Progress in Neuropsychopharmacology & Biological Psychiatry 109 (2021) 110231

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Progress in Neuropsychopharmacology & Biological

Psychiatry
journal homepage: www.elsevier.com/locate/pnp

Epigenetics: A missing link between early life stress and depression

Mario F. Juruena a, b, *, Romayne Gadelrab b, Anthony J. Cleare a, b, Allan H. Young a, b
a
Centre for Affective Disorders, Department of Psychological Medicine, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, Denmark Hill, London
SE5 8AF, UK
b
South London and Maudsley NHS Foundation Trust (SLaM), UK

A B S T R A C T

Research has suggested a relationship between early life stress, and depression in particular longer episodes of depression with treatment resistant outcomes.
However, the underlying mechanisms for this association remain poorly understood. Molecular studies indicate that, in general, the hereditary character of psy­
chiatric disorders are polygenic, multifactorial and highly complex, with innumerable low-effect genetic variants interacting with each other. In addition, the
importance of the environment and its interaction with genes has pointed to a fundamental role of epigenetic mechanisms in psychiatric disorders, such as
methylation of deoxyribonucleic acid (DNA), alterations, histone actions and regulation of gene expression by non-coding ribonucleic acids (RNAs). This article
provides an overview of the interplay of epigenetics, the HPA axis, early life stress and the development of depression. Advances in our knowledge of epigenetics in
the context of early life stress and depression provide a new understanding of the genetic influence on psychopathology and could lead to the identification of new
targets for clinical intervention.

1. Introduction
The hereditary character of psychiatric disorders has been known for
years, but the specific genetic bases responsible for the risk and
vulnerability to them are still being studied. The field of neuroscience
has grown a lot thanks to the emergence of new techniques in genetics
and neuroimaging that have allowed the study of brain activation pat­
terns “in vivo”, in the most diverse life situations, and during the per­
formance of different tasks (Hillman, 2007).Today, it is possible with the
resources of molecular biology, to analyze genetic material, manipu­
lating the expression of selected genes, visualise synapses, neural
sprouting, studying the electrical activity of nerve cells, ion channels,
neurotransmitters, neuroreceptors and much more. These technological
advances plus transdisciplinary cooperation, the possibility for online
communication, and research through networked databases, has made it
possible for neurosciences to achieve a complex and integrated approach
to understanding the human mind. Due to this mutual cooperation be­
tween scholars, the term epigenetics came to gain prominence in the
scientific world as “non-genetic inheritance”, and its meaning - epi (from
the Greek: επί-over = above) - genetics = epigenetics = “above of ge­
netics “- that is to say “the study of changes produced in gene expression
caused by mechanisms other than changes in the sequence of DNA
bases”(Waddington, 1956). It has been well researched that Early life
stress can contribute to development of depression later in life. (Liu,
2017). However, understanding how early life stress may contribute to
depression through the model of epigenetics, brings a new under­
standing to the disorder and a potential target for further research and
possible treatment. It’s important to establish a correlation between the
various studies of the human brain, which analyze neuroplasticity,
epigenetics, genetics, circuits and neurotransmitters, thus enabling a
new interpretation of mental illnesses.
Our aim is to review the epigenetic relationship between early life
stress and depressive disorders. The literature demonstrated it is a strong
example of a field of study that can be more fully understood from an
integrative perspective. We hypothesised that Early stressful life events
play an important role in the pathogenesis of depression, being well
established as acute triggers of psychiatric illness. The methods are
limited, as do not follow a systematic methodology or metanalysis, but
reflect the limitations in the field. However, all titles and abstracts were
reviewed initially, and the selection criteria related to our aim and hy­
pothesis outlined above was applied. Only articles published in English
language peer-reviewed journals were considered for inclusion, while all
of the full-text articles were examined. Thus, in this review article we
summarize the main reported findings about the consequences of ELS in
HPA axis functioning and in the responsivity of MR/GR receptors in
depression.

* Corresponding author at: Centre for Affective Disorders, Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King’s
College London, Room M3.24, PO72, 16 De Crespigny Park, Denmark Hill, London SE5 8AF, UK.
E-mail address: mario.juruena@kcl.ac.uk (M.F. Juruena).

https://doi.org/10.1016/j.pnpbp.2020.110231
Received 30 September 2020; Received in revised form 6 December 2020; Accepted 21 December 2020
Available online 28 December 2020
0278-5846/© 2020 Elsevier Inc. All rights reserved.
M.F. Juruena et al. Progress in Neuropsychopharmacology & Biological Psychiatry 109 (2021) 110231

2. Epigenetics consequence is the silencing of a specific region of DNA, preventing the

The concept of epigenetics arose in the 1940s, with biologist Conrad
Waddington, to describe the interaction between genes and the envi­
ronment that allows the emergence of phenotypes (Deans and Maggert,
2015) Today, epigenetic events are defined as: “the structural adapta­
tion of chromosomal regions so as to register, signal or perpetuate
altered activity states” (Bird, 2007) Epigenetics refers to the regulation
of DNA transcription without alteration of the original sequence and is
controlled by DNA methylation, histone modification and non-coding
RNAs (Jaenisch and Bird, 2003; Ptak and Petronis, 2010).
Epigenetic mechanisms consider the interaction between the in­
dividual’s genetic heritage and environmental factors, analyzing this
process as intracellular changes in the expression of genetic material,
which culminate in determining the characteristics exhibited by the
individual. Epigenetic mechanisms concern, fundamentally, the means
and processes by which the biological determination of the organism is
updated and expressed throughout its development (Rutter et al., 2006;
Dudley et al., 2011).
Evidence that epigenetic mechanisms are at play in humans with
depression and childhood adversity are the increases in epigenetic
marks found in brain and in white cells in these individual (McGowan
et al., 2009) Thus, sensitization and cross sensitization to stressors, ep­
isodes, and abuse substances would appear to involve the accumulation
of pathological epigenetic marks on DNA, histones, or microRNA
(Meaney and Syzf, 2005; Labonte et al., 2013).
The epigenetic alteration of DNA, that is, its gene expression, can
occur due to different processes, such as phosphorylation, acetylation
and methylation. DNA methylation is one of the most researched
epigenetic mechanisms in the field and consists, in general, in the
addition of a chemical element (a methyl group) to a specific region of
DNA. According to current hypotheses, methylation is a common pro­
cess in the embryonic phase and throughout development, and its main
synthesis of proteins that would characterize its activation. Thus, this
epigenetic mechanism would produce stable changes in the production
of proteins in that region of DNA, permanently altering the expression of
genetic inheritance (Rutten and Mill, 2009; Sweatt, 2009), see Fig. 1.
Epigenetic phenomena play a critical role in regulating neural
functions, not only in the brains of children, but also in the brains of
adults, so that the influences of the environment on the action and
expression of the genetic load remain in progress throughout life. The
epigenetic model offers a general explanation for the gradual con­
struction of vulnerability, which begins with exposure to harmful
environmental factors in early periods of development, passes through
the modification of gene expression as a result of this exposure, and
reaches cell physiology and the functioning of the organism that confer
an increased risk for the development of the disease (Jirtle and Skinner,
2007; Borelli et al., 2008).
3. Hypothalamic-Pituitary-Adrenal (HPA) axis
With the introduction of the analysis of variations in the expression
of genetic heritage, researchers have been forced to reformulate their
hypotheses and to increasingly consider the influence of the environ­
ment. If the environment is valued as an important element in the causal
chain that, as we have seen, does not lead directly to the disease, but
confers different degrees of vulnerability and resilience, one can argue in
favor of the social dimension in contemporary biological knowledge.
Several biological mechanisms have been involved in the patho­
physiology of depression; in this work the focus is on the Hypothalamic-
Pituitary-Adrenal (HPA) axis.
Activation of the HPA axis is essentially the main adaptive mecha­
nism that allows the human body to maintain physiological stability in
response to signs of general tension (stress) (Cozma et al., 2017). The
importance of this system is underlined by its conservation through

Fig. 1. Diagram of the epigenetic properties of cortisol and the glucocorticoid receptor (GR) stimulation, this receptor exists in almost every tissue of the human
body, at the cytoplasm with chaperonin proteins with numerous proteins (HSP56, HSP90). After cortisol the glucocorticoid (GC) bind as GR ligands. Then the GR
experiences an alteration disconnected from the HSP and migrated to the cell nucleus from the cytoplasm, modulating negatively or positively to alter the gene
transcription. GC also appear to exert its effects directly in the cell mitochondria. (Adapted from Juruena, 2014.)

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M.F. Juruena et al. Progress in Neuropsychopharmacology & Biological Psychiatry 109 (2021) 110231

species and the maintenance of the dynamic response capacity
throughout life. The dynamics of the HPA axis require a strictly
controlled balance of excitation and inhibition for an adequate response
to stress and adaptation to environmental demand (Herman et al.,
2016).
The HPA axis has gained more prominence in studies, where this axis
plays a fundamental role in responding to external and internal stimuli,
including psychological stressors (Juruena, 2014). HPA axis activity has
been identified as a key biological marker of risk for depression
(LeMoult et al., 2015). Substantial literature has documented the link
between major depressive disorder and abnormalities in HPA activity
(Krishnan and Nestler, 2008; Juruena, 2014; Gerritsen et al., 2017;
Wichmann et al., 2017). Most of what is known about the functioning of
the HPA axis in depressed individuals is based on studies of HPA axis
activity and pharmacological challenge studies designed to test negative
feedback mechanisms on the HPA axis, such as the dexamethasone
suppression test (Ferguson et al., 2017; van Neijenhof et al., 2018) and
the prednisolone suppression test (Juruena et al., 2006, 2009, 2010).
Conclusions from this study suggest that a subset of individuals with
major depressive disorder in melancholic and/or treatment resistant
episode have elevated baseline cortisol levels associated with the re­
sponses of the hormones ACTH and cortisol (Burke et al., 2005; Juruena
et al., 2009). This is justified when one observes the effect of axis hy­
peractivity in these depressed people. Hyperactivity is perceived by
increased concentrations of cortisol in plasma, saliva, urine and cere­
brospinal fluid (CSF). It can also be perceived by the exaggerated
response of cortisol after stimulation with adrenocorticotropic hormone
and enlargement of the pituitary and adrenal glands followed by nega­
tive feedback to the axis that results in the blocking of circulating
cortisol flags. Fig. 2 illustrates this process of negative feedback from the
Hypothalamus-Pituitary-Adrenal Axis (Juruena et al., 2017).
In stressful situations, the human body starts a cascade of events in
the HPA axis - CRH is released by the hypothalamus, triggering adre­
nocorticotropic hormone (ACTH) release by the pituitary, which, finally,
stimulates the release of cortisol into the bloodstream by the adrenal
cortex. Cortisol, to start its action, needs to bind to its intracellular re­
ceptors – 2 different types: type I or mineralocorticoid receptor (MR) and
type II or glucocorticoid receptor (GR; Juruena, 2014; De Kloet et al.,
2005; Joëls et al., 2009). Under stressful situations, hippocampal, hy­
pothalamic and pituitary GRs start binding to cortisol (Carroll et al.,

Fig. 2. Schematic diagram of Hypothalamic–Pituitary–Adrenal (HPA) Axis negative feedback. It describes HPA axis regulation and negative feedback (− ) of cortisol
via glucocorticoid receptors (GRs) and mineralocorticoid receptors (MRs). Including Hippocampus, Amygdala, Raphe Nucleus, Locus Coeruleus and relation via
serotonin (5HT) and Noradrenaline (NA) with GR/MRs and Adrenal Hormones. (Adapted from Juruena et al., 2017).

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M.F. Juruena et al.
1976). When cortisol binds to MR and GR, it acts to suppress the
increased excitability, to recover from the stress-induced activation, and
to start the reactive feedback and the facilitation of mnemonic formation
(Juruena et al., 2013). Recent systematic review (Berardelli et al., 2020)
found that HPA axis activity is involved in suicide risk, with or without
psychiatric conditions. The HPA axis dysfunction, as HPA axis hyper­
activity, may influence on suicide risk. Assessing HPA axis dysregulation
might represent a fruitful strategy for identifying new treatment targets
and improving suicide risk prediction (Berardelli et al., 2020).
Substantial evidence then indicates that chronic elevation of cortisol
levels and dysfunction of the HPA axis feedback system play a prominent
role in responses to stress. However, chronic activation of the HPA axis
induces damage and pathological responses (Palma et al., 2007).
Because of this, cortisol has been routinely used as a biomarker of psy­
chological stress and related mental or physical illnesses. Cortisol is
produced by the adrenal cortex in response to a stimulus on the HPA
axis, and acts on glucocorticoid and mineralocorticoid receptors. In the
central nervous system, MR receptors appear to be more expressed in
limbic regions, especially the hippocampus, while GRs are expressed
diffusely in the brain (Herman et al., 1989). Most studies consider, for
example, salivary cortisol levels as a reliable measure of adaptation of
the hypothalamic-pituitary-adrenal axis to stress (Castro et al., 2000).
The term stress is used to encompass the psychophysical challenges
encountered in daily life, that is, the integrated response to coping with
adverse situations. These challenges reflected in sentiment can be highly
adaptive from an evolutionary point of view because they are taught to
deal with similar circumstances in the future (McEwen, 2018).
The pathophysiology of the stress response (see Fig. 3) is part of the
concept of allostasis, which is the short-term process of achieving ho­
meostasis through physiological or behavioral changes that involve
maintaining stability In the long run, it is called the allostatic load,
which is the individual’s physiological degradation as a result of
repeated cycles of allostasis (McEwen, 2018).
4. Early life stress (ELS)
The relative concept of early brain damage is based on evidence that
there are critical periods of development that represent a single window
Fig. 3. The physiological process of stress goes through three phases. The alarm
or alert phase (there is a rupture of the organism’s internal balance and
mobilization to face the stressor). The resistance phase, where the physiological
and behavioral responses are observed, with the intention of maintaining ho­
meostasis. At this moment the action of the hormone cortisol is strongly found,
from this activation, the organism is able to respond with its best physical and
cognitive performance to neutralize the stressor. The last phase, the exhaustion
phase, is considered a critical phase for the organism in the adaptive response,
because the longer the process of coping with the stressor, the organism re­
mains chronically offering a response, with behavioral and physiological
changes that were previously adaptive. and now they start to generate an en­
ergy overload leading to system exhaustion (Adapted from McEwen, 2018).
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Progress in Neuropsychopharmacology & Biological Psychiatry 109 (2021) 110231
of development, which cannot be reversed or repeated in a later period
(Lupien et al., 2009). While each sub-region follows a careful sequential
development schedule, it must be synchronized, with time, with other
interconnected regions, so that the final product results intact and fit in
the mature structure. The greatest task of the developing brain is to
establish correct patterns of connections in a given period of time,
without which there will be distortions in the coordinated maturation of
different brain components that will lead to the disruption of ordered
growth, thus compromising the elaboration of the neural circuit (Lupien
et al., 2009).
The literature suggests ELS as a predictive factor for the development
and onset of psychiatric disorders in adults (Martins-Monteverde et al.,
2019). Early life stress refers to traumatic incidents that occur during
childhood and adolescence and is defined differently depending on the
author or questionnaire used to measure it. These incidents range from
experiencing childhood adversities and maltreatment such as abuse,
parental divorce or death, being in a traumatic accident and deprivation
of food (Bernstein et al., 2003).
In agreement with Bernstein et al. (2003) childhood maltreatment
may be subdivided into the following domains:
A. Physical abuse: physical aggression by someone older, with the risk
of or result of injury.
B. Emotional abuse: verbal aggression that affects the welfare or morale
of the child or any conduct that humiliates, embarrasses, or threatens
the child.
C. Sexual abuse: any type of sexual contact or conduct between a child
and someone older.
D. Emotional neglect: failure of caretakers to provide for basic
emotional and psychological needs such as love, motivation, and
support.
E. Physical neglect: failure of caretakers to provide for basic physical
needs such as feeding, a home, security, supervision, and health.
Developmental research suggests that early life stress affects
emotional, behavioral, social and cognitive development (Juruena,
2014; Bremner et al., 2007). This perspective considers childhood an
important time for development and propose that experiencing trauma
during this period may increase the susceptibility of developing psy­
chopathology in adulthood (McCrory et al., 2012).
5. Depression
Major Depressive Disorder (MDD) is one of the most frequent causes
of disability worldwide (GBD 2017 Disease and Injury Incidence and
Prevalence Collaborators, 2018). Despite this, a significant amount of
cases remain under-recognised, are not adequately treated or do not
respond to medications, although effective and well-established treat­
ments are now available for depression (Cipriani et al., 2018). A primary
concern within MDD is Treatment-Resistant Depression (TRD). There
has been uncertainty around a clear definition and the real prevalence of
TRD, but it is calculated that around 50–60% of depressed patients do
not reach satisfactory remission after the administration of an approved
treatment for an adequate time and at an adequate dose (Fava, 2003;
Dold and Kasper, 2017). Only 30% of depressed patients who receive
adequate treatment achieve the ultimate end-point of treatment, that is
complete recovery or remission (Trivedi et al., 2006). Furthermore,
approximately one-third of cases of depression are defined as treatment-
resistant (Sackeim, 2001), with cases of TRD reaching 40% of total
depressed individuals in some studies (Souery et al., 2007). Other
studies found a high rate of recurrence in the short term, with approx­
imately 80% of TRD patients relapsed within one year and with the
probability of recovery in 10 years of only 40% (Fekadu et al., 2009).
These findings highlight the importance of possible cumulative ef­
fects of repeated episodes of major depression on the HPA axis and may
have relevance to the later development of TRD. Prevention and early
M.F. Juruena et al.
recognition of recurrent and resistant depressive episodes may prevent
these cumulative adverse effects. Additional research into the neuro­
endocrine and behavioral effects of stressors and a cognitive
vulnerability-stress model with regard to the quality, intensity, and
timing of life adversity is needed for a more complete understanding of
the complex relationship between stress, HPA axis function, and psy­
chopathology in TRD.
6. Early life stress and depression
Previous studies looking at the association between ELS and
depression have assessed the relationship between ELS history and the
risk of developing unipolar depression, depressive symptoms or treat­
ment response but, few explore how the independent effects of ELS
subtypes differently affect the illness course of depression. Evaluating
the independent effect of these subtypes may reveal how early life
maltreatment plays an essential role in unipolar depression. Studies
investigating subjects with clinical depression have reported more
adversity in childhood than individuals who do not have a depression
diagnosis (Edwards et al., 2003). Together, the evidence establishes
early life stress as a significant predictor for depression in adulthood
(Liu, 2017). ELS has been associated with more severe courses of
depression (Kessler and Magee, 1994) with results from epidemiological
studies proposing that adults with ELS history have a two-fold increase
risk of longer and more lifetime depressive episodes as compared to
adults with no history of ELS (Nanni et al., 2012). Other studies have
found a correlation between ELS and an earlier age of depression onset
(Teicher et al., 2009; Gladstone et al., 1999), more severe depressive
symptoms (Dube et al., 2001) and poorer treatment outcomes (John­
stone et al., 2009; Tunnard et al., 2014). Another review identified ELS
as a significant predictor that can increase the risk of depression onset,
maintain symptoms of depression and increase recurrence of the disor­
der, psychotic symptoms and suicide attempts (Carr et al., 2013; Tun­
nard et al., 2014). In addition to the frequency of the occurrence of
depression being widely known, studies show that about one quarter to
one third of abused children will meet the criteria for major depression
when they reach the end of their 20s.; (Mello et al., 2007; Vaever et al.,
2016).
Adversity in early life also influences neurodevelopment, and the
prefrontal cortex, as it has a long period of maturation, which extends
into adolescence, and is especially vulnerable to childhood experiences.
For example, institutionalized children, victims of psychosocial depri­
vation (insufficient or absent stimulation), have been found to have
impaired executive function (Rutter et al., 2012).
It is interesting to note that early stress events appear to have an
important effect on the HPA axis, which could predispose individuals to
developing depression during adulthood (Heim et al., 2008; Holsboer,
1999; Shea et al., 2005; Tyrka et al., 2008; Juruena, 2014).
History of Early Life Stress, as child abuse, neglect or stressful
experience as parental loss have been associated with significantly
increased risk for developing Treatment resistant depression (Heim
et al., 2000; Tofoli et al., 2011; Martins et al., 2011). This data revealing
that the severity of Early Life Stress and its subtypes correlate with the
severity of depression (Martins et al., 2011). One of the mechanisms
thought to be involved in these abnormalities is the impaired feedback
inhibition of the HPA axis by circulating glucocorticoids (Juruena,
2014).
Early stress is probably related to more than just the occurrence of
the stressor and can be associated with the intensity, duration, stage of
development of the victim and response to physiological stress at the
time of stress. Presumably, only stressors that result in significant or
sustained stress responses characterized by the HPA axis or other im­
mune system activity would influence vulnerability to psychiatric ill­
nesses (Saleh et al., 2017).
As the HPA axis is activated in response to stressors, stressful events
in early life can also have a significant etiological role in the
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Progress in Neuropsychopharmacology & Biological Psychiatry 109 (2021) 110231
abnormalities of this axis found in people with psychiatric disorders
(Heim et al., 2000; Holsboer, 1999; Shea et al., 2005; Tyrka et al., 2008).
Studies suggest that stress in the early stages of development can induce
persistent changes in the ability of the HPA axis to respond to adult stress
and that this mechanism could lead to greater susceptibility to depres­
sion (Holsboer, 1999; Shea et al., 2005; Juruena, 2014). Evidence in­
dicates that early adverse experiences combined with genetic
background culminate in the sensitization of certain brain circuits to an
acute stressor. Consequently, changes in the reactivity of the HPA axis
occur which, when persistent, result in an imbalance in the axis mod­
ulation (Juruena, 2014; Lupien et al., 2009).
It has been suggested that early life traumatic experiences produce
alterations in inflammation and HPA axis abnormalities both of which
increase vulnerability to stress (Heim et al., 2010). Clinical and exper­
imental evidence document that inflammation and increased peripheral
cytokine levels are associated with depression-like symptoms and neu­
ropsychological disturbances in humans. (Grigoleit et al., 2011).
Furthermore, the administration of pro-inflammatory agents such as
endotoxin lipopolysaccharide (LPS) can induce depressive symptoms in
humans. (Grigoleit et al., 2011).
7. Epigenetics of HPA axis in depression with history of ELS
Although, some conditions impact the response of the HPA axis, such
as early and recent stressors and psychological state, not every indi­
vidual exposed to early life stress will necessarily develop a psychiatric
disorder, and not every adult with a psychiatric disorder will have suf­
fered some experience of abuse or neglect in childhood. This demon­
strates the importance of genetic character and individual vulnerability
in the development of depressive disorders (Raabe and Spengler, 2013).
The developing brain is very sensitive to the effects of early exposure
to stressors especially due to the reprogramming of a series of stress-
sensitive gene pathways (Bondar and Merkulova, 2016). Thus, early
stress is a powerful risk factor for mental illnesses, such as depression,
which can lead to a prolonged course of the disease and a weaker
response to treatment (Raabe and Spengler, 2013). Inconsistent evi­
dence suggests that both physical and sexual abuse are associated with
doubling the risk of attempted suicide in young people (Mello et al.,
2007). This provides an additional molecular rationale for early pre­
vention of episodes and substance abuse and minimization of stressors in
order to not only inhibit these mechanisms of illness progression, but
also to inhibit the accumulation of the associated adverse epigenetic
marks.
Research has found elevated CRH levels in brain regions such as the
frontopolar and dorsomedial prefrontal cortex, in people who had
committed suicide (Merali et al., 2004). As well as differences in CRF
binding sites in the frontal cortex. In an evaluation comparing 26 suicide
patients with 29 controls, there was a significant 23% reduction in the
number of CRF binding sites in the frontal cortex of suicide patients.
(Nemeroff et al., 1988).
In a study examining adolescent females at risk of suicidal behaviors
(n = 138), investigated HPA axis stress responses by measuring cortisol
levels before and after stressors (Giletta et al., 2015). Compared to
healthy controls, adolescents in the hyperresponsive group were at a
higher risk of suicidal ideation three months later. The salivary cortisol
baseline was also studied in patients with major affective disorders (n =
69) showing that those with a suicide attempt history had lower baseline
cortisol levels compared to those without a suicide attempt history
(Keilp et al., 2016).
An increased vulnerability to non-suicidal self-injury and suicidal
behaviors seems to be related to experiences of childhood trauma mainly
in females, who seem to be more vulnerable (Serafini et al., 2017).
Several studies found that patients with multiple episodes of unipolar
depression exhibited greater cortisol levels (Rybakowski and Twar­
dowska, 1999). This data could underline the findings of Sher et al.
(2004) that demonstrated that the number of previous major depressive
M.F. Juruena et al. Progress in Neuropsychopharmacology & Biological Psychiatry 109 (2021) 110231

episodes was a predictor of cortisol response to fenfluramine adminis­
tration in depressed subjects (Sher et al., 2004). Sheline and colleagues
also found that the number of previous major depressive episodes is a
predictor of a cortisol response to fenfluramine administration in
depressed patients (Sheline et al., 1999)”. These findings are in accord
with earlier studies that found a significant main effect of age on base­
line cortisol, older age being associated with higher baseline cortisol
(Seeman et al., 2001).
This neurobiological rationale for clinical treatment and prevention
of the three types of environmentally mediated sensitization converges
with the clinical imperative of early sustained prophylaxis.
8. Early life stress and stress-related genes
It is important to highlight the existence of genetic factors in sus­
ceptibility to affective diseases. Adverse parental experiences can have a
transgenerational impact based on offspring exposure to the associated
adversity (Post et al., 2015). In addition, there is a second kind of
transmission that is not based on exposure to the parental behaviors, see
Fig. 4. It appears that some of the epigenetic marks of the parents are not
erased at fertilization and are transferred to the next generation (Post,
2016). (See Fig. 5.)
The developing brain is very sensitive to the effects of early exposure
to stressors especially due to the reprogramming of a series of stress-
sensitive gene pathways (Bondar and Merkulova, 2016). The relation­
ship between depressive disorder, polymorphic genes and stress and the
environment has been proven (Uher, 2014). In recent years, research has
increasingly focused on elucidating the genetic mechanisms involved in
depression. Complete genome association studies (GWAS) have
advanced the understanding of the genetic mechanisms of certain psy­
chiatric disorders but have not yet been sufficient to fully elucidate the
genetic basis of depression (Michaelson, 2017).
McGowan et al. (2009), demonstrated the association between abuse
during childhood and the epigenetic decrease of the glucocorticoid re­
ceptor in the hippocampus. In that study, it was discovered that a group
of suicides with a history of child abuse expressed a lower number of
glucocorticoid receptors in the hippocampus, associated with methyl­
ation of the promoter of the gene encoding such receptors. With the
reduction in the rate of transcription of the gene and, consequently, the
decrease in the levels of receptors, this methylation may have made
individuals less tolerant to stress, favoring suicide. Another study
described, carried out in New Zealand, found that a different set of those
genes associated with depression seems to contribute to violent and
antisocial behavior in genetically vulnerable adults who suffered abuse
during childhood (Caspi et al., 2002).
There have been some animal studies which illustrate the effects of
early life adversity on the stress response. Rats with reduced maternal
care displayed an anxious phenotype and higher corticosterone levels in
response to stress. It was noted that the rats had reduced hippocampal
expression of glucocorticoid receptors as a consequence of increased
methylation at the gene promotor (Meaney and Syzf, 2005).
Barlow et al. (2020) put two models of interference between genes
and the environment. One is the diathesis-stress model, in which in­
dividuals inherit tendencies to express certain traits or behaviors that
can be activated when exposed to stressful experiences and the other
would be the model of the gene-environment correlation, suggested by
psychologists, who through several studies have found that the network
of interrelationships between genes and the environment is even more
complex than even the new discoveries imagined.
According to this model, the genetic load can increase the likelihood
that an individual will experience stressful events during life that,
consequently, will cause the activation of the gene. For example, people
with genetic vulnerability to develop a certain disorder, may also have a
personality trait, an impulsivity, which exposes them to environmental

Fig. 4. Epigenetic perpetuation of the impact of early life stress, adversity and trauma on behavioral phenotype. Epigenetic processes provide a framework for
understanding the biological mechanisms by which pre-natal and post-natal environmental events influence offspring behavior. Epigenetic modifications, such as
DNA methylation, can confer long-term phenotypic changes. Epigenetic processes are sensitive to the environment. As a result, environmental stress, adversity, or
trauma can trigger epigenetic modification across the developmental spectrum, from parental exposures that affect germ cells (pre-conception) to offspring exposures
stemming from the intrauterine and/or early postnatal environment. During development, there are critical biological windows in which environmental influences
are more likely to alter epigenetic processes and influence behavioral phenotype.

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M.F. Juruena et al.
Fig. 5. Conceptual Epigenetic Pathway: The Impact of Environmental Stress Leading to Depression.
risk factors that trigger the genetic vulnerability related to the disorder.
Genetic influences in general, are much less powerful than is believed.
The environment, even acting subtly, can shape and maintain itself in
the biological interactions that shape who we are. Epigenetics may
partly explain the mechanism by which environmental factors modulate
the risk of depression. DNA methylation patterns are heritable, possibly
explaining part of the heritability of depression. However, they are also
modulated by environmental exposure through the activity of a specific
group of enzymes called DNA methyltransferases and a number of
translocation family of proteins, responsible for DNA methylation and
demethylation, respectively (Klengel et al., 2014).
In a study HPA axis-coupled CpG sites were investigated in 88 in­
dividuals who had attempted suicide, researchers found methylation
shifts linked to the severity of suicide attempts. Two CRH associated CpG
sites were significantly hypomethylated in the high risk group (n = 31)
these epigenetic changes were noted in the CRH gene and related to
severity of suicide attempts (Jokinen et al., 2018).
Studies examining global genome methylation in depression
compared to healthy controls did not find consistent findings. Moreover,
the interpretation of alternations in global methylation levels would not
be easy under the pathogenetic point of view. Methylation candidate
gene association studies had sparse and often not replicated findings,
mainly because they do not capture the polygenicity of the disease. A
Mental disorders no longer have only one cause and come to be seen
with a multiplicity of causes, which combined, generate the greatest
vulnerability to depression. This vulnerability would be linked to envi­
ronmental and genetic factors, which are the basis for the emergence of
depressive episodes. The vulnerability to psychiatric disorders arises
from exposure to environmental factors during critical periods of brain
development. These processes of epigenetic regulation, which occur in
the interaction between environment and genes, are long lasting and can
be passed on to subsequent generations together with the genes to which
they are linked (Smoller et al., 2019).
7
Progress in Neuropsychopharmacology & Biological Psychiatry 109 (2021) 110231
9. Limitations
The role of epigenetics in the pathogenesis of depression remains
poorly understood so far, in terms of genetic regions/genes showing
abnormal methylation, differences between tissues, and causal mecha­
nisms responsible for the different methylation patterns seen in
depression compared to controls. Moreover, in the investigation of Early
Life Stress and depression, most studies used tests for assessing the HPA
axis preferentially assessing GR. In particular, probes that assess func­
tioning of both GR and MR should be used. A better understanding of the
mechanisms by which exposure to Early Life Stress leads to HPA axis
impairment and vulnerability to depression will allow new approaches
to early intervention, including, among others, targeted pharmacologic
and psychoeducational strategies. These is review is also limited, as do
not follow a systematic methodology or metanalysis, but reflect the
limitations in the field.
Future studies should approach risk factors for depression from
different levels of theoretical integration taking into full account the
environment versus gene interaction.
10. Conclusions
Early life stress impact in the brain, mind and body interface for
increased reactivity to adult stress life events resulting in multiple
adverse psychiatric and organic consequences. Stressful childhood
events and HPA axis overactivity in adulthood have been linked in
several studies. Epigenetic phenomena play a critical role in regulating
neural functions, so that the influences of the environment on the action
and expression of the genetic load remain in progress throughout life.
The epigenetic model however offers a general explanation for the
gradual construction of vulnerability, which begins with exposure to
harmful environmental factors in early periods of development, passes
through the modification of gene expression as a result of this exposure,
and reaches cell physiology and the functioning of the organism that
confer an increased risk for the development of the disease. Research has
M.F. Juruena et al.
postulated that epigenetic processes such as DNA methylation patterns
are heritable, possibly explaining part of the heritability of depression,
further research is required in this area.
Declaration of Competing Interest
MF Juruena Honorary Consultant at South London and Maudsley
NHS Foundation Trust (SLaM-NHS UK) supported by NIHR, BRC, SLaM-
NHS UK and Clinical Senior Lecturer at King’s College London. Professor
AH Young is the Director of the Centre for Affective Disorders and is
supported by the National Institute for Health Research (NIHR);
Biomedical Research Centre (BRC) at SLaM-NHS UK IoPPN, King’s
College London. Professor AJ Cleare is supported by NIHR, BRC and
SLaM-NHS UK. The views expressed are those of the authors and not
necessarily those of the NHS, the NIHR, or the Department of Health. MF
Juruena has within the last year received honoraria for speaking from
Janssen, Lundbeck, Libbs, Bionomics, EMS, and Daiichi Sankyo. AJ
Cleare has within the last 3 years received honoraria for lectures or
consulting from Astra Zeneca, Lundbeck, Livanova, Janssen & Allergan,
and a research grant from Lundbeck. AH Young received honoraria for
lectures and advisory boards for all major pharmaceutical companies
with drugs used in affective and related disorders. Investigator-initiated
studies from AZ, Eli Lilly and Lundbeck. R Gadelrab has no conflicts of
interest to declare. Only the authors were involved in the study design
and preparation of this report.
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