GLUCOCORTICOIDS AND MOOD

Status of Glucocorticoid Alterations in

Post-traumatic Stress Disorder
Rachel Yehuda
The Traumatic Stress Studies Program, Department of Psychiatry, The Mount Sinai
School of Medicine, New York, New York, USA
The PTSD Program at the James J. Peters Veterans Affairs Medical Center, Bronx,
New York, USA

The current status of glucocorticoid alterations in post-traumatic stress disorder (PTSD)

will be described in this chapter. Emphasis will be placed on data that suggest that at
least some glucocorticoid-related observations in PTSD reflect pretraumatic gluco-
corticoid status. Recent observations have provided some evidence that pretraumatic
glucocorticoid alterations may arise from genetic, epigenetic, and possibly other envi-
ronmental influences that serve to increase the likelihood of developing PTSD following
trauma exposure, as well as modulate attendant biological alterations associated with
its pathophysiology. Current studies in the fteld of PTSD employ glucocorticoid chal-
lenge strategies to delineate effects of exogenously administered glucocorticoids on
neuroendocrine, cognitive, and brain function. Results of these studies have provided
an important rationale for using glucocorticoid strategies in the treatment of PTSD.

Key words: acth; cortisol; depression; dexamethasone; glucocorticoid receptors

Introduction Hyperarousal symptoms, such as insomnia, ir-

The initial conception of post-traumatic
stress disorder (PTSD) as first described in the
Diagnostic and Statistical Manual of Mental
Disorders (DSM)-III was that this condition rep-
resented a universal human response to expo-
sure to extremely traumatic experiences, de-
fined as both markedly distressing, and unusual
or rare in a person’s experience.1 Three dis-
tinct, but co-occurring, symptom groups are
present in PTSD. Re-experiencing symptoms
are intrusions of the traumatic memory in
the form of distressing images, nightmares,
or dissociative experiences, such as flashbacks.
Avoidance symptoms include actively avoid-
ing reminders of the traumatic event, includ-
ing persons, places, or things associated with
the trauma, and more passive behaviors re-
flecting emotional numbing and constriction.
Address for correspondence: Rachel Yehuda, Ph.D., Bronx VA
OOMH, 130 West Kingsbridge Road, Bronx, NY 10468. Voice: 718-
584-9000 ext. 6964. Rachel.Yehuda@med.va.gov
Glucocorticoids and Mood: Ann. N.Y. Acad. Sci. 1179: 56–69 (2009).
doi: 10.1111/j.1749-6632.2009.04979.x § c 2009 New York Academy of Sciences.
ritability, impaired concentration, hypervigi-
lance, and increased startle responses, concern
more “physiologic” manifestations of trauma
exposure. In the DSM-IV , these symptoms
must impair social, occupational, or interper-
sonal function, and persist in tandem for at least
a month following the trauma.2
It was implicit in both the original and re-
vised definitions of PTSD that the most impor-
tant predictor of PTSD would be the type and
severity of trauma exposure. Reciprocally, the
presence of PTSD provided post hoc confirma-
tion of trauma exposure. The strong theoretical
link between exposure to events at the extreme
end of the stress response spectrum and PTSD
provided the rationale for hypothesizing that
biological alterations in this disorder, partic-
ularly those associated with glucocorticoids,
would be similar to those observed in basic sci-
ence models of stress.3
The normal fear response is characterized
by a series of biological reactions that help
the body cope with stress. Activation of the

56
Yehuda: Glucocorticoids in PTSD
sympathetic nervous system (SNS) and the re-
lease of adrenaline allow the organism to in-
crease its physiologic capacity for “fight-or-
flight” in response to threat 4 and facilitate
consolidation of the threat memory.5 The si-
multaneous activation of the hypothalamic-
pituitary-adrenal (HPA) axis, culminating in the
release of cortisol, helps contain the stress re-
sponse when the threat is removed.6 As stress-
activated biological reactions are suppressed as
a result of cortisol inhibition, elevated corti-
sol levels also exert a negative feedback inhibi-
tion at the pituitary, hypothalamus, hippocam-
pus, and amygdala—sites initially responsible
for the stimulation of cortisol release.7 Negative
feedback inhibition occurs due to the presence
of glucocorticoid receptors (GRs) and leads to
the restoration of basal hormone levels.8
Early biological studies in PTSD hypoth-
esized increases in both cortisol and cate-
cholamines. However, only the latter were
found to be elevated.9–11 The first neuroen-
docrine study of cortisol in PTSD demon-
strated lower 24-h urinary cortisol excretion in
PTSD compared to persons with other psychi-
atric diagnoses. 12 Although these results were
initially difficult to interpret, it soon became
clear that (1) only a minority of persons ex-
posed to trauma failed to recover from initial
fear reactions and move on to develop PTSD,
and that (2) traumatic exposures that had been
presumed to be rare were common occur-
rences.13–15 These epidemiologic observations
resulted in a paradigm shift with respect to the
conceptual link between trauma exposure and
PTSD.3,16 That is, rather than representing the
normative response to trauma, it seemed more
appropriate to describe PTSD as a failure to
engage the biological mechanisms associated
with recovery and physiologic homeostasis.16,17
This conceptual change provided an important
context for understanding glucocorticoid alter-
ations in PTSD. Indeed, if PTSD represented
a specific biological phenotype representing a
failure of recovery, lower cortisol levels could
represent an important biological correlate of
this phenomenon.
57
Glucocorticoid Alterations in
Chronic PTSD: Overview
Alterations of the HPA axis are a predomi-
nant feature of PTSD pathophysiology. While
there are exceptions in the literature, it appears
that PTSD is associated with a unique profile
in that corticotropin-releasing hormone (CRH)
levels appear to be increased18–20 while urinary
and plasma levels of cortisol are lower or at least
not elevated, compared to nonexposed persons
without PTSD.21–26 Increased cortisol suppres-
sion in response to dexamethasone (DEX) has
also been observed in most studies, reflecting an
enhanced negative feedback inhibition.27–39 An
important feature of this profile is that it differs
from that observed in acute and chronic stress
and depression, which has been classically asso-
ciated with increased CRH and cortisol levels,
reduced cortisol suppression to DEX, and re-
duced GR responsiveness.40–44
Indeed, it is presumed that the enhanced
negative feedback inhibition reflects a greater
responsiveness of the GRs, as suggested by
demonstrations of changes in GR number and
responsiveness in response to DEX administra-
tion and other challenges.35,45–47 Although it is
easy to reach the erroneous conclusion that the
lower cortisol levels reflect a less active HPA
axis, this does not appear to be the case. Circa-
dian rhythm of cortisol reflects a more dynamic
regulatory pattern, as confirmed by mathemat-
ical modeling of cortisol oscillations over the
diurnal cycle.22,48,49 Furthermore, hormonal
responses to naturalistic and laboratory provo-
cations suggest an exaggerated hormonal (and
subjective) response to stress.50,51 In some cases,
but more rarely, elevated cortisol levels have
been reported in PTSD. Together, these find-
ings imply that although cortisol levels may be
generally lower, the adrenal gland is certainly
capable of producing adequate amounts of cor-
tisol in response to challenge.52
Table 1 presents a summary of the biological
findings in PTSD that report on some aspect of
glucocorticoid function. While it is beyond the
scope of the paper to review each of the findings
58 Annals of the New York Academy of Sciences

TABLE 1. Compatibility of Findings in PTSD with in detail, it could be noted that almost all of the
Enhanced Negative Feedback Inhibition observations that have been made in relation to
Enhanced glucocorticoid alterations in PTSD are consis-
negative tent with the idea of enhanced responsiveness to
Finding in PTSD feedback glucocorticoids or increased GR sensitization.
Lower ambient cortisol yes Since most studies have been cross-sectional in
levels12,56,57,60,63,64,70,71,80–84 nature, and confined to persons with chronic
Normal or variable cortisol yes PTSD, it has been difficult to determine the ori-
levels20,35,54,62,65–67,72 gin of these alterations and the extent to which
Higher cortisol levels51,53,55,59,79 yesa they are central to PTSD pathophysiology.
Increased circadian rhythm of yes
cortisol48,58,60,69
Decreased circadian rhythm of cortisol86 no
Normal ACTH levels51,62,70,71,76 yes The Role of Glucocorticoid
Low β-endorphin levels69 yesb Alterations in PTSD
Increased corticotropin-releasing yes Pathophysiology
factor(CRF) levels in cerebrospinal
fluid19,20
Increased glucocorticoid receptor yes Though initial observations connected low
number57,68 cortisol levels and related findings of HPA axis
Increased glucocorticoid receptor yes alterations to PTSD pathophysiology, several
responsiveness46 converging findings suggest that these cortisol-
Normal cortisol levels following 1 mg yes
dexamethasone (DEX)33,54,73,74
related alterations may reflect a pre-existing
Decreased cortisol levels following 0.5 mg yes vulnerability trait that increases the probabil-
DEX28,35,37,39 ity of developing PTSD following trauma ex-
Increased cortisol levels following 1 mg no posure. In some longitudinal studies evaluating
DEX60,75 trauma survivors beginning in the immediate
Decreased number of cytosolic yes
glucocorticoid receptors following DEX
aftermath of exposure, there was an attenuated
compared to baseline receptors35 rise in cortisol immediately after the trauma in
Increased ACTH suppression following yes those at greater risk for developing PTSD or
DEX administration 30,36,38 who actually did develop PTSD.3 This finding
Increased ACTH levels to high dose yes has tended to be confined to samples evaluating
metyrapone58
cortisol in response to a similar event exposure.
Decreased ACTH levels to low dose no
metyrapone71 Thus, lower cortisol levels were associated with
Decreased ACTH levels following CRF61,72 yes prior assault in a study of consecutively appear-
Increased ACTH levels following no ing rape victims to an emergency room hours
CRF26,62,77,78 after rape.85 Lower cortisol levels were also ob-
Decreased ACTH levels following yes served in association with PTSD symptoms in
cholecystokinin (CCK)-470
Increased ACTH levels following no
a group of motor vehicle accident victims 86,87
naloxone76 and in 88
response to the natural disaster of an ice
Increased ACTH levels following stress51,76 yes storm. In contrast, cortisol differences were
Increased cortisol response to ACTH62 no not observed in a large cohort of civilians pre-
Decreased cortisol response to ACTH70 yes senting to the emergency department in re-
a Higher cortisol levels are only consistent with en- sponse to a wide range of events ranging from
hanced negative feedback to the extent that they represent terrorism to accidents based on the subsequent
transient elevations. development of PTSD.89 Possibly, such a dif-
bTo the extent that β-endorphin is co-released with
ferentiation requires a relatively homogenous
ACTH and reflects ACTH, this finding is compatible.
This table demonstrates that the model of enhanced sample with similar risk factors for exposure to
negative feedback is compatible with 18 of these 24 ob- a particular traumatic event or PTSD following
servations of HPA alterations in PTSD. that event.
Yehuda: Glucocorticoids in PTSD
Interestingly, in studies finding evidence of
low cortisol in association with PTSD or
PTSD risk, there was also evidence of greater
SNS arousal as reflected by catecholamine
levels.12,55,90–92 Other reports (in which cor-
tisol levels were not examined) also demon-
strated sympathetic arousal as determined by
increased heart rate.93–95 It may be that in-
creased SNS activation reflects an inadequately
contained acute stress response. In the above
study of civilians, neither lower cortisol levels
nor elevated catecholamines were observed in
the acute aftermath of trauma.89,96
That lower cortisol levels reflect PTSD risk
has also been supported by studies of individu-
als at risk for PTSD based not on trauma ex-
posure, but rather on the risk factor of parental
PTSD. Parental PTSD has been demonstrated
to increase the prevalence of PTSD following
trauma exposure by as much as threefold.97
In a sample of Holocaust offspring, lower cor-
tisol levels were also observed in association
with parental PTSD.98 Offspring of Holocaust
survivors with PTSD also showed significantly
enhanced cortisol responses to 0.50 mg DEX
compared to offspring of Holocaust survivors
without PTSD and demographically compa-
rable controls.99 In addition, urinary cortisol
levels were negatively correlated with severity
of parental PTSD symptoms, even after con-
trolling for PTSD symptoms in offspring. 100
The finding that low cortisol is associated with
parental PTSD was recently replicated in a co-
hort of infants of mothers exposed while preg-
nant to the World Trade Center attacks on
9/11/2001, in whom significantly lower sali-
vary cortisol levels were observed in the sub-
group of offspring born to mothers who de-
veloped PTSD from this event compared to
infants whose mothers did not.101
An attenuated cortisol response in the acute
aftermath of trauma in those at greater risk for
PTSD may result in a cascade in which there is
increased SNS activation, leading to an exag-
gerated catecholamine response to the trauma.
The resulting excess catecholamine response,
in turn, could initiate a process in which trau-
59
matic memories become “over-consolidated”
or inappropriately remembered due to an ex-
aggerated level of distress. 102,103 The primary
mechanism through which catecholamines fa-
cilitate memory formation is by maintaining
organisms at a high level of arousal. 5 This
response is modulated by adrenal steroids. 104
Thus, if there is insufficient cortisol signaling,
catecholamine-induced arousal might be pro-
longed and distress increased. 17 Both circum-
stances might impair memory consolidation or
lead to increased fear conditioning to more gen-
eralized stimuli. If low cortisol levels represent a
pre-existing characteristic reinforced by “over-
consolidation” at the time of the trauma, then
failing to properly contain the SNS response to
traumatic reminders could perpetuate the in-
trusive and hyperarousal symptoms of chronic
PTSD, leading to the elaboration of avoidance
symptoms that commonly occur in the disorder
even over years or decades.
The above discussion is important because
it suggests that cortisol levels (and related glu-
cocorticoid alterations) in PTSD reflect pre-
trauma characteristics. Thus, the role of gluco-
corticoid alterations in PTSD pathophysiology
may be more as precipitants or facilitators of
the disorder following trauma exposure than as
consequences of exposure per se. This formu-
lation is appealing because a central question
in trying to understand the biological basis of
PTSD as a response to extreme stress involves
resolving why only a minority of those exposed
develop the disorder. That there is a biologi-
cal vulnerability explains why some persons ex-
perience exaggerated arousal and distress and
move on to develop a condition characterized
by sustained arousal, while others are able to
achieve homeostasis in response to exposures
of similar magnitude.
Genetic and Nongenetic
Contributions to PTSD Risk
Because PTSD is a disorder precipitated
by exposure to an event, elucidating the
60
pathophysiology of this disorder requires de-
lineating molecular manifestations of environ-
mental impacts on gene activity. However, be-
cause there are clearly risk factors for PTSD,
some of which may be constitutional, it is im-
portant to consider a wide range of biologi-
cal contributors to the HPA axis alterations
that have been observed. These include ge-
netic polymorphisms, permanent changes in
gene expression resulting from epigenetic mod-
ifications, and transient and reversible changes
reflecting day-to-day alterations in biological
processes, as well as the role of ongoing environ-
mental perturbations on these latter processes.
The most compelling evidence for an as-
sociation between genetic factors and PTSD
has been provided by findings of an increased
prevalence of PTSD among trauma survivors
who also had a twin with PTSD compared to
trauma survivors whose exposed twin did not
develop PTSD.105–107 This was first demon-
strated in a cohort of combat veterans, in which
the risk for developing PTSD after trauma ex-
posure was significantly greater for monozy-
gotic than for dizygotic noncombat exposed
co-twins of PTSD-affected probands,106 and
then repeated in a population-based study in
civilians. These observations suggested that it
would be possible to detect specific suscepti-
bility genes for PTSD. Significant associations
were found with a variable number tandem
repeat polymorphism in an untranslated re-
gion of the dopamine transporter gene108 with
a reduced number of repeats in 93 chronic
PTSD patients compared with 95 non-PTSD
trauma survivors. In another study, no as-
sociation was found between two GR poly-
morphisms, N363S and BclI, and the diag-
nosis of PTSD in 118 chronic PTSD pa-
tients compared with 42 unaffected control sub-
jects, though PTSD patients homozygous for
the BclI GG genotype tended to be more re-
sponsive to a peripheral test of glucocorticoid
sensitivity (dermal vessel vasoconstrictor assay)
and displayed more severe PTSD symptoms.45
Both of these studies were comprised of rela-
tively small convenience samples. A more re-
Annals of the New York Academy of Sciences
cent observation has been the finding of an
interaction between childhood trauma expo-
sure and polymorphisms in FKBP5, a GR
chaperone gene.109 Reduced expression of this
gene would be consistent with increased GR
responsiveness.
The limited number of gene-related find-
ings in PTSD may reflect the complexity in-
volved in executing research in this area. Al-
ternatively, if the failure to find susceptibility
genes for PTSD continues, this may suggest
that PTSD risk is related to enduring pre-
traumatic changes that are not based on dif-
ferences in genetic polymorphisms, but rather
on differences in genes related to epigenetic
alterations. Epigenetic mechanisms offer the
possibility of defining pathways by which en-
vironmental risk factors might directly alter the
expression of a gene, thus forming a basis for in-
dividual differences in a function relating to the
gene and, perhaps, vulnerability to a disease or
disorder.
Epigenetics refers to a transgenerationally
transmissible functional change in the genome
that can be altered by environmental events
and does not involve an alteration of se-
quence.110,111 Methylation of polymerase II
promoters is an efficient way of gene si-
lencing and accordingly provides a concrete
molecular mechanism through which genetic-
environmental interactions occur.112 Such
mechanisms are likely to be highly relevant to
PTSD and might specifically explain the origin
of glucocorticoid-related alterations associated
with PTSD and PTSD-risk.
DNA methylation has been shown to be
a mechanism for programming the activity
of genes regulating HPA activity by early life
events (i.e., differences in maternal care),113,114
paralleling observations that early life events
are associated both with the development of
PTSD115–117 and the HPA axis alterations de-
scribed in this condition.21,118,119 Such changes
in rat pups result in permanent changes in hip-
pocampal GR expression and HPA function120
and provide a clear molecular link between
early environment and gene expression and
Yehuda: Glucocorticoids in PTSD
function. Interestingly, the alterations observed
are in the same direction as those described in
PTSD (i.e., increased GR sensitivity, enhanced
cortisol suppression to DEX, lower cortisol),
offering proof of principle that environmental
exposures can result in such changes. It is there-
fore possible that epigenetic alterations underlie
some of the HPA changes observed, particu-
larly in relation to parental PTSD, and there-
fore explain the stable neuroendocrine pattern
observed in PTSD. The extent to which epi-
genetic mechanisms are involved in other risk
factors thought to reflect more “constitutional”
alterations is not clear but remains an exciting
horizon for future investigations.
Stability of Glucocorticoid
Alterations in PTSD
If glucocorticoid alterations are related to
PTSD risk, it becomes important to under-
stand the extent to which such alterations can
be altered over time. Although some biological
risk factors associated with glucocorticoid al-
terations would be immutable (i.e., genotype),
others might not. To date, there are only a
few longitudinal biological studies examining
aspects of glucocorticoid alterations in PTSD
over time. Thus, it is not possible to know
whether some or all of the observed changes
are stable. However, this is an important emerg-
ing area. This question becomes particularly
interesting when the longitudinal trajectory of
PTSD symptoms is considered. The conven-
tional dogma of PTSD, at least in the early
years following the appearance of this diagno-
sis, was that it was a chronic and stable disorder.
However, PTSD may also be a dynamic disor-
der, with symptom severity reaching high and
low points depending on a wide range of factors
generally associated with concurrent environ-
mental stressors.
The initial observation of low cortisol in
PTSD was based on a longitudinal study ex-
amining cortisol levels at four intervals during
patient hospitalization. 12 This study empha-
61
sized the stability of both cortisol levels and
PTSD, yet in a follow-up, replication study, the
same authors reported marked lability of corti-
sol levels in association with symptom change
during specialized therapeutic programs, in
which there is an emphasis on reliving trau-
matic exposures.121 A recent longitudinal study
of Holocaust survivors also demonstrated that
in those whose symptom status remained rel-
atively unchanged over a 10-year period, cor-
tisol levels were highly correlated at Time 1
and Time 2.122 If anything, there were con-
sistent decrements in total mean 24-h cortisol
levels. This was particularly true in the group
that had developed PTSD at Time 2 but had
not had the disorder at Time 1. In the group
that recovered from PTSD by Time 2 after
having the disorder at Time 1, cortisol levels
increased.
If glucocorticoid alterations represent pre-
existing vulnerability factors that determine bi-
ological responses at the time of the trauma,
they may be stable measures or may not
change as PTSD symptoms change. Alterna-
tively, different components of the HPA axis
may be regulated differently, such that some
glucocorticoid-related alterations are more
trait-like, while others are more related to
symptom severity. Few treatment studies to date
have incorporated glucocorticoid alterations
before and after treatment as either predic-
tors of response (consistent with trait) or state-
measures reflecting symptom severity. In one
study, treatment responders to psychotherapy
showed increases in cortisol levels compared
to pretreatment levels, whereas nonresponders
continued to manifest lower cortisol levels. 123
These observations are consistent with our re-
cent data demonstrating lower cortisol in non-
responders at post-treatment compared to pre-
treatment with psychotherapy.124
Glucocorticoid Challenge Strategies
The increased responsiveness of the GRs re-
ported in PTSD may amplify the effects of
62
endogenous cortisol.16,21,44,125,126 A more clas-
sic understanding of low cortisol is that it re-
sults in reduced cortisol signaling.127 Direct
administration of cortisol provides a power-
ful challenge strategy to differentiate between
these two alternatives. Although there are only
a few studies examining the effects of exoge-
nously administered glucocorticoids in PTSD,
they are informative. When administered as
an intravenous bolus (17.5 mg), hydrocortisone
produced a greater decrease in corticotropin
(ACTH) in combat veterans with PTSD com-
pared to combat veterans without PTSD. This
finding suggests an exaggerated negative feed-
back effect of the GRs. 128 Similarly, a study
examining the effect of 30 mg of oral hydro-
cortisone on trace eyeblink conditioning also
demonstrated an exaggerated suppression ef-
fect in PTSD.129 Trace eyeblink conditioning
is a hippocampal-dependent associative learn-
ing task that is thought to reflect hippocampal
function. However, because it can be manipu-
lated by glucocorticoids, it is also a good probe
of GR responsiveness. In both of these studies,
hydrocortisone administration produced an ef-
fect directionally similar to the one produced
in comparison subjects, but it did so in a more
exaggerated manner.
The effect of hydrocortisone administration
on memory performance in PTSD has also
been examined. Here, interpretations of hydro-
cortisone’s effects are somewhat complicated by
the bidirectional effects of glucocorticoids on
memory performance observed in normal sub-
jects. Declarative and working memory were
measured in combat veterans who received the
i.v. bolus of 17.5 mg of hydrocortisone one
day, and placebo another day 2 weeks later
(in a randomized, double-blind design counter-
balanced for order). Hydrocortisone improved
performance in declarative memory in both
groups but preferentially improved working
memory only in combat veterans with PTSD,
such that there was no longer a group differ-
ence in performance as had been observed on
the placebo day.130 Furthermore, there was a
correlation between the extent of improvement
Annals of the New York Academy of Sciences
in working memory and the extent to which
hydrocortisone suppressed plasma ACTH lev-
els. The association between hydrocortisone’s
effects on cognition and endocrine measures re-
inforces the links among neuroendocrine status,
PTSD symptomatology, and measures of clini-
cal pathology in this disorder. Indeed, there are
numerous studies documenting working mem-
ory dysfunction in PTSD.
Assessment of regional relative glucose
metabolic rate (rGMR) in the hippocampus
and amygdala and discrete regions of in-
terest in the prefrontal cortex in response
to hydrocortisone and placebo was also per-
formed, measured by radio-labeled 2-deoxy-
2-[18F]fluoro-D-glucose positron emission to-
mography (18FDG PET).131 On the placebo
day, group differences in hemispheric lateral-
ity of rGMR were observed following placebo
administration, reflecting lower rGMR in the
right hippocampus and ventral amygdala, and
higher rGMR in the left ventral amygdala in
the PTSD group compared to the non-PTSD
group. Hydrocortisone administration reduced
these group differences in laterality, such that
hippocampal rGMR increased in the PTSD
group and decreased in the non-PTSD group.
Hydrocortisone also reversed laterality differ-
ences in rGMR in the amygdala. In the gray
matter of the anterior cingulate cortex (ACC),
hydrocortisone reduced rGMR in the PTSD
group and slightly increased metabolism in the
non-PTSD group, consistent with central glu-
cocorticoid responsiveness. The net effect of
hydrocortisone was to restore a normal inverse
association between the ACC and amygdala
in the PTSD group, but to disrupt this neural
network in the non-PTSD group. The magni-
tude of improvement in working memory cor-
related with greater hemispheric laterality in
the dorsal amygdala following hydrocortisone
in both groups. These findings indicate that
restorative effects of even a single dose of hydro-
cortisone on metabolism and working memory
provide a rationale for examining the therapeu-
tic benefits of glucocorticoids in aging PTSD
subjects.
Yehuda: Glucocorticoids in PTSD
Glucocorticoid Treatment
The idea that glucocorticoid administration
could be beneficial in PTSD might be sup-
ported by at least some of the neuroendocrine
alterations in this disorder. In reality, how-
ever, the therapeutic effects of glucocorticoids
in relation to PTSD were discovered by acci-
dent. Indeed, it was noted several years ago
that patients who received high doses of gluco-
corticoids (cortisone) for the treatment of sep-
tic shock were significantly less likely to suf-
fer from traumatic recollections of the event or
develop PTSD.132,133 Subsequent randomized
trials confirmed that the effects of glucocorti-
coids in the prevention of PTSD resulted from
decreasing the traumatizing effects of mem-
ory.134,135 These observations in trauma sur-
vivors led to an initial pilot cross-over study of
low-dose glucocorticoids that demonstrated a
significant reduction in chronic PTSD, which
the authors attributed to the effects of cortisol in
impairing retrieval of traumatic memories.136
Interestingly, animal studies have also con-
firmed the potential utility of cortisol-related
treatments in preventing “PTSD-related” con-
sequences of fear conditioning.137
Alternatively, it is possible that cortisol treat-
ment is an intervention that potentially offsets
the low cortisol observed in PTSD. If low cor-
tisol facilitates a pathologic neurobiology in
PTSD (i.e., through reduced cortisol signal-
ing, increasing exposure to endogenous cate-
cholamines, etc.),26,40,138,139 the administration
of cortisol over time might result in recalibra-
tion of HPA axis regulation. However, it is
probably more beneficial in this case to recal-
ibrate GR responsiveness more directly with
a GR antagonist. Although this has not yet
been tried in humans, in a recently developed
paradigm in which rats are exposed to single
prolonged stress (SPS), administration of a GR
antagonist prior to SPS exposure prevented the
normally observed potentiation of fear condi-
tioning in the amygdala, impaired long-term
potentiation in the hippocampus, enhanced in-
hibition of the HPA axis, and increased ex-
63
pression of GRs in the hippocampus. 140 In-
activating GRs in the amygdala post-retrieval
similarly blocked processing of the “trau-
matic memory” (i.e., behavioral response to
conditioning).141 Given the role of GRs in
both traumatic memory processing and PTSD
pathophysiology, it is reasonable to consider
approaches that include the use of GR block-
ers, such as mifepristone, in the treatment of
PTSD.
Conclusions and Future Directions
The volume of different, and sometimes dis-
parate, observations in PTSD suggest that glu-
cocorticoid alterations associated with the dis-
order are complex and may not be confined to
singular aspects of HPA axis functioning. Fur-
thermore, to the extent that glucocorticoid al-
terations reflect pretraumatic history, whether
genetic, epigenetic, or based on early envi-
ronmental exposures, there may be individual
differences in these alterations among persons
with PTSD. There is now strong evidence that
some features of glucocorticoid alterations in
PTSD may be altered prior to trauma expo-
sure, but the implications of this for under-
standing other aspects of glucocorticoid status
in PTSD are not clear. Future studies should ex-
amine how different components of HPA axis
alterations may be differentially regulated. The
next generation of studies should aim to apply
more rigorous tests of the neuroendocrinology
of PTSD based on developmental issues, the
longitudinal course of the disorder, and individ-
ual differences that affect these processes. No
doubt such studies will require a closer exami-
nation of a wide range of biological responses,
including the cellular and molecular mecha-
nisms involved in adaptation to stress, and an
understanding of the relationship between the
endocrine findings and other identified biolog-
ical alterations in PTSD. These latter studies
will contribute to the identification of targets
for intervention with glucocorticoid-related
treatments.
64
Acknowledgments
This work was supported by NIH: R01
MH064675-02, R01 MH64104-01, VA Merit
Funds, and DOD funds. The author wishes to
acknowledge Janelle Wohltmann, Casey Sara-
pas, Chuck Burton, and Michelle Pelcovitz for
assisting in the preparation of this manuscript.
Conflicts of Interest
The author declares no conflicts of interest.
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