, et al.
Figure 2. Model of epigenetic mechanisms in mental disorder risk and resilience.
CH3=methyl group
& Maier, 1999; Daskalakis, Bagot, Parker, Vinkers, & de Kloet, 2013;
McEwen, 2003; Zubin & Spring, 1977). In turn, the concept of resilience
does not merely entail positive environmental constellations or the
absence of adversity, but rather successful adaptation in the face of
adversity (Rutten et al., 2013). In light of the fact that experience of
negative life events or chronic stress does not necessarily lead to psy-
chopathology, alternative concepts have gained traction, including the
“stress inoculation” model, which postulates that early experiences of
moderate stress can actually protect against the effects of environ-
mental insults later in life (Parker, Buckmaster, Schatzberg, & Lyons,
2004), the “match-mismatch” hypothesis entailing that mental disorder
susceptibility can result from a “mismatch” between early and adult
environments and, consequently, an impaired ability to cope with
challenge (Nederhof & Schmidt, 2012), and – in a quite similar vein -
the “predictive adaptive response” hypothesis, which proposes that
cues received in early life program the development of a phenotype that
is normally adapted to later environmental conditions and that negative
health outcomes arise from a mismatch between the predicted and
actual environment (Bateson, Gluckman, & Hanson, 2014). Therefore,
while research into the deleterious consequences of stress experiences –
i.e., increased vulnerability for psychopathology – has led us towards an
increased understanding of the pathomechanisms of mental disorders,
spotlighting positive mental health outcomes despite exposure to ad-
versity can promote essential insights into the mechanisms facilitating
resilience and, importantly, the epigenetic correlates operating at the
intersection between vulnerability and resilience. For instance, a study
of 24 nurses working in a high-stress environment observed lower
SLC6A4 promoter methylation relative to a low work stress control
group (Alasaari et al., 2012), possibly indicating a compensatory, i.e.
adaptive effect promoting resilience given evidence from clinical sam-
ples on increased SLC6A4 methylation to be associated with mental
disorder susceptibility (for review, see Palma-Gudiel & Fananas, 2017).
Accordingly, the eventual consequences of stress experience are likely
mediated by epigenetic mechanisms functioning as a switch between,
ultimately, risk and resilience.
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Clinical Psychology Review 77 (2020) 101830
6.3. Psychotherapy-epigenetics: mechanisms of action and clinical
implications
As summarized above, there is a growing body of evidence that
psychological interventions may exert their impact in part via epige-
netic regulation of gene expression in line with Eric Kandel’s early
dictum “insofar as psychotherapy is successful in bringing about sub-
stantive changes in behaviour, it does so by producing alterations in
gene expression” (Kandel, 1998). Psychotherapy has been suggested to
function as an “epigenetic drug’” (Stahl, 2012) capable of inducing
epigenetic modifications by exercising its effects on neurobiological
circuits which are ultimately reflected on a clinical symptom level (see
Fig. 2). The precise molecular mechanisms of action in mediating
psychotherapeutic outcome are yet to be determined, and several open
questions remain. Animal models have provided evidence for epigenetic
mechanisms to shape cognitive processes and memory formation (Day
& Sweatt, 2011; Halder et al., 2016; Levenson & Sweatt, 2005; Rudenko
& Tsai, 2014) and to be involved in fear acquisition, consolidation and
extinction as a preclinical model of anxiety-related phenotypes (Kwapis
& Wood, 2014). Promising animal studies applying psychoenviron-
mental interventions have shown environmental enrichment to exert an
effect on a behavioral (e.g. reductions in anxiety-related behavior,
improved task learning or facilitated memory retrieval) (Laviola,
Hannan, Macri, Solinas, & Jaber, 2008; Reynolds, Lane, & Richards,
2010) as well as on a neurobiological level (van Praag, Kempermann, &
Gage, 2000): for instance, environmental enrichment in animal models
of mental and neurodegenerative disorders has been linked to mor-
phological changes such as dendritic and synaptic growth and neuro-
genesis in the hippocampus as well as molecular alterations including
neurotransmitter levels, neurotransmitter receptor expression and
neurotrophin expression (for review, see Alwis & Rajan, 2014;
Baroncelli et al., 2010). With particular focus on epigenetic changes,
environmental enrichment was observed to induce histone acetylation
and methylation and to re-constitute learning behavior and access to
long-term memories after significant brain atrophy and neuronal loss
M.A. Schiele, et al.
had already occurred (Fischer, Sananbenesi, Wang, Dobbin, & Tsai,
2007). Assuming learning processes to be at the core of psychother-
apeutic change (Kandel, 1998), it might be speculated that similar
epigenetic remodeling and reprogramming may underlie therapeutic
mechanisms of action. However, extensive research is needed in order
to address the underlying molecular signature and consequences of
environmental influences as a whole and of psychotherapeutic inter-
ventions in particular. A further challenge in therapyepigenetic re-
search pertains to the conceptual characteristics of psychotherapy.
Psychotherapeutic interventions differ greatly in theoretical back-
ground, approach, methodology, treatment plan, setting, duration,
specificity, and techniques. So far, the psychotherapeutic interventions
studied comprise CBT, exposure therapy, mindfulness-based stress re-
duction or disorder specific approaches like DBT in BPD; notwith-
standing, epigenetic changes occurring over the course of other psy-
chotherapies including, but not limited to, psychoanalysis and
psychodynamic therapies, systemic therapy, schema therapy, or newer
approaches such as acceptance and commitment therapy (Hayes, Levin,
Plumb-Vilardaga, Villatte, & Pistorello, 2013), metacognitive therapy
(Wells, 2002) or interpersonal therapy (Cuijpers, Donker, Weissman,
Ravitz, & Cristea, 2016) have yet to be addressed. Psychotherapy is
highly effective in the treatment of mental disorders, however, the
mechanisms of action conveying psychotherapeutic change are not yet
fully understood, and several challenges pertaining to the assessment of
treatment mediators and mechanisms remain (for review see Kazdin,
2007). Yet, it would clearly address a growing clinical need to de-
termine the impact of the putative specific and non-specific, i.e. more
general and shared across different schools of psychotherapy, me-
chanisms of action in in relation to neurobiological changes occurring
concurrently and, thus, to revisit the “Dodo bird conjecture” – i.e. the
proposition that common factors shared across different psychother-
apeutic approaches account for a large proportion of treatment effec-
tiveness stemming from Saul Rosenzweig’s (1936) seminal work (see
also e.g. Hofmann & Barlow, 2014; Luborsky, Diguer, Luborsky, &
Schmidt, 1999; Marcus, O'Connell, Norris, & Sawaqdeh, 2014;
Wampold et al., 1997) – from a molecular perspective. Systematically
comparing different psychotherapeutic approaches would allow to
differentiate whether epigenetic change is possibly specific, or whether
therapy outcome in general is facilitated through, or effectively based
on, common biological mechanisms. Along these lines, it would be
worthwhile to additionally look into epigenetic effects of lifestyle in-
terventions such as meditation, yoga or other relaxation techniques,
particularly since practices eliciting relaxation responses as the coun-
terpart of the stress response have been demonstrated to evoke ex-
pression rate changes in genes associated with pro-inflammatory re-
sponses, stress-related cellular signaling, energy metabolism,
mitochondrial functioning, insulin secretion and telomere maintenance
(Bhasin et al., 2013). On an epigenetic level, a pilot study analyzing the
DNA methylome in blood cells of long-term meditators and meditation-
naïve controls identified a protective effect of meditation against an
estimator of intrinsic epigenetic age acceleration (Chaix et al., 2017),
which might confer an increased resilience towards chronic diseases
with comparably late onset. Another study investigating the impact of
an 8-week yoga intervention in distressed women discerned a potential
immuno-regulatory effect of meditation, with reduced tumor necrosis
factor gene (TNF) methylation in the yoga group as compared to the
control group (Harkess, Ryan, Delfabbro, & Cohen-Woods, 2016).
Likewise, other lifestyle interventions such as physical activity and
exercise have been proposed to exert a preventive effect on mental
disorder onset and to be involved in mediating resilient functioning
(Ströhle, 2009). A first epigenetic study in this field suggests differential
BDNF methylation to be associated with exercise in combat-exposed
veterans with and without current PTSD (Voisey et al., 2019). Given
some evidence from animal studies for physical exercise as an epige-
netic modulator of neural plasticity and cognitive function (see
Fernandes, Arida, & Gomez-Pinilla, 2017; Voisin, Eynon, Yan, & Bishop,
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Clinical Psychology Review 77 (2020) 101830
2015), systematic human studies are warranted to further explore the
potential of lifestyle interventions to modulate mental disorder risk on
an epigenetic level.
In sum, advances in our understanding of how psychotherapy and
lifestyle interventions translate on a molecular level could subsequently
inform clinical practice, paving the way for personalized treatment
options by selecting modes of treatment established on multi-level in-
formation and might aid in reducing treatment resistance rates. Finally,
the stability of symptomatic as well as epigenetic effects remains to be
elucidated. Gaining an improved understanding of the mechanisms
mediating treatment effects would give rise to devising strategies to
ensure that effects are preserved in a long-term manner, which, from a
clinical point of view, could be absolutely crucial in relapse prevention.
6.4. Targetable markers for preventive interventions increasing resilience
In light of the recently burgeoning body of research into the po-
tential of epigenetic modifications to predict mental disorder risk and
treatment outcome as well as of psychotherapeutic interventions to
target – and potentially reverse - epigenetic risk patterns as reviewed
above, this direction carries great promise for preventive interventions
to potentially compensate for putative vulnerability factors pre-
cipitating mental disorder onset – or to strengthen factors and resources
associated with resilient functioning (see Fig. 2). First promising evi-
dence in this regard emerges from a study showing response to a
mindfulness-based preventive intervention to go along with decreasing
SLC6A4 methylation (Stoffel et al., 2019) as well as studies reporting
reduced harsh parenting conferred by a family-centered prevention
training (Brody, Yu, et al., 2016) or the presence of supportive family
environments despite racial discrimination (Brody, Miller, et al., 2016)
to protect against accelerated epigenetic aging. Future studies are
warranted to investigate the malleability of epigenetic risk patterns by
preventive interventions more thoroughly in analogy to therapy-epi-
genetic research. Further trials probing the long-term stability of pre-
vention-mediated epigenetic effects in longitudinal approaches would
be of great clinical relevance, informing preventive-therapeutic proce-
dures (e.g. application of booster sessions, augmentation strategies) in
increasing – and maintaining – resilience. Moreover, human studies
might in particular aim to validate the emerging evidence from pre-
clinical studies of resilience-increasing epigenetic patterns, such as
transgenerational effects of maternal care via epigenetic mechanisms
(Champagne, 2008). Thus, although currently still in its infancy, epi-
genetic research holds great promise as targets for preventive inter-
ventions in at-risk individuals, that could be used to effectively antici-
pate and preclude disorder onset in the future.
6.5. Transgenerational relevance of epigenetics
First evidence points to the transgenerational transmission of epi-
genetic marks of acquired information across generations to shape de-
velopmental and phenotypic variation in offspring (see Fig. 2). It re-
mains to be clarified, however, whether epigenetic transport of trauma
effects into subsequent generations necessarily increases vulnerability
to negative mental health outcomes or may on a molecular level also
serve to facilitate the ability to adapt to a changing environment, i.e.
promote resilience, in the offspring (Yehuda, Lehrner, & Bierer, 2018).
Accordingly, these epigenetic processes may have evolved in order to
program the phenotype to effectively and rapidly adapt to new en-
vironmental demands (Fischer, 2014; Gapp et al., 2016; Yeshurun &
Hannan, 2019). Along those lines, it might be feasible that epigenetic
changes arising from successful psychotherapy could be transferred to
future generations and thus promote the ”transgenerational preven-
tion” of mental disorders by pre-emptively equipping future genera-
tions with adaptive coping abilities on both a phenotypic and genomic
level and eventually decrease the risk for disorder manifestation in
subsequent generations. Nonetheless, at present, caution is warranted
M.A. Schiele, et al.
in the interpretation of transgenerational evidence. The proposed cau-
sative links between molecular adaptations and intergenerational phe-
notypic manifestations are not yet conclusively proven, the im-
plementation of which is not trivial. Future studies need to address the
co-segregation of epigenetic information with specific phenotypic traits
while taking into account effects attributable to genetic, ecological and
cultural inheritance (Horsthemke, 2018; Nagy & Turecki, 2015).
6.6. Limitations
Although advances in epigenetic research are of keen interest to
psychology and psychiatry, they are not without challenges and pitfalls.
The high sensitivity to external input and the highly dynamic nature of
epigenetic mechanisms that on the one hand allow for rapid and, cru-
cially, inducible change, can on the other hand simultaneously pose a
source of confounding effects. Biological confounders known to affect
epigenetic patterns such as age (Xiao, Wang, & Kong, 2019), sex
(Yousefi et al., 2015), ethnicity (Fraser, Lam, Neumann, & Kobor,
2012), body mass index (Sayols-Baixeras et al., 2017), smoking beha-
vior (Li et al., 2018) or nutritional aspects (Gadecka & Bielak-
Zmijewska, 2019) may introduce critical biases limiting the inter-
pretation of epigenetic data. Another caveat in epigenetic research
pertains to the ”tissue issue” (Bakulski, Halladay, Hu, Mill, & Fallin,
2016) owing to the fact that epigenetic studies so far have mostly (with
the exception of investigations in post-mortem samples) relied on per-
ipheral tissues, which precludes definite conclusions from being drawn
regarding CNS processes. However, given the difficulty to obtain re-
levant brain tissue specimen in humans in vivo, the identification of
epigenetic patterns in surrogate peripheral biomaterial such as whole
blood, saliva or buccal cells as a proxy for brain epigenetic markers is
necessary. In support of this endeavor, several studies have compared
epigenetic patterns obtained in peripheral and central tissue: In rats, a
direct correlation between catechol-O-methyltransferase (COMT) me-
thylation in peripheral mononuclear blood cells and the prefrontal
cortex was observed (Ursini et al., 2011). In a comparison of epi-
genome-wide blood and brain DNA methylation patterns in differen-
tially reared rhesus macaques, a considerable functional overlap was
observed in DNA methylation profiles in T lymphocytes and prefrontal
tissue (Provencal et al., 2012). In a similar vein, in humans, some inter-
individual variation in epigenome-wide DNA methylation as measured
in post-mortem brain samples and whole blood was reflected across
tissues (Davies et al., 2012). In a positron emission tomography (PET)
study measuring cerebral MAOA activity, peripheral MAOA methyla-
tion detected in leukocytes was found to inversely correlate with brain
MAOA levels in healthy men (Shumay, Logan, Volkow, & Fowler,
2012). However, for several other genes highly tissue-specific methy-
lation patterns emerge (cf. in silico analyses using databases such as
BECon (Edgar, Jones, Meaney, Turecki, & Kobor, 2017; available at
https://redgar598.shinyapps.io/BECon) or IMAGE-CpG (Braun et al.,
2019; available at https://han-lab.org/methylation/default/
imageCpG). Also, overlap in DNA methylation levels measured in
saliva, buccal cells and blood is limited, and it has been suggested that
DNA methylation patterns in saliva may be closer to that of brain tissue
than DNA methylation in blood or buccal cells (Braun et al., 2019; Lowe
et al., 2013; Smith et al., 2015). Taken together, peripheral DNA me-
thylation may partly function as a viable surrogate biomarker for cen-
tral processes, but is not unequivocally related to brain function. In
light of the fact that most research on the functional and mechanistic
characteristics of epigenetic processes comes from preclinical studies,
translation of animal findings to humans – and in turn back-transla-
tion, i.e. validation of human findings in animal models – seems war-
ranted though challenging given the limited comparability of available
(endo)phenotypes (see Lesch, 2011).
Similarly, epigenetic processes are not only tissue specific, but can
act in a cell type specific manner. For instance, distinctive DNA me-
thylation patterns between neuronal and glial cells have been observed,
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Clinical Psychology Review 77 (2020) 101830
and variation in DNA methylation appears to be higher in neuronal cells
in response to the environment (Iwamoto et al., 2011). Therefore, cell
type composition should be taken into account in the analysis of epi-
genetic data (Montaño et al., 2013), and single cell approaches (“single-
cell epigenomics”) constitute a most promising future direction towards
a better understanding of epigenetic mechanisms (Kelsey, Stegle, &
Reik, 2017).
Next to biological confounders as reviewed above, technical aspects
such as sample storage at the appropriate temperature can constitute
another source of confounding effects. Along these lines, DNA methy-
lation arrays are susceptible to batch effects arising from random, un-
systematic fluctuations in laboratory conditions and handling. Several
methods have been suggested to adjust for batch effects, including re-
commendations for experimental designs and statistical approaches
(see for example Leek et al., 2010).
Finally, in a chicken-and-egg conundrum with regard to epigenetic
change occurring concomitantly with clinical change, it remains to be
elucidated whether epigenetic change evokes psychotherapeutic effects
or occurs as a function of therapy response. Longitudinal designs would
be most informative in this regard and allow for a better delineation of
cause from effect.
6.7. Future research
Despite recent advances in epigenetic investigations into mental
disorder onset, maintenance and treatment, several open questions re-
main that are of great promise for future research directions. One major
challenge entails disentangling the molecular mechanisms and con-
sequences of psychotherapy whilst also taking into account different
schools, forms, and approaches. Large randomized controlled trials
(RCTs) are needed to address this novel layer in the quest for de-
termining the optimal therapeutic match for an individual patient,
ideally by applying longitudinal intervention trials.
To date, efforts in identifying epigenetic correlates of mental dis-
orders and their treatment have mostly focused on DNA methylation
and less is known about other epigenetic processes introduced above,
such as hydroxymethylation, histone modifications, or miRNAs. Given
the considerable and intricate cross-talk of multiple epigenetic me-
chanisms (Molina-Serrano, Schiza, & Kirmizis, 2013), combinatory
approaches would be most valuable in furthering our understanding of
how psychotherapy effects are transported.
In addition to an intermediary role in translating between genes and
the environment, epigenetic mechanisms may be determined by genetic
variation itself as evidenced by the fact that DNA methylation has been
shown to frequently occur in an allele-specific manner (He et al., 2015;
Meaburn, Schalkwyk, & Mill, 2010; Shoemaker, Deng, Wang, & Zhang,
2010). Consequently, mapping of haplotype-dependent allele-specific
DNA methylation (hap-ASM) and methylation-eQTLs may further
explain the interplay between genetic and environmental factors and
aid in identifying disease-associated regulatory sequences (Do et al.,
2017) in combined G × EpiG × E multi-level approaches.
Further research into the functional consequence and biological
relevance of DNA methylation changes at particular CpG sites is war-
ranted, preferably in “multi-omic” approaches by combining epige-
netics with transcriptomics or in silico approaches (Ng et al., 2017).
Such integrative studies on epigenetics and the ”omics” – tran-
scriptomics, proteomics, metabolomics and microbiomics – could an-
swer central questions, for instance following first hints that methio-
nine, biotin, and acetyl group donor metabolites produced by the gut
flora may affect epigenetic modifications (e.g. Househam, Peterson,
Mills, & Chopra, 2017; Strachan, Zhao, Roy-Byrne, Fowler, & Bacus,
2018). Along these lines, interactions between the epigenome and the
immune system could be explored in elucidating the underlying pa-
thophysiology of mental disorders and the potential effect of psy-
chotherapy in alleviating this maladaptive crosstalk. These multi-level
analyses of multidimensional data entail the necessity of highly
M.A. Schiele, et al.
complex bioinformatic approaches in sufficiently powered samples.
Since mental disorders constitute complex genetic disorders, a
multitude of interacting epigenetic variations is expected; therefore,
shifting the field from candidate gene approaches to EWAS, ideally
combined with GWAS, would prove fruitful in unraveling the complex
biochemical nature of mental disorders in the future.
While the role of epigenetic mechanisms in translating between
environmental input and an individual's genetic background is un-
disputed, several sources of variability remain that have yet to be
identified. Investigations utilizing longitudinal family cohorts starting
before conception and including well-characterized, extensively phe-
notyped probands (Latendresse, Musci, & Maher, 2018; Provencal &
Binder, 2015) by collecting detailed documentation of environmental
events including frequency, sequence and individually perceived va-
lence to disentangle whether epigenetic patterns are cause, correlation
or consequence of the pathological state, and to furthermore identify
critical time periods during which the early environment can impact
brain and mental health development (Andersen, 2003). Additionally,
positive, counteracting and potentially resilience-increasing environ-
mental factors should be taken into consideration.
Given the sex-specific impact of adverse environment on DNA me-
thylation (e.g. Massart et al., 2016; Ostlund et al., 2016) and sex-spe-
cific findings in studies on psychotherapeutic effects on methylation
(e.g. Schiele et al., 2018; Ziegler et al., 2016), upcoming studies may
want to systematically consider sex-specific effects in the susceptibility
to psychopathology and the mediation of beneficial treatment effects in
synopsis with epigenetic information (for review, see Tiwari &
Gonzalez, 2018).
Intermediate (endo)phenotypes of mental disorders as well as the
different constructs advocated by the NIMH's Research Domain Criteria
(RDoC) framework may constitute promising targets in epigenetic re-
search. For instance, future research may want to employ an “imaging
epigenetic” approach in order to determine therapyepigenetic effects on
an intermediate (endo)phenotype level given a wealth of previous re-
search on psychotherapy effects on a neural networks level (for review,
see Fournier & Price, 2014). Exemplarily, experiences of childhood
trauma, male gender, and smaller hippocampal volume were in-
dependently associated with greater peripheral SLC6A4 methylation
(Booij et al., 2015). SLC6A4 methylation was furthermore found to be
related to insula activation during the processing of emotional stimuli
in major depressive disorder (Frodl et al., 2015). Methylation of an
AluJb element in the SLC6A4 promoter was also associated with
amygdala reactivity in depression (Schneider et al., 2018). In social
phobia, OXTR methylation was related to differential amygdala re-
activity to social phobia-related verbal stimuli (Ziegler et al., 2015).
OXTR methylation was furthermore found to interact with callous-un-
emotional traits in predicting frontoparietal activation and amygdala-
frontoparietal disconnection, brain systems critical to decoding and
integrating socioaffective information, in youths with conduct disorder
(Aghajani et al., 2018). Along these lines, future studies should address
psychotherapy effects in synopsis with epigenetic and neuroimaging
information in order to increase our understanding of epigenetic
changes with brain function, for instance by applying PET in order to
directly visualize epigenetic processes in the central nervous system
(Wang, Schroeder, & Hooker, 2014).
Studies mostly in preclinical models suggest drugs modulating epi-
genetic mechanisms that may lead to the development of novel, in-
novative treatment options such as HDAC or DNMT inhibitors (cf.
Whittle & Singewald, 2014). Such “epigenetic drugs” might serve to
catalyze psychotherapeutic effects by enhancing learning and neuronal
plasticity and facilitating fear extinction (Gavin, Chase, & Sharma,
2011). Yet, clinical application is still a long way off, and several ca-
veats such as the lack of selectivity and specificity of currently available
agents remain (see Szyf, 2015).
Moreover, nutrition can influence the epigenetic machinery, and
first studies have focused on the impact of haematopoietic drugs, folic
15
Clinical Psychology Review 77 (2020) 101830
acid and vitamin B12 (see Peedicayil, 2012). Along those lines, epige-
netic modifiers such as S-adenosyl methionine (SAM-e) - a natural
ubiquitous methyl-group donor approved as nutritional supplement -
folic acid or vitamin B12 (cobalamin) could potentially be used as add-
on nutritional therapies in mental disorders and open up promising
paths for additional research, however, current evidence is still limited
(for review, see Dome, Tombor, Lazary, Gonda, & Rihmer, 2019)
Lastly, it is important to keep in mind the ethical, social and legal
implications of epigenetic research, necessitating the implementation of
“epigenet(h)ics”, i.e. guidelines and policies for clinical and scientific
use of epigenetic information (Dyke et al., 2019; Thomas, 2015).
7. Conclusion
Mental disorders are associated with epigenetic changes, however,
it has still not been resolved whether these modifications are cause or
consequence of the elemental pathophysiology. Epigenetic alterations
arise in response to environmental signals and are modifiable by psy-
chotherapy, though the underlying mechanisms of action are yet to be
fully discerned. While epigenetic research holds great promise re-
garding the prediction, prevention, and personalized treatment of
mental disorders, it is still in its infancy and limited in its clinical ap-
plication at the moment. Future investigations will have to explore the
causality of how intervention effects are internalized on the molecular
level and how to best translate novel insights relating to epigenetic
modifications into clinical practice. The field of epigenetics opens up
novel avenues, increasing our understanding of the intricate multi-level
etiology of mental disorders which is hoped to strengthen the inter-
disciplinary dialogue between the fields of neurobiology/genetics with
psychology/psychotherapy to their mutual benefit.
Role of funding sources
This work was partly supported by the Deutsche
Forschungsgemeinschaft (DFG, German Research Foundation) – project
number 44541416 – TRR 58 “Fear, Anxiety, Anxiety Disorders”, (pro-
jects C02 and Z02 to KD) and the German Ministry of Research and
Education (BMBF, 01EE1402F, PROTECT-AD, project P5 to KD). The
funding sources had no further role in study design, in the collection,
analysis and interpretation of data, in the writing of the report, and in
the decision to submit the paper for publication.
Contributors
MAS, MGG and KD managed the literature search and wrote the
manuscript. All authors contributed to and have approved the final
version of the manuscript.
Declaration of Competing Interest
KD is a member of the Janssen Pharmaceuticals, Inc. Steering
Committee Neurosciences. All other authors declare that they have no
conflicts of interest.
Acknowledgements
MAS and KD are members of the Anxiety Disorders Research
Network (ADRN), European College of Neuropsychopharmacology
(ECNP). We gratefully acknowledge the support by S. Meixensberger
and C. Ziegler in the preparation of this manuscript.
References
Abdolmaleky, H. M., Zhou, J. R., & Thiagalingam, S. (2015). An update on the epigenetics
of psychotic diseases and autism. Epigenomics, 7, 427–449.
Aghajani, M., Klapwijk, E. T., Colins, O. F., Ziegler, C., Domschke, K., Vermeiren, R., &
M.A. Schiele, et al.
van der Wee, N. J. A. (2018). Interactions between oxytocin receptor gene methy-
lation and callous-unemotional traits impact socioaffective brain systems in conduct-
disordered offenders. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, 3,
379–391.
Alasaari, J. S., Lagus, M., Ollila, H. M., Toivola, A., Kivimaki, M., Vahtera, J., ... Paunio, T.
(2012). Environmental stress affects DNA methylation of a CpG rich promoter region
of serotonin transporter gene in a nurse cohort. PLoS One, 7, e45813.
Alwis, D. S., & Rajan, R. (2014). Environmental enrichment and the sensory brain: The
role of enrichment in remediating brain injury. Frontiers in Systems Neuroscience, 8,
156.
Alyamani, R. A. S., & Murgatroyd, C. (2018). Epigenetic programming by early-life stress.
Progress in Molecular Biology and Translational Science, 157, 133–150.
Andersen, S. L. (2003). Trajectories of brain development: point of vulnerability or
window of opportunity? Neuroscience and Biobehavioral Reviews, 27, 3–18.
Babenko, O., Kovalchuk, I., & Metz, G. A. (2015). Stress-induced perinatal and transge-
nerational epigenetic programming of brain development and mental health.
Neuroscience and Biobehavioral Reviews, 48, 70–91.
Bakulski, K. M., Halladay, A., Hu, V. W., Mill, J., & Fallin, M. D. (2016). Epigenetic
research in neuropsychiatric disorders: the "tissue issue" Current Behavioral
Neuroscience Reports, 3, 264–274.
Bakusic, J., Schaufeli, W., Claes, S., & Godderis, L. (2017). Stress, burnout and depression:
A systematic review on DNA methylation mechanisms. Journal of Psychosomatic
Research, 92, 34–44.
Bale, T. L. (2014). Lifetime stress experience: Transgenerational epigenetics and germ cell
programming. Dialogues in Clinical Neuroscience, 16, 297–305.
Baroncelli, L., Braschi, C., Spolidoro, M., Begenisic, T., Sale, A., & Maffei, L. (2010).
Nurturing brain plasticity: Impact of environmental enrichment. Cell Death and
Differentiation, 17, 1092–1103.
Bartel, D. P. (2004). MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell,
116, 281–297.
Bateson, P., Gluckman, P., & Hanson, M. (2014). The biology of developmental plasticity
and the predictive adaptive response hypothesis. The Journal of Physiology, 592,
2357–2368.
Bayer, T. A., Falkai, P., & Maier, W. (1999). Genetic and non-genetic vulnerability factors
in schizophrenia: the basis of the "two hit hypothesis" Journal of Psychiatric Research,
33, 543–548.
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.
Belsky, J., & Pluess, M. (2009). Beyond diathesis stress: Differential susceptibility to en-
vironmental influences. Psychological Bulletin, 135, 885–908.
Berkel, T. D., & Pandey, S. C. (2017). Emerging role of epigenetic mechanisms in alcohol
addiction. Alcoholism, Clinical and Experimental Research, 41, 666–680.
Bhasin, M. K., Dusek, J. A., Chang, B. H., Joseph, M. G., Denninger, J. W., Fricchione, G.
L., ... Libermann, T. A. (2013). Relaxation response induces temporal transcriptome
changes in energy metabolism, insulin secretion and inflammatory pathways. PLoS
One, 8, e62817.
Bishop, J. R., Lee, A. M., Mills, L. J., Thuras, P. D., Eum, S., Clancy, D., ... Lim, K. O.
(2018). Methylation of FKBP5 and SLC6A4 in relation to treatment response to
mindfulness based stress reduction for posttraumatic stress disorder. Frontiers in
Psychiatry, 9, 418.
Boks, M. P., de Jong, N. M., Kas, M. J., Vinkers, C. H., Fernandes, C., Kahn, R. S., ...
Ophoff, R. A. (2012). Current status and future prospects for epigenetic psycho-
pharmacology. Epigenetics, 7, 20–28.
Boks, M. P., van Mierlo, H. C., Rutten, B. P., Radstake, T. R., De Witte, L., Geuze, E., ...
Vermetten, E. (2015). Longitudinal changes of telomere length and epigenetic age
related to traumatic stress and post-traumatic stress disorder.
Psychoneuroendocrinology, 51, 506–512.
Booij, L., Szyf, M., Carballedo, A., Frey, E. M., Morris, D., Dymov, S., ... Frodl, T. (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.
Braun, P. R., Han, S., Hing, B., Nagahama, Y., Gaul, L. N., Heinzman, J. T., ... Shinozaki,
G. (2019). Genome-wide DNA methylation comparison between live human brain
and peripheral tissues within individuals. Translational Psychiatry, 9, 47.
Brody, G. H., Miller, G. E., Yu, T., Beach, S. R., & Chen, E. (2016). Supportive family
environments ameliorate the link between racial discrimination and epigenetic aging:
A replication across two longitudinal cohorts. Psychological Science, 27, 530–541.
Brody, G. H., Yu, T., Chen, E., Beach, S. R., & Miller, G. E. (2016). Family-centered
prevention ameliorates the longitudinal association between risky family processes
and epigenetic aging. Journal of Child Psychology and Psychiatry, 57, 566–574.
Chaix, R., Alvarez-Lopez, M. J., Fagny, M., Lemee, L., Regnault, B., Davidson, R. J., ...
Kaliman, P. (2017). Epigenetic clock analysis in long-term meditators.
Psychoneuroendocrinology, 85, 210–214.
Champagne, F. A. (2008). Epigenetic mechanisms and the transgenerational effects of
maternal care. Frontiers in Neuroendocrinology, 29, 386–397.
Cimino, S., Cerniglia, L., Ballarotto, G., Marzilli, E., Pascale, E., D'Addario, C., ... Tambelli,
R. (2017). DNA methylation at the DAT promoter and risk for psychopathology:
Intergenerational transmission between school-age youths and their parents in a
community sample. Frontiers in Psychiatry, 8, 303.
Cuijpers, P., Donker, T., Weissman, M. M., Ravitz, P., & Cristea, I. A. (2016). Interpersonal
psychotherapy for mental health problems: A comprehensive meta-analysis. The
American Journal of Psychiatry, 173, 680–687.
Daskalakis, N. P., Bagot, R. C., Parker, K. J., Vinkers, C. H., & de Kloet, E. R. (2013). The
three-hit concept of vulnerability and resilience: Toward understanding adaptation to
16
Clinical Psychology Review 77 (2020) 101830
early-life adversity outcome. Psychoneuroendocrinology, 38, 1858–1873.
Davies, M. N., Volta, M., Pidsley, R., Lunnon, K., Dixit, A., Lovestone, S., ... Mill, J. (2012).
Functional annotation of the human brain methylome identifies tissue-specific epi-
genetic variation across brain and blood. Genome Biology, 13, R43.
Day, J. J., & Sweatt, J. D. (2011). Epigenetic mechanisms in cognition. Neuron, 70,
813–829.
Dias, B. G., & Ressler, K. J. (2014). Parental olfactory experience influences behavior and
neural structure in subsequent generations. Nature Neuroscience, 17, 89–96.
Do, C., Shearer, A., Suzuki, M., Terry, M. B., Gelernter, J., Greally, J. M., & Tycko, B.
(2017). Genetic-epigenetic interactions in cis: A major focus in the post-GWAS era.
Genome Biology, 18, 120.
Dome, P., Tombor, L., Lazary, J., Gonda, X., & Rihmer, Z. (2019). Natural health products,
dietary minerals and over-the-counter medications as add-on therapies to anti-
depressants in the treatment of major depressive disorder: A review. Brain Research
Bulletin, 146, 51–78.
Domschke, K., Tidow, N., Kuithan, H., Schwarte, K., Klauke, B., Ambree, O., ... Deckert, J.
(2012). Monoamine oxidase A gene DNA hypomethylation - A risk factor for panic
disorder? The International Journal of Neuropsychopharmacology, 15, 1217–1228.
Domschke, K., Tidow, N., Schrempf, M., Schwarte, K., Klauke, B., Reif, A., ... Deckert, J.
(2013). Epigenetic signature of panic disorder: A role of glutamate decarboxylase 1
(GAD1) DNA hypomethylation? Progress in Neuro-Psychopharmacology & Biological
Psychiatry, 46, 189–196.
Dudley, K. J., Li, X., Kobor, M. S., Kippin, T. E., & Bredy, T. W. (2011). Epigenetic me-
chanisms mediating vulnerability and resilience to psychiatric disorders. Neuroscience
and Biobehavioral Reviews, 35, 1544–1551.
Dyke, S. O. M., Saulnier, K. M., Dupras, C., Webster, A. P., Maschke, K., Rothstein, M., ...
Joly, Y. (2019). Points-to-consider on the return of results in epigenetic research.
Genome Medicine, 11, 31.
Ebner, N. C., Lin, T., Muradoglu, M., Weir, D. H., Plasencia, G. M., Lillard, T. S., ...
Connelly, J. J. (2019). Associations between oxytocin receptor gene (OXTR) me-
thylation, plasma oxytocin, and attachment across adulthood. International Journal of
Psychophysiology, 136, 22–32.
Edgar, R. D., Jones, M. J., Meaney, M. J., Turecki, G., & Kobor, M. S. (2017). BECon: A
tool for interpreting DNA methylation findings from blood in the context of brain.
Translational Psychiatry, 7, e1187.
Farrell, C., Doolin, K., N, O. L., Jairaj, C., Roddy, D., Tozzi, L., ... O'Keane, V. (2018). DNA
methylation differences at the glucocorticoid receptor gene in depression are related
to functional alterations in hypothalamic-pituitary-adrenal axis activity and to early
life emotional abuse. Psychiatry Research, 265, 341–348.
Fernandes, J., Arida, R. M., & Gomez-Pinilla, F. (2017). Physical exercise as an epigenetic
modulator of brain plasticity and cognition. Neuroscience and Biobehavioral Reviews,
80, 443–456.
Fischer, A. (2014). Epigenetic memory: The Lamarckian brain. The EMBO Journal, 33,
945–967.
Fischer, A., Sananbenesi, F., Wang, X., Dobbin, M., & Tsai, L. H. (2007). Recovery of
learning and memory is associated with chromatin remodelling. Nature, 447,
178–182.
Fournier, J. C., & Price, R. B. (2014). Psychotherapy and neuroimaging. Focus (American
Psychiatric Publishing), 12, 290–298.
Franklin, T. B., Russig, H., Weiss, I. C., Graff, J., Linder, N., Michalon, A., ... Mansuy, I. M.
(2010). Epigenetic transmission of the impact of early stress across generations.
Biological Psychiatry, 68, 408–415.
Fraser, H. B., Lam, L. L., Neumann, S. M., & Kobor, M. S. (2012). Population-specificity of
human DNA methylation. Genome Biology, 13, R8.
Frodl, T., Szyf, M., Carballedo, A., Ly, V., Dymov, S., Vaisheva, F., ... Booij, L. (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.
Gadecka, A., & Bielak-Zmijewska, A. (2019). Slowing down ageing: The role of nutrients
and microbiota in modulation of the epigenome. Nutrients, 11.
Gapp, K., Bohacek, J., Grossmann, J., Brunner, A. M., Manuella, F., Nanni, P., & Mansuy,
I. M. (2016). Potential of environmental enrichment to prevent transgenerational
effects of paternal trauma. Neuropsychopharmacology, 41, 2749–2758.
Garg, E., Chen, L., Nguyen, T. T. T., Pokhvisneva, I., Chen, L. M., Unternaehrer, E., ...
Mavan Study, T. (2018). The early care environment and DNA methylome variation
in childhood. Development and Psychopathology, 30, 891–903.
Gavin, D. P., Chase, K. A., & Sharma, R. P. (2011). Enhancement of psychotherapy using
epigenetic modulating drugs. Medical Hypotheses, 77, 121–124.
Gibbs, J. R., van der Brug, M. P., Hernandez, D. G., Traynor, B. J., Nalls, M. A., Lai, S. L.,
... Singleton, A. B. (2010). Abundant quantitative trait loci exist for DNA methylation
and gene expression in human brain. PLoS Genetics, 6, e1000952.
Gottschalk, M. G., & Domschke, K. (2016). Novel developments in genetic and epigenetic
mechanisms of anxiety. Current Opinion in Psychiatry, 29, 32–38.
Gottschalk, M. G., & Domschke, K. (2018). Oxytocin and anxiety disorders. Current Topics
in Behavioral Neurosciences, 35, 467–498.
Gratten, J., Wray, N. R., Keller, M. C., & Visscher, P. M. (2014). Large-scale genomics
unveils the genetic architecture of psychiatric disorders. Nature Neuroscience, 17,
782–790.
Gregory, R. I., Chendrimada, T. P., Cooch, N., & Shiekhattar, R. (2005). Human RISC
couples microRNA biogenesis and posttranscriptional gene silencing. Cell, 123,
631–640.
Gregory, R. I., Yan, K. P., Amuthan, G., Chendrimada, T., Doratotaj, B., Cooch, N., &
Shiekhattar, R. (2004). The microprocessor complex mediates the genesis of
microRNAs. Nature, 432, 235–240.
Guerrero-Bosagna, C. (2019). From epigenotype to new genotypes: Relevance of epige-
netic mechanisms in the emergence of genomic evolutionary novelty. Seminars in Cell
M.A. Schiele, et al.
& Developmental Biology, 97, 86–92.
Haas, B. W., Filkowski, M. M., Cochran, R. N., Denison, L., Ishak, A., Nishitani, S., &
Smith, A. K. (2016). Epigenetic modification of OXT and human sociability.
Proceedings of the National Academy of Sciences of the United States of America, 113,
E3816–E3823.
Halder, R., Hennion, M., Vidal, R. O., Shomroni, O., Rahman, R. U., Rajput, A., ... Bonn, S.
(2016). DNA methylation changes in plasticity genes accompany the formation and
maintenance of memory. Nature Neuroscience, 19, 102–110.
Hamilton, S. P. (2009). Linkage and association studies of anxiety disorders. Depression
and Anxiety, 26, 976–983.
Han, L. K. M., Aghajani, M., Clark, S. L., Chan, R. F., Hattab, M. W., Shabalin, A. A., ...
Penninx, B. (2018). Epigenetic aging in major depressive disorder. The American
Journal of Psychiatry, 175, 774–782.
Harkess, K. N., Ryan, J., Delfabbro, P. H., & Cohen-Woods, S. (2016). Preliminary in-
dications of the effect of a brief yoga intervention on markers of inflammation and
DNA methylation in chronically stressed women. Translational Psychiatry, 6, e965.
Hayes, S. C., Levin, M. E., Plumb-Vilardaga, J., Villatte, J. L., & Pistorello, J. (2013).
Acceptance and commitment therapy and contextual behavioral science: Examining
the progress of a distinctive model of behavioral and cognitive therapy. Behavior
Therapy, 44, 180–198.
He, J., Sun, M. A., Wang, Z., Wang, Q., Li, Q., & Xie, H. (2015). Characterization and
machine learning prediction of allele-specific DNA methylation. Genomics, 106,
331–339.
Hernando-Herraez, I., Garcia-Perez, R., Sharp, A. J., & Marques-Bonet, T. (2015). DNA
methylation: Insights into human evolution. PLoS Genetics, 11, e1005661.
Hoehe, M. R., & Morris-Rosendahl, D. J. (2018). The role of genetics and genomics in
clinical psychiatry. Dialogues in Clinical Neuroscience, 20, 169–177.
Hofmann, S. G., & Barlow, D. H. (2014). Evidence-based psychological interventions and
the common factors approach: The beginnings of a rapprochement? Psychotherapy
(Chicago, Ill.), 51, 510–513.
Horsthemke, B. (2018). A critical view on transgenerational epigenetic inheritance in
humans. Nature Communications, 9, 2973.
Horvath, S. (2013). DNA methylation age of human tissues and cell types. Genome Biology,
14, R115.
Househam, A. M., Peterson, C. T., Mills, P. J., & Chopra, D. (2017). The effects of stress
and meditation on the immune system, human microbiota, and epigenetics. Advances
in Mind-Body Medicine, 31, 10–25.
Howe, A. S., Buttenschon, H. N., Bani-Fatemi, A., Maron, E., Otowa, T., Erhardt, A., ... De
Luca, V. (2016). Candidate genes in panic disorder: Meta-analyses of 23 common
variants in major anxiogenic pathways. Molecular Psychiatry, 21, 665–679.
van IJzendoorn, M. H., Caspers, K., Bakermans-Kranenburg, M. J., Beach, S. R., &
Philibert, R. (2010). Methylation matters: Interaction between methylation density
and serotonin transporter genotype predicts unresolved loss or trauma. Biological
Psychiatry, 68, 405–407.
Iwamoto, K., Bundo, M., Ueda, J., Oldham, M. C., Ukai, W., Hashimoto, E., ... Kato, T.
(2011). Neurons show distinctive DNA methylation profile and higher interindividual
variations compared with non-neurons. Genome Research, 21, 688–696.
Jaaskelainen, T., Makkonen, H., & Palvimo, J. J. (2011). Steroid up-regulation of FKBP51
and its role in hormone signaling. Current Opinion in Pharmacology, 11, 326–331.
Jawaid, A., Roszkowski, M., & Mansuy, I. M. (2018). Transgenerational epigenetics of
traumatic stress. Progress in Molecular Biology and Translational Science, 158, 273–298.
Jenuwein, T., & Allis, C. D. (2001). Translating the histone code. Science, 293, 1074–1080.
Jimenez, J. P., Botto, A., Herrera, L., Leighton, C., Rossi, J. L., Quevedo, Y., ... Luyten, P.
(2018). Psychotherapy and genetic neuroscience: An emerging dialog. Frontiers in
Genetics, 9, 257.
Kahl, K. G., Georgi, K., Bleich, S., Muschler, M., Hillemacher, T., Hilfiker-Kleinert, D., ...
Frieling, H. (2016). Altered DNA methylation of glucose transporter 1 and glucose
transporter 4 in patients with major depressive disorder. Journal of Psychiatric
Research, 76, 66–73.
Kandel, E. R. (1998). A new intellectual framework for psychiatry. The American Journal
of Psychiatry, 155, 457–469.
Kanherkar, R. R., Bhatia-Dey, N., & Csoka, A. B. (2014). Epigenetics across the human
lifespan. Frontiers in Cell and Development Biology, 2, 49.
Kaywin, L. (1960). An epigenetic approach to the psychoanalytic theory of instincts and
affects. Journal of the American Psychoanalytic Association, 8, 613–658.
Kazdin, A. E. (2007). Mediators and mechanisms of change in psychotherapy research.
Annual Review of Clinical Psychology, 3, 1–27.
Kelsey, G., Stegle, O., & Reik, W. (2017). Single-cell epigenomics: Recording the past and
predicting the future. Science, 358, 69–75.
Khulan, B., Manning, J. R., Dunbar, D. R., Seckl, J. R., Raikkonen, K., Eriksson, J. G., &
Drake, A. J. (2014). Epigenomic profiling of men exposed to early-life stress reveals
DNA methylation differences in association with current mental state. Translational
Psychiatry, 4, e448.
Klengel, T., Dias, B. G., & Ressler, K. J. (2016). Models of intergenerational and trans-
generational transmission of risk for psychopathology in mice.
Neuropsychopharmacology, 41, 219–231.
Klengel, T., Mehta, D., Anacker, C., Rex-Haffner, M., Pruessner, J. C., Pariante, C. M., ...
Binder, E. B. (2013). Allele-specific FKBP5 DNA demethylation mediates gene-
childhood trauma interactions. Nature Neuroscience, 16, 33–41.
Klengel, T., Pape, J., Binder, E. B., & Mehta, D. (2014). The role of DNA methylation in
stress-related psychiatric disorders. Neuropharmacology, 80, 115–132.
Klinger-Konig, J., Hertel, J., Van der Auwera, S., Frenzel, S., Pfeiffer, L., Waldenberger,
M., ... Grabe, H. J. (2019). Methylation of the FKBP5 gene in association with FKBP5
genotypes, childhood maltreatment and depression. Neuropsychopharmacology, 44,
930–938.
Knoblich, N., Gundel, F., Bruckmann, C., Becker-Sadzio, J., Frischholz, C., & Nieratschker,
17
Clinical Psychology Review 77 (2020) 101830
V. (2018). DNA methylation of APBA3 and MCF2 in borderline personality disorder:
Potential biomarkers for response to psychotherapy. European
Neuropsychopharmacology, 28, 252–263.
Kundakovic, M., & Champagne, F. A. (2015). Early-life experience, epigenetics, and the
developing brain. Neuropsychopharmacology, 40, 141–153.
Kwapis, J. L., & Wood, M. A. (2014). Epigenetic mechanisms in fear conditioning:
Implications for treating post-traumatic stress disorder. Trends in Neurosciences, 37,
706–720.
Latendresse, S. J., Musci, R., & Maher, B. S. (2018). Critical issues in the inclusion of
genetic and epigenetic information in prevention and intervention trials. Prevention
Science, 19, 58–67.
Laviola, G., Hannan, A. J., Macri, S., Solinas, M., & Jaber, M. (2008). Effects of enriched
environment on animal models of neurodegenerative diseases and psychiatric dis-
orders. Neurobiology of Disease, 31, 159–168.
Leek, J. T., Scharpf, R. B., Bravo, H. C., Simcha, D., Langmead, B., Johnson, W. E., ...
Irizarry, R. A. (2010). Tackling the widespread and critical impact of batch effects in
high-throughput data. Nature Reviews. Genetics, 11, 733–739.
Lesch, K. P. (2011). When the serotonin transporter gene meets adversity: The con-
tribution of animal models to understanding epigenetic mechanisms in affective
disorders and resilience. Current Topics in Behavioral Neurosciences, 7, 251–280.
Levenson, J. M., & Sweatt, J. D. (2005). Epigenetic mechanisms in memory formation.
Nature Reviews. Neuroscience, 6, 108–118.
Levinson, D. F. (2006). The genetics of depression: A review. Biological Psychiatry, 60,
84–92.
Li, S., Wong, E. M., Bui, M., Nguyen, T. L., Joo, J. E., Stone, J., ... Hopper, J. L. (2018).
Causal effect of smoking on DNA methylation in peripheral blood: A twin and family
study. Clinical Epigenetics, 10, 18.
Lim, L. P., Lau, N. C., Garrett-Engele, P., Grimson, A., Schelter, J. M., Castle, J., ...
Johnson, J. M. (2005). Microarray analysis shows that some microRNAs down-
regulate large numbers of target mRNAs. Nature, 433, 769–773.
Lowe, R., Gemma, C., Beyan, H., Hawa, M. I., Bazeos, A., Leslie, R. D., ... Ramagopalan, S.
V. (2013). Buccals are likely to be a more informative surrogate tissue than blood for
epigenome-wide association studies. Epigenetics, 8, 445–454.
Luborsky, L., Diguer, L., Luborsky, E., & Schmidt, K. A. (1999). The efficacy of dynamic
versus other psychotherapies - Is it true that "everyone has won and all must have prizes"? -
An update. Washington: Amer Psychiatric Press, Inc.
Marcus, D. K., O'Connell, D., Norris, A. L., & Sawaqdeh, A. (2014). Is the Dodo bird
endangered in the 21st century? A meta-analysis of treatment comparison studies.
Clinical Psychology Review, 34, 519–530.
Massart, R., Nemoda, Z., Suderman, M. J., Sutti, S., Ruggiero, A. M., Dettmer, A. M., ...
Szyf, M. (2016). Early life adversity alters normal sex-dependent developmental
dynamics of DNA methylation. Development and Psychopathology, 28, 1259–1272.
McEwen, B. S. (2003). Mood disorders and allostatic load. Biological Psychiatry, 54,
200–207.
McGowan, P. O., Sasaki, A., D'Alessio, A. C., Dymov, S., Labonte, B., Szyf, M., ... Meaney,
M. J. (2009). Epigenetic regulation of the glucocorticoid receptor in human brain
associates with childhood abuse. Nature Neuroscience, 12, 342–348.
Meaburn, E. L., Schalkwyk, L. C., & Mill, J. (2010). Allele-specific methylation in the
human genome: Implications for genetic studies of complex disease. Epigenetics, 5,
578–582.
Mehta, D., Klengel, T., Conneely, K. N., Smith, A. K., Altmann, A., Pace, T. W., ... Binder,
E. B. (2013). Childhood maltreatment is associated with distinct genomic and epi-
genetic profiles in posttraumatic stress disorder. Proceedings of the National Academy
of Sciences of the United States of America, 110, 8302–8307.
Millan, M. J. (2014). The epigenetic dimension of Alzheimer's disease: Causal, con-
sequence, or curiosity? Dialogues in Clinical Neuroscience, 16, 373–393.
Miller, C. W. T. (2017). Epigenetic and neural circuitry landscape of psychotherapeutic
interventions. Psychiatry Journal, 2017, 5491812.
Molina-Serrano, D., Schiza, V., & Kirmizis, A. (2013). Cross-talk among epigenetic
modifications: Lessons from histone arginine methylation. Biochemical Society
Transactions, 41, 751–759.
Monk, C., Feng, T., Lee, S., Krupska, I., Champagne, F. A., & Tycko, B. (2016). Distress
during pregnancy: Epigenetic regulation of placenta glucocorticoid-related genes and
fetal neurobehavior. The American Journal of Psychiatry, 173, 705–713.
Montaño, C. M., Irizarry, R. A., Kaufmann, W. E., Talbot, K., Gur, R. E., Feinberg, A. P., &
Taub, M. A. (2013). Measuring cell-type specific differential methylation in human
brain tissue. Genome Biology, 14, R94.
Nagy, C., & Turecki, G. (2015). Transgenerational epigenetic inheritance: An open dis-
cussion. Epigenomics, 7, 781–790.
Nederhof, E., & Schmidt, M. V. (2012). Mismatch or cumulative stress: Toward an in-
tegrated hypothesis of programming effects. Physiology & Behavior, 106, 691–700.
Nestler, E. J., Pena, C. J., Kundakovic, M., Mitchell, A., & Akbarian, S. (2016). Epigenetic
basis of mental illness. Neuroscientist, 22, 447–463.
Ng, B., White, C. C., Klein, H. U., Sieberts, S. K., McCabe, C., Patrick, E., ... De Jager, P. L.
(2017). An xQTL map integrates the genetic architecture of the human brain's tran-
scriptome and epigenome. Nature Neuroscience, 20, 1418–1426.
Oberlander, T. F., Weinberg, J., Papsdorf, M., Grunau, R., Misri, S., & Devlin, A. M.
(2008). Prenatal exposure to maternal depression, neonatal methylation of human
glucocorticoid receptor gene (NR3C1) and infant cortisol stress responses. Epigenetics,
3, 97–106.
Ostlund, B. D., Conradt, E., Crowell, S. E., Tyrka, A. R., Marsit, C. J., & Lester, B. M.
(2016). Prenatal stress, fearfulness, and the epigenome: Exploratory analysis of sex
differences in DNA methylation of the glucocorticoid receptor gene. Frontiers in
Behavioral Neuroscience, 10, 147.
Ouellet-Morin, I., Wong, C. C., Danese, A., Pariante, C. M., Papadopoulos, A. S., Mill, J., &
Arseneault, L. (2013). Increased serotonin transporter gene (SERT) DNA methylation
M.A. Schiele, et al.
is associated with bullying victimization and blunted cortisol response to stress in
childhood: A longitudinal study of discordant monozygotic twins. Psychological
Medicine, 43, 1813–1823.
Palma-Gudiel, H., & Fananas, L. (2017). An integrative review of methylation at the
serotonin transporter gene and its dialogue with environmental risk factors, psy-
chopathology and 5-HTTLPR. Neuroscience and Biobehavioral Reviews, 72, 190–209.
Parent, J., Parade, S. H., Laumann, L. E., Ridout, K. K., Yang, B. Z., Marsit, C. J., ... Tyrka,
A. R. (2017). Dynamic stress-related epigenetic regulation of the glucocorticoid re-
ceptor gene promoter during early development: The role of child maltreatment.
Development and Psychopathology, 29, 1635–1648.
Park, C., Rosenblat, J. D., Brietzke, E., Pan, Z., Lee, Y., Cao, B., ... McIntyre, R. S. (2019).
Stress, epigenetics and depression: A systematic review. Neuroscience and
Biobehavioral Reviews, 102, 139–152.
Parker, K. J., Buckmaster, C. L., Schatzberg, A. F., & Lyons, D. M. (2004). Prospective
investigation of stress inoculation in young monkeys. Archives of General Psychiatry,
61, 933–941.
Peedicayil, J. (2004). Psychosocial factors in the pathogenesis of mental disorders. The
British Journal of Psychiatry, 185, 520.
Peedicayil, J. (2012). Role of epigenetics in pharmacotherapy, psychotherapy and nu-
tritional management of mental disorders. Journal of Clinical Pharmacy and
Therapeutics, 37, 499–501.
Perroud, N., Paoloni-Giacobino, A., Prada, P., Olie, E., Salzmann, A., Nicastro, R., ...
Malafosse, A. (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.
Perroud, N., Rutembesa, E., Paoloni-Giacobino, A., Mutabaruka, J., Mutesa, L., Stenz, L.,
... Karege, F. (2014). The Tutsi genocide and transgenerational transmission of ma-
ternal stress: Epigenetics and biology of the HPA axis. The World Journal of Biological
Psychiatry, 15, 334–345.
Perroud, N., Salzmann, A., Prada, P., Nicastro, R., Hoeppli, M. E., Furrer, S., ... Malafosse,
A. (2013). Response to psychotherapy in borderline personality disorder and me-
thylation status of the BDNF gene. Translational Psychiatry, 3, e207.
van Praag, H., Kempermann, G., & Gage, F. H. (2000). Neural consequences of environ-
mental enrichment. Nature Reviews. Neuroscience, 1, 191–198.
Prados, J., Stenz, L., Courtet, P., Prada, P., Nicastro, R., Adouan, W., ... Perroud, N.
(2015). Borderline personality disorder and childhood maltreatment: A genome-wide
methylation analysis. Genes, Brain, and Behavior, 14, 177–188.
Provencal, N., & Binder, E. B. (2015). The effects of early life stress on the epigenome:
From the womb to adulthood and even before. Experimental Neurology, 268, 10–20.
Provencal, N., Suderman, M. J., Guillemin, C., Massart, R., Ruggiero, A., Wang, D., ...
Szyf, M. (2012). The signature of maternal rearing in the methylome in rhesus ma-
caque prefrontal cortex and T cells. The Journal of Neuroscience, 32, 15626–15642.
Radtke, K. M., Ruf, M., Gunter, H. M., Dohrmann, K., Schauer, M., Meyer, A., & Elbert, T.
(2011). Transgenerational impact of intimate partner violence on methylation in the
promoter of the glucocorticoid receptor. Translational Psychiatry, 1, e21.
Radtke, K. M., Schauer, M., Gunter, H. M., Ruf-Leuschner, M., Sill, J., Meyer, A., & Elbert,
T. (2015). Epigenetic modifications of the glucocorticoid receptor gene are associated
with the vulnerability to psychopathology in childhood maltreatment. Translational
Psychiatry, 5, e571.
Reif, A., Weber, H., Domschke, K., Klauke, B., Baumann, C., Jacob, C. P., ... Deckert, J.
(2012). Meta-analysis argues for a female-specific role of MAOA-uVNTR in panic
disorder in four European populations. American Journal of Medical Genetics. Part B,
Neuropsychiatric Genetics, 159B, 786–793.
Reynolds, S., Lane, S. J., & Richards, L. (2010). Using animal models of enriched en-
vironments to inform research on sensory integration intervention for the re-
habilitation of neurodevelopmental disorders. Journal of Neurodevelopmental
Disorders, 2, 120–132.
Rijlaarsdam, J., Pappa, I., Walton, E., Bakermans-Kranenburg, M. J., Mileva-Seitz, V. R.,
Rippe, R. C., ... van, I. M. H. (2016). An epigenome-wide association meta-analysis of
prenatal maternal stress in neonates: A model approach for replication. Epigenetics,
11, 140–149.
Riley, B., & Kendler, K. S. (2006). Molecular genetic studies of schizophrenia. European
Journal of Human Genetics, 14, 669–680.
Roberts, S., Keers, R., Breen, G., Coleman, J. R. I., Johren, P., Kepa, A., ... Wong, C. C. Y.
(2019). DNA methylation of FKBP5 and response to exposure-based psychological
therapy. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics, 180,
150–158.
Roberts, S., Keers, R., Lester, K. J., Coleman, J. R., Breen, G., Arendt, K., ... Wong, C. C.
(2015). Hpa axis related genes and response to psychological therapies: Genetics and
epigenetics. Depression and Anxiety, 32, 861–870.
Roberts, S., Lester, K. J., Hudson, J. L., Rapee, R. M., Creswell, C., Cooper, P. J., ... Eley, T.
C. (2014). Serotonin transporter [corrected] methylation and response to cognitive
behaviour therapy in children with anxiety disorders. Translational Psychiatry, 4,
e444.
Rodgers, A. B., Morgan, C. P., Bronson, S. L., Revello, S., & Bale, T. L. (2013). Paternal
stress exposure alters sperm microRNA content and reprograms offspring HPA stress
axis regulation. The Journal of Neuroscience, 33, 9003–9012.
Rosenzweig, S. (1936). Some implicit common factors in diverse methods of psy-
chotherapy. American Journal of Orthopsychiatry, 6, 412–415.
Rudenko, A., & Tsai, L. H. (2014). Epigenetic modifications in the nervous system and
their impact upon cognitive impairments. Neuropharmacology, 80, 70–82.
Rutten, B. P., Hammels, C., Geschwind, N., Menne-Lothmann, C., Pishva, E., Schruers, K.,
... Wichers, M. (2013). Resilience in mental health: Linking psychological and neu-
robiological perspectives. Acta Psychiatrica Scandinavica, 128, 3–20.
Sayols-Baixeras, S., Subirana, I., Fernandez-Sanles, A., Senti, M., Lluis-Ganella, C.,
Marrugat, J., & Elosua, R. (2017). DNA methylation and obesity traits: An epigenome-
18
Clinical Psychology Review 77 (2020) 101830
wide association study. The REGICOR study. Epigenetics, 12, 909–916.
Schiele, M. A., & Domschke, K. (2018). Epigenetics at the crossroads between genes,
environment and resilience in anxiety disorders. Genes, Brain, and Behavior, 17,
e12423.
Schiele, M. A., Kollert, L., Lesch, K. P., Arolt, V., Zwanzger, P., Deckert, J., ... Domschke,
K. (2019). Hypermethylation of the serotonin transporter gene promoter in panic
disorder-Epigenetic imprint of comorbid depression? European
Neuropsychopharmacology, 29, 1161–1167.
Schiele, M. A., Ziegler, C., Holitschke, K., Schartner, C., Schmidt, B., Weber, H., ...
Domschke, K. (2016). Influence of 5-HTT variation, childhood trauma and self-effi-
cacy on anxiety traits: a gene-environment-coping interaction study. Journal of Neural
Transmission (Vienna), 123, 895–904.
Schiele, M. A., Ziegler, C., Kollert, L., Katzorke, A., Schartner, C., Busch, Y., ... Domschke,
K. (2018). Plasticity of functional MAOA gene methylation in acrophobia. The
International Journal of Neuropsychopharmacology, 21, 822–827.
Schneider, I., Kugel, H., Redlich, R., Grotegerd, D., Burger, C., Burkner, P. C., ... Hohoff, C.
(2018). Association of serotonin transporter gene AluJb methylation with major
depression, amygdala responsiveness, 5-HTTLPR/rs25531 polymorphism, and stress.
Neuropsychopharmacology, 43, 1308–1316.
Schuebel, K., Gitik, M., Domschke, K., & Goldman, D. (2016). Making sense of epige-
netics. The International Journal of Neuropsychopharmacology, 19.
Shoemaker, R., Deng, J., Wang, W., & Zhang, K. (2010). Allele-specific methylation is
prevalent and is contributed by CpG-SNPs in the human genome. Genome Research,
20, 883–889.
Shumay, E., Logan, J., Volkow, N. D., & Fowler, J. S. (2012). Evidence that the methy-
lation state of the monoamine oxidase A (MAOA) gene predicts brain activity of MAO
A enzyme in healthy men. Epigenetics, 7, 1151–1160.
Singh-Taylor, A., Molet, J., Jiang, S., Korosi, A., Bolton, J. L., Noam, Y., ... Baram, T. Z.
(2018). NRSF-dependent epigenetic mechanisms contribute to programming of
stress-sensitive neurons by neonatal experience, promoting resilience. Molecular
Psychiatry, 23, 648–657.
Sipahi, L., Uddin, M., Hou, Z. C., Aiello, A. E., Koenen, K. C., Galea, S., & Wildman, D. E.
(2014). Ancient evolutionary origins of epigenetic regulation associated with post-
traumatic stress disorder. Frontiers in Human Neuroscience, 8, 284.
Skinner, M. K. (2015). Environmental epigenetics and a unified theory of the molecular
aspects of evolution: A Neo-Lamarckian concept that facilitates Neo-Darwinian evo-
lution. Genome Biology and Evolution, 7, 1296–1302.
Smearman, E. L., Almli, L. M., Conneely, K. N., Brody, G. H., Sales, J. M., Bradley, B., ...
Smith, A. K. (2016). Oxytocin receptor genetic and epigenetic variations: Association
with child abuse and adult psychiatric symptoms. Child Development, 87, 122–134.
Smith, A. K., Kilaru, V., Klengel, T., Mercer, K. B., Bradley, B., Conneely, K. N., ... Binder,
E. B. (2015). DNA extracted from saliva for methylation studies of psychiatric traits:
evidence tissue specificity and relatedness to brain. American Journal of Medical
Genetics. Part B, Neuropsychiatric Genetics, 168b, 36–44.
Smoller, J. W. (2016). The genetics of stress-related disorders: PTSD, depression, and
anxiety disorders. Neuropsychopharmacology, 41, 297–319.
Stahl, S. M. (2012). Psychotherapy as an epigenetic 'drug': Psychiatric therapeutics target
symptoms linked to malfunctioning brain circuits with psychotherapy as well as with
drugs. Journal of Clinical Pharmacy and Therapeutics, 37, 249–253.
Stenz, L., Schechter, D. S., Serpa, S. R., & Paoloni-Giacobino, A. (2018). Intergenerational
transmission of DNA methylation signatures associated with early life stress. Current
Genomics, 19, 665–675.
Stoffel, M., Aguilar-Raab, C., Rahn, S., Steinhilber, B., Witt, S. H., Alexander, N., & Ditzen,
B. (2019). Effects of mindfulness-based stress prevention on serotonin transporter
gene methylation. Psychotherapy and Psychosomatics, 88, 317–319.
Strachan, E., Zhao, J., Roy-Byrne, P. P., Fowler, E., & Bacus, T. (2018). Study design and
rationale for the mood and methylation study: A platform for multi-omics in-
vestigation of depression in twins. Twin Research and Human Genetics, 21, 507–513.
Ströhle, A. (2009). Physical activity, exercise, depression and anxiety disorders. Journal of
Neural Transmission (Vienna), 116, 777–784.
Suzuki, M. M., & Bird, A. (2008). DNA methylation landscapes: Provocative insights from
epigenomics. Nature Reviews. Genetics, 9, 465–476.
Sweder, K. S., & Hanawalt, P. C. (1993). Transcription-coupled DNA repair. Science, 262,
439–440.
Szyf, M. (2015). Epigenetics, a key for unlocking complex CNS disorders? Therapeutic
implications. European Neuropsychopharmacology, 25, 682–702.
Szyf, M., & Bick, J. (2013). DNA methylation: A mechanism for embedding early life
experiences in the genome. Child Development, 84, 49–57.
Tay, N., Macare, C., Liu, Y., Ruggeri, B., Jia, T., Chu, C., ... Consortium, I. (2019). Allele-
specific methylation of SPDEF: a novel moderator of psychosocial stress and sub-
stance abuse. The American Journal of Psychiatry, 176, 146–155.
Teicher, M. H., & Samson, J. A. (2013). Childhood maltreatment and psychopathology: A
case for ecophenotypic variants as clinically and neurobiologically distinct subtypes.
The American Journal of Psychiatry, 170, 1114–1133.
Teschler, S., Bartkuhn, M., Kunzel, N., Schmidt, C., Kiehl, S., Dammann, G., & Dammann,
R. (2013). Aberrant methylation of gene associated CpG sites occurs in borderline
personality disorder. PLoS One, 8, e84180.
Thomas, C. R. (2015). Epigenetics and child psychiatry: Ethical and legal issues.
Behavioral Sciences & the Law, 33, 644–652.
Thomas, M., Knoblich, N., Wallisch, A., Glowacz, K., Becker-Sadzio, J., Gundel, F., ...
Nieratschker, V. (2018). Increased BDNF methylation in saliva, but not blood, of
patients with borderline personality disorder. Clinical Epigenetics, 10, 109.
Tiwari, A., & Gonzalez, A. (2018). Biological alterations affecting risk of adult psycho-
pathology following childhood trauma: A review of sex differences. Clinical
Psychology Review, 66, 69–79.
Tozzi, L., Farrell, C., Booij, L., Doolin, K., Nemoda, Z., Szyf, M., ... Frodl, T. (2018).
M.A. Schiele, et al.
Epigenetic changes of FKBP5 as a link connecting genetic and environmental risk
factors with structural and functional brain changes in major depression.
Neuropsychopharmacology, 43, 1138–1145.
Tyrka, A. R., Price, L. H., Marsit, C., Walters, O. C., & Carpenter, L. L. (2012). Childhood
adversity and epigenetic modulation of the leukocyte glucocorticoid receptor:
Preliminary findings in healthy adults. PLoS One, 7, e30148.
Uher, R. (2014). Gene-environment interactions in severe mental illness. Frontiers in
Psychiatry, 5, 48.
Unternaehrer, E., Bolten, M., Nast, I., Staehli, S., Meyer, A. H., Dempster, E., ...
Meinlschmidt, G. (2016). Maternal adversities during pregnancy and cord blood
oxytocin receptor (OXTR) DNA methylation. Social Cognitive and Affective
Neuroscience, 11, 1460–1470.
Unternaehrer, E., Luers, P., Mill, J., Dempster, E., Meyer, A. H., Staehli, S., ...
Meinlschmidt, G. (2012). Dynamic changes in DNA methylation of stress-associated
genes (OXTR, BDNF) after acute psychosocial stress. Translational Psychiatry, 2, e150.
Unternaehrer, E., Meyer, A. H., Burkhardt, S. C., Dempster, E., Staehli, S., Theill, N., ...
Meinlschmidt, G. (2015). Childhood maternal care is associated with DNA methy-
lation of the genes for brain-derived neurotrophic factor (BDNF) and oxytocin re-
ceptor (OXTR) in peripheral blood cells in adult men and women. Stress, 18, 451–461.
Ursini, G., Bollati, V., Fazio, L., Porcelli, A., Iacovelli, L., Catalani, A., ... Bertolino, A.
(2011). Stress-related methylation of the catechol-O-methyltransferase Val 158 allele
predicts human prefrontal cognition and activity. The Journal of Neuroscience, 31,
6692–6698.
Vinkers, C. H., Geuze, E., van Rooij, S. J. H., Kennis, M., Schur, R. R., Nispeling, D. M., ...
Boks, M. P. (2019). Successful treatment of post-traumatic stress disorder reverses
DNA methylation marks. Molecular Psychiatry. https://doi.org/10.1038/s41380-019-
0549-3.
Voisey, J., Lawford, B., Bruenig, D., Harvey, W., Morris, C. P., Young, R. M., ... Initiative,
P. (2019). Differential BDNF methylation in combat exposed veterans and the asso-
ciation with exercise. Gene, 698, 107–112.
Voisin, S., Eynon, N., Yan, X., & Bishop, D. J. (2015). Exercise training and DNA me-
thylation in humans. Acta Physiologica (Oxford, England), 213, 39–59.
Wampold, B. E., Mondin, G. W., Moody, M., Stich, F., Benson, K., & Ahn, H. N. (1997). A
meta-analysis of outcome studies comparing bona fide psychotherapies: Empirically,
“all must have prizes” Psychological Bulletin, 122, 203–215.
Wang, C., Schroeder, F. A., & Hooker, J. M. (2014). Visualizing epigenetics: Current
advances and advantages in HDAC PET imaging techniques. Neuroscience, 264,
186–197.
Weaver, I. C., D'Alessio, A. C., Brown, S. E., Hellstrom, I. C., Dymov, S., Sharma, S., ...
Meaney, M. J. (2007). The transcription factor nerve growth factor-inducible protein
a mediates epigenetic programming: altering epigenetic marks by immediate-early
genes. The Journal of Neuroscience, 27, 1756–1768.
Weder, N., Zhang, H., Jensen, K., Yang, B. Z., Simen, A., Jackowski, A., ... Kaufman, J.
(2014). Child abuse, depression, and methylation in genes involved with stress,
neural plasticity, and brain circuitry. Journal of the American Academy of Child and
Adolescent Psychiatry, 53(417-24), e5.
Wells, A. (2002). Emotional disorders and metacognition: Innovative cognitive therapy. John
Wiley & Sons.
Whittle, N., & Singewald, N. (2014). HDAC inhibitors as cognitive enhancers in fear,
anxiety and trauma therapy: Where do we stand? Biochemical Society Transactions, 42,
569–581.
Wiegand, C., Heusser, P., Klinger, C., Cysarz, D., Bussing, A., Ostermann, T., &
Savelsbergh, A. (2018). Stress-associated changes in salivary microRNAs can be de-
tected in response to the Trier Social Stress Test: An exploratory study. Scientific
Reports, 8, 7112.
Wochnik, G. M., Ruegg, J., Abel, G. A., Schmidt, U., Holsboer, F., & Rein, T. (2005).
FK506-binding proteins 51 and 52 differentially regulate dynein interaction and
nuclear translocation of the glucocorticoid receptor in mammalian cells. The Journal
of Biological Chemistry, 280, 4609–4616.
Xiao, F. H., Wang, H. T., & Kong, Q. P. (2019). Dynamic DNA methylation during aging: A
"prophet" of age-related outcomes. Frontiers in Genetics, 10, 107.
Yang, B. Z., Zhang, H., Ge, W., Weder, N., Douglas-Palumberi, H., Perepletchikova, F., ...
Kaufman, J. (2013). Child abuse and epigenetic mechanisms of disease risk. American
Journal of Preventive Medicine, 44, 101–107.
Yehuda, R., Daskalakis, N. P., Bierer, L. M., Bader, H. N., Klengel, T., Holsboer, F., &
Binder, E. B. (2016). Holocaust exposure induced intergenerational effects on FKBP5
methylation. Biological Psychiatry, 80, 372–380.
Yehuda, R., Daskalakis, N. P., Desarnaud, F., Makotkine, I., Lehrner, A. L., Koch, E., ...
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.
19
Clinical Psychology Review 77 (2020) 101830
Yehuda, R., Lehrner, A., & Bierer, L. M. (2018). The public reception of putative epige-
netic mechanisms in the transgenerational effects of trauma. Environmental
Epigenetics, 4 dvy018.
Yeshurun, S., & Hannan, A. J. (2019). Transgenerational epigenetic influences of paternal
environmental exposures on brain function and predisposition to psychiatric dis-
orders. Molecular Psychiatry, 24, 536–548.
Yousefi, P., Huen, K., Dave, V., Barcellos, L., Eskenazi, B., & Holland, N. (2015). Sex
differences in DNA methylation assessed by 450 K BeadChip in newborns. BMC
Genomics, 16, 911.
Youssef, N. A., Lockwood, L., Su, S., Hao, G., & Rutten, B. P. F. (2018). The effects of
trauma, with or without PTSD, on the transgenerational DNA methylation alterations
in human offsprings. Brain Sciences, 8.
Zannas, A. S. (2016). Editorial perspective: Psychological stress and epigenetic aging -
What can we learn and how can we prevent? Journal of Child Psychology and
Psychiatry, 57, 674–675.
Zannas, A. S., Arloth, J., Carrillo-Roa, T., Iurato, S., Roh, S., Ressler, K. J., ... Mehta, D.
(2015). Lifetime stress accelerates epigenetic aging in an urban, African American
cohort: Relevance of glucocorticoid signaling. Genome Biology, 16, 266.
Zannas, A. S., & Chrousos, G. P. (2017). Epigenetic programming by stress and gluco-
corticoids along the human lifespan. Molecular Psychiatry, 22, 640–646.
Zannas, A. S., & West, A. E. (2014). Epigenetics and the regulation of stress vulnerability
and resilience. Neuroscience, 264, 157–170.
Ziegler, C., Dannlowski, U., Brauer, D., Stevens, S., Laeger, I., Wittmann, H., ... Domschke,
K. (2015). Oxytocin receptor gene methylation: converging multilevel evidence for a
role in social anxiety. Neuropsychopharmacology, 40, 1528–1538.
Ziegler, C., & Domschke, K. (2018). Epigenetic signature of MAOA and MAOB genes in
mental disorders. Journal of Neural Transmission (Vienna), 125, 1581–1588.
Ziegler, C., Grundner-Culemann, F., Schiele, M. A., Schlosser, P., Kollert, L., Mahr, M., ...
Domschke, K. (2019). The DNA methylome in panic disorder: A case-control and
longitudinal psychotherapy-epigenetic study. Translational Psychiatry, 9, 314.
Ziegler, C., Richter, J., Mahr, M., Gajewska, A., Schiele, M. A., Gehrmann, A., ...
Domschke, K. (2016). MAOA gene hypomethylation in panic disorder-reversibility of
an epigenetic risk pattern by psychotherapy. Translational Psychiatry, 6, e773.
Zubin, J., & Spring, B. (1977). Vulnerability–A new view of schizophrenia. Journal of
Abnormal Psychology, 86, 103–126.
Katharina Domschke, MA, MD, PhD, is Full Professor of Psychiatry and Chair of the
Department of Psychiatry and Psychotherapy, University of Freiburg, Germany.
Additionally, she holds an Adjunct Professorship at the Medical University of Vienna,
Austria. Prof. Domschke completed her studies and postgraduate education in medicine
and psychology at the University of Muenster, Germany, and Trinity College Dublin,
Ireland, as well as at Boston University, Boston, MA, USA, and Maastricht University, The
Netherlands. After her residency in psychiatry at the Universities of Bonn and Muenster,
Germany, she worked as an attending physician and associate professor at the
Department of Psychiatry, University of Muenster, Germany. In 2012, she was appointed
Full Professor of Psychiatry at the University of Wuerzburg, Germany, where she worked
as attending physician and from 2014 through 2016 as vice chair. Prof. Domschke’s
clinical expertise is on diagnostics and therapy in adult psychiatry, particularly depres-
sion, anxiety disorders, stress-related disorders and obsessive-compulsive disorders.
Scientifically, applying genetic/epigenetic, imaging genetic and therapy(epi)genetic ap-
proaches she is interested in the identification of multilevel markers for the prediction,
indicated prevention and personalized treatment of mental disorders. Her work is re-
flected by to date over 260 publications in peer-reviewed journals, two books and 30 book
chapters. Prof. Domschke is a member of the National Academy of Sciences Leopoldina
and has received the Research Award of the World Federation of Societies of Biological
Psychiatry (WFSBP), the Fellowship Award of the World Psychiatric Association (WPA),
the Fellowship Award of the European College of Neuropsychopharmacology (ECNP), the
Research Award of the German Society of Biological Psychiatry (DGBP), and the Research
Award of the German Society of Psychiatry, Psychotherapy and Neurology (DGPPN).
Prof. Domschke has received funding from, e.g., the EU, the German Research Foundation
(DFG), and the German Ministry of Research and Education (BMBF). She is a fellow of the
ACNP, full member of the ECNP, SOBP, ISPG and the German Society of Psychiatry,
Psychotherapy and Neurology (DGPPN), executive secretary of the German Society of
Biological Psychiatry (DGBP) and vice president of the German Society of Anxiety
Research (GAF). Prof. Domschke serves on the editorial boards of the International
Journal of Neuropsychopharmacology, Journal of Psychiatric Research, Nervenarzt,
PLoSONE, Pharmacopsychiatry, Progress in Neuropsychopharmacology & Biological
Psychiatry, Acta Neuropsychiatrica, World Journal of Biological Psychiatry, International
Journal of Methods in Psychiatric Research as well as Frontiers in Molecular Psychiatry,
and is a regular reviewer for over 60 SCI-listed international journals.