Disease Markers 30 (2011) 77–87
Epigenetic aspects of posttraumatic stress
Ulrike Schmidt, Florian Holsboer∗and Theo Rein
Max Planck Institute of Psychiatry, Munich, Germany
and Neuro Novag GmbH, Munich, Germany
Abstract. Development of psychiatric diseases such as posttraumatic stress disorder (PTSD) invokes, as with most complex
diseases, both genetic and environmental factors. The era of genome-wide high throughput technologies has sparked the
initiation of genotype screenings in large cohorts of diseased and control individuals, but had limited success in identification of
disease causing genetic variants. It has become evident that these efforts at the genomic level need to be complemented with
endeavours in elucidating the proteome, transcriptome and epigenetic profiles. Epigenetics is attractive in particular because
there is accumulating evidence that the lasting impact of adverse life events is reflected in certain covalent modifications of the
In this review, we outline the characteristics of PTSD as a stress-related disease and survey recent developments revealing
epigenetic aspects of stress-related disorders in general. There is also increasing direct evidence for gene programming and
epigenetic components in PTSD.Finally, we discuss treatment options inthe light of recent discoveries of epigenetic mechanisms
of psychotropic drugs.
The term epigenome refers to the entirety of all
molecular control elements programming the genome
Accordingly, distinct epigenetic defects are reported
for a variety of diseases and some of them are already
known to constitute a main pathogenetic mechanism,
e.g. in patients suffering from Rett syndrome.
One of the major environmental factors established
as inducer of epigenetic changes is stress. Stress is
known to contribute to the pathogenesis of a variety of
disorders, including the majority of psychiatric disor-
order (PTSD). There is robust evidence for epigenetic
contribution to the development of PTSD-like symp-
toms in rodents while so far there are only few studies
epigenetic changes and the onset and perpetuation of
PTSD symptoms in humans. Generally, it is unlikely
∗Corresponding author: Dr. Florian Holsboer, E-mail: holsboer@
gle epigenetic modification, inasmuch as many differ-
ent genetic variants are conveyingdisease susceptibili-
ty. These diseases present with highly variable clinical
signs and symptoms but these diverse features cannot
be linked to specific genetic and epigenetic variations.
In fact it is likely that they derive from a complex web
of connected but different causes.
traumatic PTSD after having been exposed to a trau-
matic event . PTSD only occurs if a (yet still un-
matic stressor. This instantly forces the supposition
that the epigenome, especially in regard to its capacity
to mediate communication between environment and
genome, might grossly contribute to PTSD pathogene-
In this review the most important molecular epige-
for a better understanding of the following paragraphs
where the dynamic principle of the epigenome includ-
ing its reagibility to environmental factors and final-
ly the current state of knowledge regarding epigenet-
ic modifications in stress-related diseases, in particular
ISSN 0278-0240/11/$27.50 2011 – IOS Press and the authors. All rights reserved
U. Schmidt et al. / Epigenetic aspects of posttraumatic stress disorder
on the basis of the most recent publications.
2. PTSD as stress-related disease
The term stress was first employed in a biological
He later broadened and popularized his concept to in-
clude inappropriate physiological response to any de-
mand. In his usage “stress” refers to the condition
and “stressor” to the stimulus triggering the unphysio-
logical response. It covers a wide range of phenome-
na, from mild irritation to drastic dysfunction that may
cause severe health breakdown mostly occurring in re-
sponse to maximal stressors.
These maximal stressors are also termed traumata;
the term trauma derives from the greek word τραµα
meaning wound. A traumatic event involves a single,
enduring or repeating experience that seriously threat-
ens the physical or psychic integrity of the concerned
person. According to DSM-IV also witnessing a seri-
ous threat or the death of another person can be clas-
sified as a traumatic event, but in any case a horrible
experience can be categorized as a traumatic incident
only if the individuals exposed in the course of the
eventexperiencedfeelingsof helplessness andmassive
horror. The disability to cope or integrate the ideas
sense of being overwhelmed.
Symptoms usually arise weeks or months, in rare
cases even decades after traumatic experiences. More-
over, diagnosing PTSD includes the assumption that
not have been appeared. Thus, the stressor precipitat-
ed the onset of PTSD which is characterized mainly
by recurrent and intrusive distressing recollections of
the event (e.g. flashbacks), nervous hyperarousal and
trauma-stimuli associated avoidance anxiety each last-
ing more than one month, thus causing significant im-
pairment in social, occupational,or other important ar-
eas of functioning.
Like other stress-related psychiatric diseases PTSD
terations. The hypothalamus-pituitary-adrenal (HPA)
axis has been the main focus of neuroendocrine re-
search in PTSD .
Perception of stress leads to synthesis and release
of corticotropin-releasing hormone (CRH) and vaso-
pressin by hypothalamicnuclei which stimulate the se-
cretion of adrenocorticotropin(ACTH) at the pituitary
molecule exerts its actions on metabolism, immunity
and brain functions. Increased and prolonged produc-
tion of CRH and cortisol explain many of the behav-
ioral, circulatory, metabolic and immune manifesta-
with chronic stress, such as PTSD.
Transient HPA-system shifts were foundin a variety
of psychiatric diseases, e.g. it is an established find-
ing that manypatients sufferingfrom major depression
(MD) display a hyperactivity of their stress hormone
system . In contrast to patients with MD, manyau-
reflected for instance by lowered serum cortisol lev-
els [11,107] and an enhanced suppression of cortisol
in the DEX/CRH-test [101,107]. However, a recent
meta-analysis of 37 studies  found no differences
PTSD and controls. But interestingly, sub-group anal-
the female patient cluster exhibited significantly lower
cortisol levels in comparison to their respective con-
trol subgroups. Despite the limitation of differences
in data collection and assessment, that meta-analysis
clearly reveals the complexityand heterogeneityof the
neuroendocrineconcomitants of PTSD .
Besides the HPA-axis, also the sympathetic nervous
system (SNS) is a key circuit in PTSD pathophysiolo-
gy. Its major neurotransmitter norepinephrine (NE) is
animportantplayerinthe centralas well as inthe auto-
locus coeruleus and interacts in concert with CRH and
vasopressin to increase fear conditioning and memory
and epinephrine from the adrenal medulla, resulting in
an organismic alarm reaction. Thus, NE is involved in
the development of two main clusters of PTSD symp-
toms, namely re-experiencing symptoms and hyper-
arousalwhichis expressedinteralia withan exaggerat-
it is not surprising that the most consistent findings in
peripheral noradrenergicactivities [32,104].
Taken together, PTSD is a stress-related disease not
only because PTSD symptoms are precipitated by a
traumatic stressor but also because this severe psychi-
atric condition is accompanied by drastic alterations in
the two major stress hormone systems.
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