Childhood Adversity and Allostatic Overload of the HypothalamicPituitary-Adrenal Axis: A Vulnerability Model for Depressive Disorders
Development and Psychopathology 23 (2011), 1017-1037
Dr Paul O Wilkinson,
University Lecturer and Honorary Consultant in Child and Adolescent Psychiatry
Prof Ian M Goodyer,
Professor and Honorary Consultant in Child and Adolescent Psychiatry
Both authors:
University of Cambridge Section of Developmental Psychiatry
Douglas House
18b Trumpington Road
Cambridge. CB2 8AH
United Kingdom
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Abstract
Childhood adversity is associated with increased risk for onset of depressive episodes. This
review will present evidence that allostatic overload of the hypothalamic-pituitary-adrenal axis
(HPAA) partially mediates this association. The HPAA is the physiological system that regulates
levels of the stress hormone cortisol. Firstly, data from animals and humans has shown that
early environmental adversity is associated with long-term dysregulation of the HPAA. This may
occur due to permanent epigenetic modification of the glucocorticoid receptor. Secondly, data
from humans has demonstrated that HPAA dysregulation is associated with increased risk of
future depression onset in healthy individuals; and pharmacological correction of HPAA
dysregulation reduces depressive symptoms. HPAA dysregulation may result in corticoidmediated abnormalities in neurogenesis in early life and/or neurotoxicity on neural systems that
subserve emotion and cognition.
Keywords: Depression, cortisol, glucocorticoid receptor, allostasis, environmental adversity
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Homeostasis, Allostasis and Allostatic Overload
Homeostasis
The American physiologist Walter Cannon proposed and developed the concept of homeostasis,
building on Claude Bernard’s concept of the ‘milieu interieur’ (Cannon, 1932). Cannon
enunciated 4 principles: (i) Our bodies require mechanisms that act to maintain constancy. (ii)
Steady-state conditions require that any tendency towards change automatically meets with
factors that resist change. For example, an increase in blood sugar results in thirst as the body
attempts to dilute the concentration of sugar in the extracellular fluid. (iii) The regulating
system that determines the homeostatic state consists of a number of cooperating mechanisms
acting simultaneously or successively. For example, blood sugar is regulated by insulin,
glucagons, and other hormones that control its release from the liver or its uptake by the
tissues. (iv) Homeostasis does not occur by chance, but is the result of organized selfgovernment.
The concept of homeostasis has been interpreted literally to mean that the purpose of
physiological regulation is to clamp each internal parameter at a ‘setpoint’ by sensing errors and
correcting them with negative feedback (see Figure 1). Based on this model, physicians and
scientists reason that some internal mechanism must be broken when a parameter deviates
from its setpoint value. Consequently clinicians, including those in mental health, design
therapies to restore the ‘inappropriate’ value to ‘normal’.
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Allostasis
The homeostasis model has contributed immeasurably to the theory and practice of scientific
medicine. Yet, all scientific models eventually encounter new facts that do not fit, and it has
been argued that this is now the case for homeostasis. In physiology, evidence accumulates that
parameters are not constant. And their variations, rather than signifying error, are designed to
reduce error. Psychiatric illnesses have causes which the homeostasis model cannot explain. In
contrast to the hypertension caused by a constricted renal artery and the diabetes caused by
immune destruction of insulin-secreting cells, no mental illnesses present as yet with an
obviously defective neural mechanism. And treating these diseases with drugs or psychological
therapies to fix low-level mechanisms that are not ‘broken’ turns out not to work particularly
well. For example the most effective therapies for the treatment of acute depressions in
adolescents are associated with up to 30% non response even by 36 weeks post treatment
(Goodyer et al., 2007; Kennard et al., 2009).
The second model, allostasis (‘stability through change’), appears to take virtually the opposite
view (Sterling & Eyer, 1988). It suggests that the goal of regulation is not constancy, but rather
fitness under natural selection. Fitness implies preventing errors and minimizing costs to the
organism. Both needs are best accomplished by using prior information to predict demand and
then adjusting all parameters to meet it (Figure 1). Thus allostasis considers an unusual
parameter value not as a failure to defend a setpoint, but rather as a response to some
prediction. And the model attributes diseases such as depression to sustained neural signals that
arise from unsatisfactory social interactions. Consequently the allostasis model would redirect
therapy, away from manipulating low-level mechanisms, toward improving higher levels in order
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to restore predictive fluctuation – which under this model is the hallmark of health (Sterling &
Eyer, 1988).
Figure 1 about here
A key distinction of allostasis over homeostasis is therefore the ability of the organism to predict
response and minimise prediction errors, in order to retain behavioral fitness in the presence of
an alteration (good or bad ) in the environment either within itself or from without.
Allostasis provides a conceptual window for mechanistic studies to determine how individual
differences develop in metabolic systems including neurocognitive systems through, in part,
experience-dependent learning. From the physiological perspective, real or interpreted threats
from the environment rapidly (seconds) initiate the sympathetic–adrenal–medullary (SAM) axis
release of catecholamines and more slowly (minutes) the hypothalamic–pituitary–adrenal (HPA)
axis secretion of glucocorticoids that mobilize energy necessary for fight-or-flight responses
(Sapolsky, Romero, & Munck, 2000). A substantial proportion of these initiations come from
bottom-up neural reactions in emotion perception areas of the brain (amygdala-hippocampal
activations). Programming and coordination of allostasis depends on the brain’s evaluation of
bottom-up physiological signals regarding perceived threat and the top down execution (frontal
and prefrontal neural systems) of behavioral and physiological regulatory response. Such top
down control leading to a co-ordinated reaction to social threats was recently demonstrated in
rhesus monkeys, showing association between cortisol response and metabolism in the
subgenual prefrontal cortex, regardless of the context in which brain activity and cortisol were
assessed (A. L. Jahn et al., 2010). This primate data is likely to be one of many such integrative
research investigations we are likely to see over the coming decade, as researchers look for
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relations between peripheral physiological markers and controlling neural systems (that may
reflect allostatic regulation).
In our view allostasis does not replace homeostasis, but expands the latter concept. In particular
allostasis provides a model for understanding how prediction error can result in disrupted
outcomes. Experience-dependent learning, if efficient, will minimize prediction error for the
future management of adverse experiences. Poor learning may impair this ability and error risk
will increase when individuals engage in future social activities that require adaptation and
response. Thus set points in resting state parameters themselves may show individual
differences within a population (for example variations in blood pressure, peripheral glucose
levels or cognitive rumination style). What allostasis opens up conceptually is the ability to
investigate the mediators that effect change in the system that may reveal mechanistically how
an individual retains wellbeing or develops deviance or illness in the face of adversities. Of key
importance for successful allostasis is that the individual has a response strategy and can predict
from the environment when this strategy should be employed with the minimum of error to
ensure that change results in continued stability and wellbeing. Researchers in this field have
over the past decade turned their attention to how allostatic failures may compromise wellbeing
and promote ill health.
Allostatic load/overload
Maintaining physiological stability by changing parameters of the internal milieu by matching
them appropriately to environmental demands is not always successful. That is there may be
faulty learning from events, resulting in an increase in prediction error when considering future
experiences (a very simple cognitive illustration is: I had a bad experience the last time
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something like this happened and I will again). In particular, exposure to recurrent or chronic
adversities may accrue a repeatedly learned response whose effects become deleterious.
Pathological models can flow from this concept, grouped collectively as allostatic failures. How
might they come about? The terms allostatic load and overload were introduced to describe
how chronic over or under activity of mediators whose effects are designed to retain fitness may
lead to wear and tear within metabolic systems and eventually impaired functioning (McEwen,
1998). Compromising brain function in this manner will inevitable raise the risk for
psychopathology (McEwen & Gianaros, 2010).
There are a number of putative pathological processes that may arise from allostatic failure as
follows: i) Not predicting the need to evoke a response. (ii) Predicting the need but not turning
on an adequate response when required. (iii) Not turning off a normative response when it is no
longer needed; (iv) Not habituating to the recurrence of the same stressor and thus not
dampening the allostatic response.
Our own group has shown that allostatic failure exists in males with conduct disorder. They do
not show the expected hypothalamic pituitary adrenal axis (HPAA) response to threat which,
although recognized cognitively, does not result in the appropriate rise in peripheral cortisol
during a provoking video task (Fairchild, van Goozen et al. 2008). Furthermore male and female
adolescents with conduct disorder do not habituate to fear stimuli, decreasing the likelihood of
an adaptive behavior response to threats in the environment (Fairchild, Stobbe, van Goozen,
Calder, & Goodyer, 2010; Fairchild, Van Goozen, Stollery, & Goodyer, 2008). These constitute
examples of allostatic failures associated with a behavioral psychopathology. They do not reveal
whether they arise as a cause or a consequence of the antisocial behavior.
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What of those conditions where there is an overactivity of a putative allostatic mediator, such as
the frequently-reported HPAA over-activity (with loss of circulating cortisol diurnal variation) in
around 50% of unipolar depressions? Whilst adaptive acutely, chronic over-production of the
SAM and HPA axis products induces a ‘domino effect’ on interconnected biological systems that
include inflammatory processes, other endocrine systems (thyroid, dehydroepiandrosterone) as
well as a concatenation of putative effects within the cell. The allostatic overload is that
metabolic systems overcompensate and eventually function sub-optimally, leaving the organism
susceptible to stress-related diseases that may occur at different points in an individual’s life.
This gives an important developmental lifecourse trajectory to the impact of allostatic failures
(Lupien, McEwen, Gunnar, & Heim, 2009).
The rest of this review focuses on how allostatic failures may arise to increase the liability for
depressive disorders over the lifecourse. We have previously outlined some of the mechanisms
that may be operating in increasing the emergence of these mental disorders in the first two
decades of life (Goodyer, 2008). In this review we outline how exposure to chronic or recurrent
environmental adversities occurring in infancy and the preschool years leads to inappropriate
HPAA activity and thereby to allostatic overload. There is a decoupling of adaptive responses,
leading to further persistent HPAA over-activity, even after the environmental adversities are no
longer present. This leads to increased risks for affective illnesses.
We shall start by presenting evidence that early environmental adversity increases the risk for
depressions. We shall then describe the normal physiology and allostatic regulation of the
HPAA. We shall present evidence from animal and human studies that early adversity leads to
allostatic overload of the HPAA and discuss potential intermediate mechanisms. Finally, we shall
present evidence that HPAA dysregulation does increase vulnerability to depression and shall
again discuss potential intermediate mechanisms.
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Early Adversities and Risk for Depression Episode Onset
There has been over a century of theory, conjecture, observations and scientific study asserting
that a child exposed to relatively persistent adverse parenting styles in the infancy period and
the preschool years is at increased risk for mental illness over the first 4 decades of the
lifecourse. For example proven child maltreatment (physical, sexual or emotional abuse) of
sufficiently negative quality to require removal into the custody of the State is associated with
depression episode onset through to the end of the fourth decade (Widom, DuMont, & Czaja,
2007). Epidemiological studies have substantially supported the association between adverse
early experiences of various types and later psychopathology. For example a community survey
of over 9000 adults in San Diego demonstrated that multiple types of childhood adversity each
increased the risk for lifetime and recent depressive symptoms in adults. Adversities measured
included emotional abuse, physical abuse, sexual abuse, mother being battered, household
substance abuse, parental separation and a criminal household member (Chapman et al., 2004).
Such associations were significant for both men and women; remained significant when
adjusting for living with a mentally ill parent (thus removing the effects of a gene-environment
correlation – it may be the sharing of depressogenic genes with a parent that leads to
depression, not the environmental adversity); and showed a dose-response relationship, with a
greater number of types of adversity associated with a greater risk for depression.
Many studies have found a similar strong association (with a clear dose-response relationship
where measured) between childhood adversity and adult depressive symptoms (Goldberg,
1994; Surtees et al., 2006) and adult depressive disorder (Caspi et al., 2003; Kendler et al., 2000;
Parker, 1979). Recent findings from the National Comorbidity Survey Replication have shown
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that multiple types of childhood adversity are associated with first-episode onset and
persistence of a wide range of psychiatric disorders (including depression) (Green et al., 2010;
McLaughlin et al., 2010). Again, there was an additive dose-response relationship between
number of adversities and risk of disorder.
The association between early environmental adversity and later depressions is not, however,
straightforward. Statistical modeling in large epidemiological studies has demonstrated
mediation by multiple intermediate variables, potentially acting with different degrees of effects
at varying life stages. These include personality (neuroticism), low self-esteem, conduct
disorder, increased risk of adverse life events, low social support, substance misuse and
difficulties in interpersonal relationships (G. W. Brown, Craig, & Harris, 2008; Kendler, Gardner,
& Prescott, 2002, 2006). Classical studies of the social origins of depression in adult females
showed that both the quality and timing of adverse experiences are important in determining
the risk of depression episode onset (G.W. Brown & Harris, 1978). Longitudinal findings suggest
that common pathways exist within individuals with differing clinical phenotypes over time
(Kessler et al., 2010). These common pathways should be the focus of future research. These
studies have not reported measurements of HPAA activity, so we are unable to establish
whether HPAA abnormalities mediate the early adversity – adult depression association, nor
whether they mediate specific aetiological pathways. Therefore this review will rely on a two
stage indirect approach: is early adversity associated with HPAA abnormalities? And are HPAA
abnormalities associated with subsequent depression?
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Physiology of the Hypothalamic-Pituitary-Adrenal Axis
As part of the body’s generic, non-specific, response to acute threatening or demanding events,
there is a transient rise in cortisol levels. Cortisol regulates the body’s specific response to
stressors. Variations in cortisol at the cellular level alters gene transcription thereby changing
metabolism, mobilising the body’s energy resources; and increases cardiovascular tone
(Argyropoulos et al., 2002; Herbert et al., 2006).
The hypothalamic-pituitary-adrenal axis provides allostatic regulation of cortisol levels.
Neurones from the parvocellular nucleus (PVN) of the hypothalamus secrete corticotrophinreleasing hormone (a 41 amino acid peptide, sometimes known as corticotrophin-releasing
factor, CRF). CRH is secreted into the hypothalamo-hypophyseal portal venous system and is
transported to the anterior pituitary gland. CRH activates CRH1 receptors of pituitary
corticoprophic cells, which leads to release of adrenocorticorphic hormone (ACTH) into the
systemic circulation. ACTH stimulates production and release of the steroid hormone cortisol
(cortisone in rodents) by the cortex of the adrenal glands (Gillespie, Phifer, Bradley, & Ressler,
2009).
Most cortisol in the blood is bound to cortisol binding globulin (CBG). CBG acts as a high affinity,
low capacity reservoir, buffers natural fluctuations in cortisol, and in particular reduces the
amount of cortisol entering the brain (cortisol is very lipophilic, and so would otherwise freely
enter the brain). In the brain, cortisol is detected by cytoplasmic glucocorticoid (GR) and
mineralocorticoid (MR) receptors. GRs are widely expressed, particularly in the hippocampus.
Expression of MR receptors is more restricted, with highest concentrations found in the
hippocampus, amygdala and lateral septum. MRs have a 10-fold greater affinity for cortisol than
GRs (Herbert, et al., 2006).
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Cortisol is detected by GR and MR at the hippocampus, PVN and pituitary and this leads to
reduced CRH and ACTH secretion, acting as a negative feedback mechanism and damping down
the stress response (Gillespie, et al., 2009). In view of the lower affinity of GR compared to
MRs, GR-mediated negative feedback occurs at higher levels of cortisol. It is clear here that if
GR receptors do not respond optimally to changes in cortisol level, then negative feedback from
high levels will not function optimally. In these circumstances this leads to continued high levels
of CRH, ACTH and cortisol thereby risking allostatic overload. This is crucial in the context of this
review, which will argue that impaired MR/GR functioning may be a key mediator between early
environmental adversity and later depression.
Cortisol levels vary greatly both within and between within individuals. In particular there is a
diurnal pattern of cortisol regulation. In humans, cortisol levels rise in the later part of the night;
there is a further increase until about 30 minutes after waking (cortisol awakening response,
CAR) followed by a gradual reduction through the waking day (Herbert, et al., 2006). Cortisol
may be higher in the morning to encourage the organism to search for more carbohydrate and
novel experiences (Gunnar & Cheatham, 2003).
Young humans do not show the same patterns of diurnal cortisol variation as adults, partly
because of the pattern of irregular sleep and daytime naps in babies. Newborns show two
peaks in cortisol, 12 hours apart, not related to time of day (Gunnar & Donzella, 2002). The
single early morning peak is not reliably established until twelve weeks (Price, Close, & Fielding,
1983). Only after four years is there significantly higher morning compared with afternoon
cortisol (Gunnar & Donzella, 2002).
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Cortisol and ACTH are present in the systemic circulation. Levels can therefore be measured
from blood. Cortisol is present in bound and free form. It is the free form that is active and
which crosses the blood-brain barrier. Consideration needs to be made as to whether free or
total cortisol is measured. Cortisol is also released into the saliva. In humans salivary levels
accurately reflect free cortisol levels, that cross the blood-brain barrier. Salivary levels are about
5% of the blood levels and positively correlate with levels in the cerebrospinal fluid (Guazzo,
Kirkpatrick, Goodyer, Shiers, & Herbert, 1996). Measurement in saliva is more acceptable to
patients, and can also be done in their own homes, meaning collection can occur at multiple
times of day in large number of participants. CRH is present in the hypophyseal portal vein. This
can be directly accessed in animal, but not human, studies. In human studies, CSF CRH (from
lumbar puncture) is used to estimate portal CRH. However, it has been noted that CRH in the
CSF may come from a variety of sources, such as the prefrontal cortex and limbic system, that
are not part of the HPAA. Therefore CSF CRH may not accurately reflect HPAA CRH (Stetler &
Miller, 2011).
Hormone levels can be measured at single or at multiple times of day. Careful consideration is
needed as to the best time(s) to collect cortisol. Urinary cortisol and metabolites can be
collected over 24 hours to estimate total daily production. We can measure HPAA reactivity to
stress. In animals, multiple methods are used to elicit stress including restraint (Coplan et al.,
1996; Liu et al., 1997; Weaver et al., 2004), separation from peers (Levine & Mody, 2003), strong
puffs of air onto the cheek (Plotsky et al., 2005) and novel environments (McCormack,
Newman, Higley, Maestripieri, & Sanchez, 2009). In humans, it has been demonstrated that a
social stressor with both social evaluation and uncontrollability is most likely to raise cortisol
(Dickerson & Kemeny, 2004). A widely used social stress test in humans is the Trier Social Stress
Test (TSST), in which participants are given a mock job interview followed by a mental arithmetic
task in front of a panel of ‘experts’, which is videotaped for ‘later analysis’ (Kirschbaum, Pirke, &
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Hellhammer, 1993). HPAA response to this test is mediated by how much the participant
believes it and their own natural ability in/anxiety towards such tasks, not just HPAA reactivity.
A physiological stress test has been developed that is less likely to be confounded by such
cognitive/emotional factors: participants take in a single tidal breath of 35% carbon dioxide
(Kaye et al., 2004). This task is generally safe, with the most common adverse event being panic
attacks. Both the TSST and the 35% CO2 test lead to significant rises in cortisol in many, but not
all, participants. Their relative effectiveness in inducing changes in the HPA axis has yet to be
reported.
We may want to investigate GR functioning. The first widely used experimental method to test
receptor activity indirectly in humans was the dexamethasone suppression test (DST) (Pfohl,
Sherman, Schlechte, & Stone, 1985). 1-2mg of oral dexamethasone is given the night of the test.
The following day, peripheral cortisol, generally blood, is measured. If central GR function well,
they are activated by the dexamethasone, leading to negative feedback of the HPAA and
reduced cortisol production the next day. High cortisol suggests impaired GR sensitivity to
cortisol leading to loss of negative feedback. The development of the
Dexamethasone/Corticotrophin Releasing Hormone (CRH) test (Heuser, Yassouridis, & Holsboer,
1994) adds an additional physiological challenge by stimulating the system to produce cortisol
from the adrenal glands. 1.5mg of oral dexamethasone is given in the evening. The following
afternoon, 100μg CRH is infused intravenously. Cortisol levels are subsequently measured;
again, high cortisol levels indicating non-suppression of the HPAA suggesting impaired GR
functioning and escape from negative feedback. The DEX/CRH test better discriminates
depressed from non-depressed participants than the DST (Heuser, et al., 1994) but neither has
sufficient sensitivity and specificity to be of clinical utility. This indicates the difficulties of clinical
heterogeneity, not a fundamental flaw in testing the effectiveness of the HPAA.
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There is growing evidence for a genetic effect on the integrity of the HPAA. Polymorphisms of
the GR gene are associated with higher basal cortisol levels, in the morning, at bedtime and over
the whole day (Rautanen et al., 2006; Rosmond et al., 2000). Polymorphisms of the
glucocorticoid receptor gene and FKBP5 (an immunophilin involved in the regulation of GR) are
associated with increased cortisol secretion in the DST (Derijk & de Kloet, 2008; van Rossum et
al., 2002) and increased cortisol response to stress (Wust et al., 2004). Two intronic single
nucleotide polymorphisms in the CRH1 receptor gene (CRHR1) are associated with lower cortisol
response to the DEX/CRH test in healthy adults, but only in individuals with a history of
childhood adversity (Tyrka et al., 2009). Therefore variation in the genes controlling the
sensitivity of various components of the HPAA are likely to contribute to individual differences in
cortisol levels both at rest and at times of demand.
Early Adversity and Dysregulation of the Hypothalamic-Pituitary-Adrenal Axis
Rodent Studies
Laboratory studies in rats have shown that prolonged (>3 hours) separation from the mother
leads to raised ACTH and corticosterone in offspring (Stanton, Gutierrez, & Levine, 1988; van
Oers, de Kloet, Whelan, & Levine, 1998). Importantly studies have demonstrated that the
effects of this undesirable separation lasted beyond the separation period itself. Thus if
prolonged separation occurs in the first 10 days of life, there is greater ACTH and corticosterone
response to stress when pups are mature adults, implying a negative effect of early adverse
environment on the programming of the HPAA (Plotsky, et al., 2005). Interestingly, pups not
separated from the mothers at all have adult HPAA reactivity intermediate between those with
prolonged separation and pups who undergo a brief 15 minute separation each day (Plotsky, et
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al., 2005; Vallee et al., 1997). This latter observations indicates a potentially positive
programming effect of intermittent separation in infancy on mature rat HPAA functions. It has
been demonstrated that after rats are briefly separated from their mothers, there is greater
positive maternal behavior: licking and grooming of pups and arched-back nursing (LG-ABN) (Liu,
et al., 1997). Higher frequency of LG-ABN by mothers is correlated with lower subsequent ACTH
and corticosterone reactivity to stress when their pups are adults (Liu, et al., 1997; Weaver, et
al., 2004). In other words, active maternal care is implicated in the development of individual
differences in rodent HPAA axis sensitivity and perhaps in contributing to setting the 'resting
state level' of the HPAA.
Interestingly there is a stress hyporesponsive period (SHRP) in the first two weeks of a rat’s life,
where basal plasma corticosterone levels and HPAA response to stress are relatively low. This
may be to protect the immature brain from the effects of high corticosterone levels (Lupien, et
al., 2009; Sanchez, 2006). Presence of the mother seems to maintain the SHRP, partly by licking
and grooming behavior (Lupien, et al., 2009; Sanchez, 2006; Sanchez, Ladd, & Plotsky, 2001; van
Oers, et al., 1998). LG-ABN may be effective at reducing HPAA response to stress via two
mechanisms: maternal licking modulates ACTH activity and effective nursing leads to more milk
entering the gut, which leads to hypoactivity of the adrenal gland (Gunnar & Cheatham, 2003).
It is therefore possible that a lack of LG-ABN reduces the buffering from the SHRP, increasing
corticosterone and/or the developing brain’s vulnerability to corticosterone. This is an example
in rodent development of putative allostatic overload with poor maternal care leading to longterm HPAA hyperactivity.
Effects of low LG-ABN during infancy on the adult HPAA in the rodent are likely to be mediated
through a number of different mechanisms both in the brain and in the periphery. Rats exposed
to either low LG-ABN or no handling (and by implication absent LG-ABN) show multiple HPAA
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abnormalities including: greater ACTH following acute restraint stress after pre-treatment with
corticosterone (and hence reduced negative feedback from GR) (Liu, et al., 1997); lower
hippocampal GR mRNA and greater CRH mRNA expression in the paraventricular nucleus of the
hypothalamus (PVNh) (Liu, et al., 1997); greater CSF CRH (Plotsky, et al., 2005); higher CRH1
receptor binding and mRNA together with greater CRH mRNA and immunoreactivity at the
PVNh, central nucleus of the amygdala, bed nucleus of the stria terminalis and the locus
coeruleus/parabrachial nucleus (Liu, et al., 1997; Plotsky, et al., 2005). This suggests that the
mechanisms whereby a sub-optimal early environment leads to impaired glucocorticoid
receptor sensitivity is due in part to reduced GR levels in the hippocampus; and both higher
brain CRH levels and CRH1 receptor up regulation across brain regions.
Combining a randomization procedure within an experimental design demonstrated that rats
born to low LG-ABN but cross-fostered and raised by high LG-ABN mothers resemble pups of
high LG-ABN rather than low LG-ABN mothers in terms of fearfulness under conditions of
novelty (Francis, Diorio, Liu, & Meaney, 1999) and methylation of glucocorticoid receptor
(Weaver, et al., 2004). A strain of mice with more reactive HPAA has HPAA response to stress
(and behavioral impairments) attenuated by being fostered by a more resilient strain (Anisman,
Zaharia, Meaney, & Merali, 1998). Rats gently brushed for 15 minutes each day had lower
corticosterone and greater GR gene expression than an unbrushed control group
(Jutapakdeegul, Casalotti, Govitrapong, & Kotchabhakdi, 2003). These studies demonstrate that
mechanistic effects on offspring HPAA are indeed likely to be due in part to the environment
rather than gene-environment correlations. This demonstrates a dynamic allostatic process
within the infant that may have lifelong impact.
Several important caveats need to be made when trying to extrapolate the results of the above
studies in rats to humans: firstly, patterns of rearing and maternal behavior are clearly very
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different between rats and humans; results from primate studies may greater resemble what
happens in humans. Secondly, rats are born with much more immature brains and HPAA than
humans, and so stress in the early days of a rat’s life may model pre-natal stress in humans
(Lupien, et al., 2009; Owen, Andrews, & Matthews, 2005). Thirdly, and importantly, the above
studies model lack of positive nurturing, not the introduction of maltreatment experiences such
as physical abuse. Human applications are therefore better considered in terms of the effects of
emotional neglect rather than physical or sexual abuse as is often assumed.
Primate Studies
Primates more closely resemble humans both in terms of maternal behavior and maturity at
birth. Caregiving is very involved, both in infancy and also into the primate equivalent of
adolescence. As well as complex parent-offspring relationships, there are important effects on
development from the wider social environment including relatives and the peer group
(Sanchez, 2006).
In primates, separation from the mother leads to greater screaming and coo calls than in nonseparated controls (Dettling, Feldon, & Pryce, 2002; Sanchez et al., 2005). It also leads to higher
cortisol levels in plasma (Bayart, Hayashi, Faull, Barchas, & Levine, 1990; Levine, 1993; Levine &
Wiener, 1988; Lyons, Martel, Levine, Risch, & Schatzberg, 1999; Sanchez, et al., 2005), and urine
(Dettling, et al., 2002). There may be a stress hyporesponsive period in primates as with
rodents, with less of a rise in cortisol in response to stressful situations if the mother is present,
compared to if the infant and mother are separated (Sanchez, 2006). The separated-control
difference in plasma cortisol was present in female, but not male, monkeys in one sex-
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differentiated study (Sanchez, et al., 2005). The authors suggested that sex steroids may
moderate the response of the HPAA to stress but there was no measurement of sex steroids to
test this postulate.
Primate infants separated from their mothers and raised with peers have greater HPAA activity
in adulthood in response to separation stress (Heim & Nemeroff, 1999). A small number of
primate mothers are actively abusive to their offspring, with behaviors that include dragging,
crushing, hitting and biting the infant (Maestripieri, 1998). When infants of abusive and nonabusive mothers had basal cortisol/ACTH and hormone response to CRH challenge tested every
6 months up to 3 years of age, there were no effects of abuse on basal levels. However,
following CRH challenge, offspring of abusive mothers had greater cortisol increase, but also a
greater reduction in ACTH, than non-abused comparison offspring (Sanchez et al., 2010).
Cortisol rise was also greater in abused female than male offspring. The authors postulated that
ACTH fell more in abused monkeys due to the effects of negative feedback from the rapid rise in
cortisol.
In addition, early adversity has been shown to exert effects on the integrity of glucocorticoid
receptor sensitivity in primates: infants with or without repeated separation from their mothers
were given a modified cortisol / CRH test in adulthood. Monkeys who were separated in infancy
showed greater suppression by pre-treatment with cortisol of the ACTH response to CRH,
suggesting greater GC receptor sensitivity (Lyons, Yang, Mobley, Nickerson, & Schatzberg, 2000).
Serotonin is a key monoamine system that modulates emotion, including inhibiting responses to
mood in rodents and primates (Cools, Roberts, & Robbins, 2008). There is considerable evidence
in rodents and primates for a neurobiological interaction between HPAA and serotonergic
systems of relevance to psychopathology (Goodyer, 2008; Goodyer, Bacon, Ban, Croudace, &
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Herbert, 2009). The serotonergic system may influence allostasis and the risk for allostatic
overload, via the HPAA in primates: Infants of abusive mothers show a greater cortisol response
to stress when 6 months old than infants of non-abusive mothers. This increase is moderated by
variations in serotonin transporter genotype (5HTTLPR), with l/s abused infants showing a
greater rise in cortisol than l/l abused infants (McCormack, et al., 2009). l/s peer-raised
macaques have greater ACTH response to separation stress at six months than l/l peer-raised
and all mother-raised macaques (Barr et al., 2004). Overall these studies point to the notion
that in some primate species there are genetic influences on the liability for offspring to respond
adversely to maternal separations and abusive maternal events. Thus homeostasis, allostasis
and the putative effects of allostatic overload are likely to vary with gene variants within
offspring. This suggests that individual differences in HPAA function, particularly at times of
demand, are moderated by genes.
The notion that early adversities in infancy are associated with HPAA deficits expressed via
cortisol hypersecretion are not consistently reported across all studies. Indeed some authors
have reported opposite findings, with early trauma being associated with reduced adult HPAA
activity. Thus Sanchez and colleagues demonstrated that separated monkeys showed flatter
diurnal cortisol rhythm 6 months later than controls, accounted for by lower morning cortisol in
separated monkeys (Sanchez, et al., 2005). The authors concluded that this study demonstrated
that repeated rises in cortisol in early life led to down-regulation of components of the HPAA.
Mothers with inconsistent requirements on how hard they must work to obtain food (variable
foraging demand, FD) show inconsistent, erratic, sometimes dismissive rearing behavior to their
infants, similar to the poor attachment behavior of some human mothers (Rosenblum &
Andrews, 1994). When these monkeys were later put under restraint stress as adolescents,
those whose mothers who had variable FD had higher CSF CRH, but lower CSF cortisol than
20
control monkeys reared by mothers with stable FD (Coplan, et al., 1996). Similar results were
found by other groups: monkeys removed from their mothers at six months of age had lower
cortisol response to peer-separation stress at 2 years and 3 years than non-separated controls
(Levine & Mody, 2003); VFD-reared macaques had lower CSF CRH than controls two years after
differential rearing (Mathew et al., 2002).
Reasons for these apparently contradictory findings are unclear. Timing of stress may be
important: when variable foraging demand begins at 10-12 weeks, there are increases in adult
CSF CRH; when VFD begins after 18 weeks, there is subsequently lower CSF CRH (Carpenter et
al., 2004). Genotype may moderate HPAA response to stress (McCormack, et al., 2009). In small
studies, genotypes may not be balanced between groups and so may confound results.
Human Studies
Exposure to stress in the first week of human life leads to a rise in cortisol. The rise in cortisol is
positively associated with the personal impact of the situation, with circumcision leading to a
larger rise than a medical examination (Gunnar, 1992; Gunnar, Fisch, Korsvik, & Donhowe,
1981). At 12 weeks of age, being taken out of the bath leads to an increase in cortisol and
maternal behavior does not influence this response. However, infants with mothers who were
more sensitive and less interfering in their behavioral style had a more rapid reduction of
cortisol back towards normal levels after this initial rise (Albers, Riksen-Walraven, Sweep, & de
Weerth, 2008). Over the first year of life, the extent of cortisol rise in response to stress in
general reduces in offspring of both sexes (Gunnar & Cheatham, 2003). This seems however to
be moderated by parenting quality: cortisol response to stress only reduces with age if
caregivers are responsive, and/or the infant has secure attachment (Gunnar & Cheatham, 2003).
21
Leaving 9 month olds with a sensitive and attentive babysitter has no effect on cortisol levels;
however leaving an infant with a babysitter who is not attentive when the child is not distressed
leads to a rise in cortisol (Gunnar, Larson, Hertsgaard, Harris, & Brodersen, 1992). This seems
to suggest that HPAA function in normal infants is sensitive to the style of caring more than who
delivers that care, at least with regards to brief separations and substitutions.
A common frequent separation that children are exposed to is pre-school care at a nursery.
Three/four year old children show the normal fall in cortisol from morning to afternoon if they
are at home, but a rise from morning to afternoon if they are in daycare (Dettling, Gunnar, &
Donzella, 1999; Tout, de Haan, Campbell, & Gunnar, 1998). The rise is cortisol is greater in
daycare centres with lower quality of care (Tout, et al., 1998); in addition, there is a greater rise
in cortisol in children having home-based non-parent care if quality of that care is poor (Dettling,
Parker, Lane, Sebanc, & Gunnar, 2000). Such a dose-response effect of poor quality day care
makes it more likely that it is the stress of separation from parents and receiving poorer quality
daycare that leads to an elevation of cortisol, rather than simply being separated.
Daycare leads to a greater rise in cortisol in children with higher negative temperament, but this
effect is only seen in low quality childcare (Dettling, et al., 2000). As temperament is under
strong genetic influence (Plomin et al., 1993), this suggests a possible gene x environment
interaction. Other research has also demonstrated negative temperament to be associated with
higher cortisol in response to stress (Kagan, Reznick, & Snidman, 1987).
Depressed children living in current conditions of environmental adversity have higher ACTH
response to CRH than depressed children with past abuse but current stable environment
(Kaufman et al., 1997). It is not just quality of care from adults that is associated with HPAA
activity: rejection by peers at pre-school is also correlated with higher cortisol levels (Gunnar &
22
Donzella, 2002). Current environment influences morning cortisol levels of 6-10 years olds:
lower socio-economic status and higher maternal depressive symptoms are correlated with
higher cortisol (Lupien, King, Meaney, & McEwen, 2000).
Such effects of early environmental adversity may last after the adversity has finished. Postnatal
depression, itself associated with poorer quality maternal care, is associated with higher cortisol
at the age of 3; and this association is strongest for depression in the first year of the infant’s life
(Gunnar & Donzella, 2002). Romanian orphans who had lived in an orphanage for more than 8
months of their life had higher cortisol levels throughout the day than early-adopted Romanians
or Canadian parent-reared children 6 years after adoption. There was a clear dose-response
effect, with higher time in an orphanage correlated with higher cortisol (Gunnar, Morison,
Chisholm, & Schuder, 2001). Pre-pubertal children with past maltreatment and current PTSD
had higher 24 hour urinary cortisol than non-maltreated comparisons, with duration of
maltreatment again correlated with cortisol (De Bellis et al., 1999). 13 year olds exposed to
maternal post-natal depression had higher and more variable morning cortisol than
comparisons who were not exposed to maternal post-natal depression, a finding not
confounded by current maternal depressive symptoms (Halligan, Herbert, Goodyer, & Murray,
2004). Adult women who had been sexually or physically abused as children had higher ACTH
and cortisol responses to a psychosocial stress test when adults compared with non-abused
comparisons (Heim et al., 2000). The type of maltreatment may be relevant to HPAA
dysregulation: in one study that carefully delineated the type of maltreatment, only children
with both sexual and physical abuse had higher (morning) cortisol than non-maltreated
comparisons there was no significant maltreated-comparison difference if maltreatment was
physical or sexual alone, or emotional/neglect (Cicchetti & Rogosch, 2001a).
23
There may be direct effects of the early environment on the control mechanisms of the HPAA
axis. For example early adversity may increase HPAA activity by directly promoting persistently
high central corticotrophin releasing hormone (CRH) secretion, leading to increases in cortisol
production from the adrenal glands. High CSF CRH in adults (healthy, with depression and with
personality disorders) has been shown to be associated with a history of childhood abuse
(Heim, Newport, Mletzko, Miller, & Nemeroff, 2008; Lee, Geracioti, Kasckow, & Coccaro, 2005),
general environmental adversity (Carpenter, et al., 2004) and low parental care (Lee, Gollan,
Kasckow, Geracioti, & Coccaro, 2006). High CRH itself may arise due to glucocorticoid receptor
(GR) down-regulation, as evidenced by the finding that childhood abuse (Heim, Mletzko,
Purselle, Musselman, & Nemeroff, 2008; Rinne et al., 2002) and parental loss (Tyrka et al., 2008)
are associated with higher cortisol response to the dexamethasone/CRH challenge test in adults
with and without depression. Abused women with major depression have lower GR binding
than healthy comparisons (Heim, Newport, et al., 2008).
However, some studies have shown opposite findings, with early adversity associated with lower
HPAA activity. Children living in neglected environments either at home (Gunnar & Cheatham,
2003) or in Romanian orphanages (living in conditions of great emotional and physical privation)
(Carlson & Earls, 1997) have been demonstrated to have flattened cortisol circadian rhythm,
with lower morning cortisol, and hence a much smaller fall in levels across the day. Armenian
adolescents living closest to the epicentre of the 1988 earthquake had lower morning salivary
cortisol levels and greater suppression of cortisol from dexamethasone five years after the
earthquake than those living further away (Goenjian et al., 1996). 12-16 year old girls with a
history of prior abuse but no history of depression had lower cortisol response to a psychosocial
stress-test than non-abused comparisons (MacMillan et al., 2009).
24
De Bellis has hypothesized that a possible reason for lower basal cortisol several years after
trauma is that at the time of trauma, there is a great increase in central CRH, and therefore
peripheral cortisol. There is subsequent compensatory pituitary CRH receptor down-regulation,
and thus lower ACTH (and cortisol). However, the HPAA is primed to be hyper-responsive to
later stress (De Bellis, 2002). Partial evidence for this theory comes from blunted ACTH
response (alongside normal cortisol response) to CRH in people several years after abuse (De
Bellis et al., 1994).
Age of adversity exposure may influence direction of effects, with adult CSF CRH positively
correlated with environmental adversity before the age of six but negatively correlated with
environmental adversity both in the perinatal period and between the ages of 6 and 13
(Carpenter, et al., 2004). Conversely, CSF CRH was found to be higher in adult women who had
childhood physical or sexual abuse after the age of six compared with before the age of six
(Heim, Newport, et al., 2008). When multiple age groups were tested, there was an association
between low socio-economic status and high morning cortisol only in elementary school (pre-11
years) and not in high school (post-11 years) children (Lupien, King, Meaney, & McEwen, 2001).
Pubertal stage at the time of testing may influence direction of results, possibly due to the
differing hormonal environment (MacMillan, et al., 2009).
A significant limitation of comparing the effects of early adversity on cortisol in studies recruiting
participants from different ages is the cross-sectional nature of such studies, and the fact that
other differences between studies may account for different results at different ages. One
longitudinal study has followed up cohorts of sexually-abused 6-16 year old females and nonabused comparisons over 16 years, and compared resting cortisol levels in mid-morning
(0900hrs-1000hrs) between groups at multiple time points (Trickett, Noll, Susman, Shenk, &
Putnam, 2010). There were two important findings: cortisol was higher in abused females than
25
non-abused comparisons up to when they were aged 15, and lower in abused females than
comparisons at older ages; cortisol was higher in abused females up to 6 years after the abuse
was reported but lower in abused females more than 6 years later. This supports De Bellis’
theory of compensatory CRH receptor down-regulation in the years following trauma (De Bellis,
2002).
Whilst these studies are demonstrating associations between early adversity and associated
changes in the HPAA, there is as yet no clear data to support a main effects model.
Several studies have shown that HPAA activity is different in people with histories of depression
and abuse compared to people with past abuse but no depression. This may reflect either the
effects of the depressed state on the HPAA; or effects of biological risk factors that both
increase the risk for depression and influence the HPAA. The physiological impact of adversity
may be mediated via effects on psychological function. For example in a factorial design, 49
healthy women were split into four groups, categorized by presence/absence of childhood
abuse and presence/absence of current depression, and underwent a psychosocial stress
challenge (Heim, et al., 2000). Rise in ACTH was significantly higher in the two abused groups
compared to the non-abused groups. However on re-analysis, cortisol rise was significantly
higher in the depressed/abused group than all three other groups (which were not significantly
different from each other), suggesting that environmental adversity on its own may not be
enough to lead to greater cortisol reactivity to stress; other factors (depression itself, or factors
which increase risk for depression) are also needed.
The same group used a similar factorial design to investigate the effects of early abuse and
current depression on HPAA response to hormonal challenge in adult females (Heim, Newport,
26
Bonsall, Miller, & Nemeroff, 2001). Women with a history of abuse but no depression had
higher ACTH response to CRH than non-depressed, non-abused comparisons. However, both
depressed groups (with and without abuse) had lower ACTH response to CRH than comparisons.
Both depressed groups (in particular the group with prior abuse) had significantly blunted
cortisol response to both CRH and ACTH. This suggests that early abuse may lead to greater
sensitization of the pituitary to CRH; however this mechanism does not take place during
depressive episodes – either state related features of the depressive state or other biological
variables associated with risk for depression dampen down such hypersensitivity. However,
there may still be down-regulation of the glucocorticoid receptor in depression + abuse, as
demonstrated by the fact that adult men with a history of childhood abuse have higher cortisol
response to the dexamethasone/CRH challenge test than non-abused comparisons; and this
effect is strongest for men with abuse and current depression (Heim, Mletzko, et al., 2008).
Similar results have been found in pre-adolescent children. An advantage of recruiting children
is that samples can be recruited with objective evidence of abuse, as documented by child
protection services. This is likely to define abuse history more objectively and accurately than
adulthood memories. Cichetti’s group have recruited serial samples of abused children and nonabused comparison children, matched for social deprivation, to summer camps and collected
cortisol in controlled conditions, at exact times of day, on multiple days. In one study, they
found that children with histories of maltreatment and current high internalizing symptoms had
higher morning and afternoon cortisol than those with maltreatment alone, current internalizing
symptoms alone or neither; and these latter three groups were not significantly different
(Cicchetti & Rogosch, 2001b). However, contrasting results have been found, even by the same
research group using similar methodology: one study demonstrated that children with both
physical and/or sexual abuse and high internalizing symptoms had a flatter diurnal cortisol slope
(ie less of a reduction in cortisol between morning and afternoon, partly due to lower morning
27
cortisol) than children in other groups; however, this was only present in those children who
were physically/sexually abused in the pre-school period (Cicchetti, Rogosch, Gunnar, & Toth,
2010). An earlier study suggested that morning cortisol was lower in maltreated children with
high depressive symptoms compared with maltreated children with lower depressive symptoms,
although the difference was not statistically significant (Hart, Gunnar, & Cicchetti, 1996). This
group have conceded that a limitation of their methods is that cortisol sampling at 09.00hrs
misses the awakening cortisol peak and so may not accurately estimate this key measure. An
independent team also found that morning cortisol was lower in depressed maltreated children
than those in other groups (Kaufman, 1991). These studies suggest a complex interplay
between adversity, and its timing, and symptoms in the aetiology of HPAA dysfunction.
These studies do demonstrate the clear possibility that the physiological consequences of severe
recurrent and/or chronic early adversities may indeed be mediated through psychological
processes, with the HPAA changes arising secondarily to the activation of psychopathology. It is
also possible that risk factors that increase the risk of psychopathology (possibly genetic) also
increase HPAA dysregulation. From the psychiatric perspective, we need better confirmation
from prospective designs that there are HPAA vulnerabilities that exert effects on activation of
an episode of mental illness.
A key limitation of most of the above studies is that they simply measure resting cortisol. This
may not be the best marker of the HPAA dysfunction that is induced by environmental adversity,
and which may increase the risk of depression. As stated by De Bellis (2002), there may be
compensation in the years after abuse to make sure that resting cortisol levels are normal, or
even lower. However, at times of stress, or immediately after awakening, there may be a
greater rise in cortisol, possibly as a result of glucocorticoid receptor down-regulation.
Differences between samples, including age, years since abuse and presence of psychiatric
28
illness, may lead to differences in degree of compensation of resting cortisol levels, rather than
underlying GR function.
Genetic moderation of the influence of early adversities on HPAA function
In the 1990s Lesch and colleagues suggested that genetic variation in the serotonin transporter
gene (5HTTLPR, which partially moderates the rate of serotonin transporter synthesis) may
reveal individual differences in mood states, including depression and anxiety (Collier et al.,
1996). In recent years there has been considerable interest in characterizing molecular genetic
vulnerability for psychopathology, in particular whether genotype moderates the effects of
environmental adversity on psychopathology. For example being a carrier of one or both short
form alleles of 5-HTTLPR is strongly positively moderates the association between depression
and childhood maltreatment (P = .00007). But there is only marginal evidence that 5-HTTLPR
moderates the association between depression and acute stressful life events (P = .03) (Karg,
Burmeister, Shedden, & Sen, 2010). This risk is particularly apparent when the environmental
effects are assessed utilizing qualitatively comprehensive interview methods rather than brief
life event checklists (Uher & McGuffin, 2010). This is unlikely to be a ‘bad’ gene (Belsky et al.,
2009; Homberg & Lesch, 2010); rather this short form conveys greater differential sensitivity for
response to environmental demands than the wild type long ‘l’ form. The hypothesis therefore
is that following exposure to adverse environments, the ‘s’ carriers will show a dose response
effect on risk for psychopathology with homozygous s/s being most susceptible and
homozygous l/l least. Whether there is a main effect of gene variant on a physiological system
such as HPAA, and therefore indicating a putative variation in allostasis and therefore allostatic
overload, has only recently begun to be investigated.
29
To date there have been only a few reports of genetic moderation by serotonergic genes on the
HPAA. What evidence there is suggests that in adolescents at known high psychosocial risk for
psychopathology, there is a dose response effect of the 5HTTLPR gene variant on circulating
morning cortisol, with levels being incrementally higher with none, one or both copies of the
short ‘s’ form of the allele in both sexes (Goodyer, et al., 2009). A positive association between
peripheral cortisol levels and s/s genotype has also been reported for older adults (O'Hara et al.,
2007). Using an experimental stress paradigm, it has been demonstrated that 9-14 year old
girls with s/s 5HTTLPR genotype have greater cortisol response to a psychosocial stress test
than girls with l/l or l/s variant (Gotlib, Joormann, Minor, & Hallmayer, 2008). Alexander and
colleagues found no main effects of either 5-HTTLPR genotype or earlier severe stressful life
events on HPAA (Alexander et al., 2009). However, there was a significant gene x environment
interaction: men with the combination of s/s and prior stressful life events had significantly
higher cortisol rise after stress than the other groups. This somewhat mirrors the primate study
described earlier which demonstrated that l/s abused infants had a greater rise in cortisol than
l/l abused infants (McCormack, et al., 2009), implying a moderating effect of the 5HTTLPR s
allele.
The evidence such as it is to date supports the notion that gene variants in 5-HTTLPR moderate
the effects of the social environment on HPAA activity, probably over the lifecourse. This makes
theoretical sense and is biologically plausible given the key role of serotonergic mechanisms in
the brain for modulating behavior, both in resting state and under stressful circumstances.
There is no reason to assume any specificity in genetic moderation of HPAA. For example gene
variants in Brain Derived Neurotrophic Factor (BDNF) have recently been shown to exert
differential effects on the liability of subsequent depression via an interaction with cortisol. Well
30
adolescents of either sex carrying the common wild type Val/66/Val BDNF variant show
increased levels of subsequent unipolar depression, but only in the presence of higher levels of
morning cortisol (Goodyer, Croudace, Dudbridge, Ban, & Herbert, 2010). This BDNF x cortisol
interaction was independent of the known interaction between 5HTTLPR s carriers and morning
cortisol in the same sample. BDNF is a developmentally-sensitive peptide with a key role in
promoting brain development and neural plasticity. These findings need replication before any
substantive implications for HPAA integrity and allostatic mechanisms can be drawn.
Nevertheless the findings illustrate the importance of examining the contribution and effects of
biological systems that are involved in brain development and behavior in influencing the
integrity and function of the HPAA.
Overall these findings suggest that allostatic overload and failure may be partially dependent on
gene variants outside of the genetic variation that is directly responsible for the control,
production and release of cortisol. These findings should also inform future research on HPAA
function and psychopathology which should become more genetically sensitive than hitherto.
Early adversity and HPAA dysregulation – possible mechanisms
Randomised experimental studies, with manipulation of early environment, provide the best
evidence for a causal link. The clearest evidence is found in cross-fostering studies, where
neonates are randomly allocated to be raised by their genetic mother or a foster mother. Such
randomised experiments are of course not possible in humans. However quantitative genetic
(QG) studies of twins can partition environmental and genetic influences on variation (Plomin, et
al., 1993). Monozygotic (MZ) twins originate from a common fertilised egg. They therefore
have identical DNA sequences (and epigenetic methylation) before the embryo splits. Any
31
difference between MZ twins is therefore due to differences in environment (pre or post natal).
Some relatively small QG studies have demonstrated that there are both environmental and
genetic influences on morning cortisol (Bartels, Van den Berg, Sluyter, Boomsma, & de Geus,
2003). However, such studies do not disentangle whether it is current or past environment that
is influencing HPAA activity.
Methylation of CpG islands within promoter regions of genes is associated with reduced gene
transcription through two epigenetic mechanisms: firstly, methylation of DNA makes it more
difficult for transcription factors to bind to DNA; secondly, methylated cystosine attracts
methylated-DNA binding proteins, attracting repressor complexes and reducing transcription,
partly by deacetylation of histones (Meaney, 2010). Such methylation may be permanent, thus
being a mechanism by which early adversity leads to permanent changes of the HPAA.
Rats are born with virtually no methylation of the transcription factor (nerve factor-inducible
protein A – NGFI-A) binding site of the promoter region (exon 17) of the hippocampal GR. Low
quality of maternal care, in particular lack of licking & grooming and arched back nursing in the
first week of life, is associated with greater methylation at this promoter region (Weaver, et al.,
2004). Cross-fostering demonstrates that this is not due to a gene-environment correlation:
pups with low LG-ABN genetic mothers who are fostered to high LG-ABN mothers have low
methylation and pups with high LG-ABN genetic mothers who are fostered to low LG-ABN
mothers have high methylation (Weaver, et al., 2004). Methylation at this site inhibits NGFI-A
binding (Weaver et al., 2007). High maternal LG is associated with greater hippocampal GR
mRNA in both infancy and adulthood (Weaver, et al., 2007) and lower corticosterone response
to stress in adulthood (Weaver, et al., 2004). The histone deacetylase inhibitor trichostatin A
(TSA) reverses demethylation. Rats raised by low LG-ABN dams but treated with TSA have GR
mRNA expression and corticosterone response to stress in adulthood similar to rats raised by
32
high LG-ABN dams, but significantly different to rats raised by low LG-ABN dams but treated
with inactive vehicle (Weaver, et al., 2004). This experimental evidence suggests that in rats at
least, early environmental adversity leads to (reversible) methylation of the GR promoter region,
leading to reduced GR expression and therefore reduced GR negative feedback and greater
corticosterone response to stress in adult life.
Serotonin has a significant role in this epigenetic modification of GR. Licking-grooming increases
hippocampal 5-HT turnover, leading to greater 5-HT7 receptor stimulation, which causes greater
NGFI-A activity, leading to demethylation at GR exon 17 (Meaney, 2010). This may explain why
polymorphisms of serotonergic genes may moderate the effects of early adversity on later HPAA
activity and depression risk (Alexander, et al., 2009; Uher & McGuffin, 2010).
One human study has demonstrated that early adversity is associated with epigenetic
modification of the GR: the post-mortem hippocampus was compared between suicide victims
with and without a history of childhood abuse and non-suicide comparison subjects. Abused
suicide victims differed from the other groups in: reduced GR mRNA; greater methylation at the
NR3C1 promotor region of GR exon 1F (equivalent to rat exon 17); and reduced NGFI-A-induced
gene expression through NR3C1. There was no difference in NR3C1 DNA sequence between
groups; there were no effects of psychiatric disorder; and non-abused suicide victims did not
differ from comparisons (McGowan et al., 2009). Childhood adversity may also lead to
epigenetic modification of genes that have an indirect effect on the HPAA: childhood abuse is
associated with greater methylation of lymphoblast serotonin transporter promoter
polymorphic region in adulthood (Beach, Brody, Todorov, Gunter, & Philibert, 2010).
However, some geneticists believe that early environmental adversity does not truly lead to
post-natal epigenetic modification (Buchen, 2010; Meaney & Ferguson-Smith, 2010), partly
33
because there is no robust demonstration of an enzyme that removes methyl groups from DNA;
for example mice lacking a putative Mbd2 demethylase gene have normal patterns of DNA
methylation (Hendrich, Guy, Ramsahoye, Wilson, & Bird, 2001). The implication is that
behavioral science is at risk of treating correlation as causation. It is important to recognize that
we do not as yet have a fundamental mechanistic understanding as to how the adverse
environment influences molecular and cellular processes (Meaney & Ferguson-Smith, 2010).
Nevertheless we believe that the current correlational evidence is positive enough to state that
epigenetic strategies should be pursued vigorously at this time until and unless it becomes
definitively proven that a mechanistic effect is not possible. The experimental evidence detailed
above demonstrates that methylation clearly occurs after birth and demethylation can be
experimentally manipulated (Weaver, et al., 2004). In humans, methylation differences have
been demonstrated at multiple loci on the genome between monozygous twins, who originate
from a single fertilized egg and who therefore start life with identical DNA sequences and
methylation (Ollikainen et al., 2010); any variation in methylation must therefore be due to
differences in (pre- or post-natal) environment.
Early adversity and HPAA dysregulation – Conclusions
In mammals, environmental adversity in early life leads to short-term activation of the HPAA,
which is an adaptive allostatic response to stress. However, there is likely to be allostatic
overload, possibly arising from repeated cycles of HPAA activation: rodents, primates and
humans with early environmental adversity seem to have a dysregulated HPAA in adulthood.
The evidence is made harder to interpret by the fact that some studies seem to show opposite
effects – with early adversity leading to both lower and higher HPAA activity. Such results may
be due to different timings of abuse, differing measurements of the HPAA and different levels of
34
confounding factors, such as genes and age, in different studies. Apparently-contradictory
findings may also occur because many studies measure resting cortisol, which may normalize, or
become lower, as a result of compensation to the underlying HPAA dysfunction.
Overall, studies seem to point towards adversity in the first few years of life being associated
with greater central CRH and systemic cortisol levels emerging in childhood and adolescence
and being persistently revealed in adulthood. The elevation in cortisol is most marked at times
when cortisol is naturally high – after awakening and after acute stress. This may be mediated
by a core deficit of downregulation of the glucocorticoid receptor, leading to reduced negative
feedback from high peripheral cortisol, leading to higher central CRH levels. The elevation in
cortisol levels is at its greatest at times of peak cortisol because it is then that the GR is
overloaded and is unable to provide adequate negative feedback. This downregulation may
occur because early adversity leads to permanent methylation, and hence epigenetic
modification, of the GR.
Dysregulation of the Hypothalamic-Pituitary-Adrenal Axis and Risk for Major
Depressive Disorder
Pathophysiological effects of HPAA dysfunction
Elevated levels of cortisol in plasma, urine and CSF (within the normal physiological range) have
long been known to be present during episodes of depression (Carroll, Curtis, Davies, Mendels,
& Sugerman, 1976; Carroll, Curtis, & Mendels, 1976). A recent meta-analysis has confirmed
these findings in adults, adolescents and children (Stetler & Miller, 2011).
35
Intra-ventricular (but not peripheral) administration of CRH to rodents causes behavior that is
similar to both depression and anxiety: reduced feeding, increased (lower dose) and decreased
(higher dose) motor activity in a novel environment, reduced sexual activity (in males and
females), enhanced startle response, more cautious behavior in an elevated plus maze,
increased freezing behavior after a shock (Dunn & Berridge, 1990). In primates, intra-ventricular
administration of CRH leads to increased vigilance and withdrawal behavior (Dunn & Berridge,
1990). Transgenic mice overexpressing central CRH show increased anxiety-like behavior. This
continues after adrenalectomy and normalisation of cortisone levels, demonstrating effects are
likely to be due to central CRH, not cortisone (Keck, Holsboer, & Muller, 2004). Mice with CRH1
receptor knockout have reduced anxiety behavior (Keck, et al., 2004). Anxiogenic effects are
mainly mediated by the CRH1 receptor, but are moderated by the CRH2 receptor, with reduced
CRH2 activation associated with greater anxiety (Keck, et al., 2004). These pre-clinical studies
clearly demonstrate that high central CRH levels are associated with depressive and anxiety
symptoms. However, caution is needed: all of these symptoms could be due to anxiety, and so
there may be no relevance to depression per se. It is possible that elevated CRH in humans
leads to greater ‘emotionality’, with environmental variables determining whether people
experience depressive disorders, anxiety disorders, or both.
Studies do suggest that increased central CRH is relevant to human depression. Some studies
have demonstrated that CSF CRH is higher in patients with depressive disorder than comparison
subjects with other psychiatric disorders or no disorders (Banki, Bissette, Arato, O'Connor, &
Nemeroff, 1987; Nemeroff et al., 1984). However, a recent meta-analysis has demonstrated no
depressed-non depressed difference in CSF CRF (Stetler & Miller, 2011). It is possible that
heterogeneity of results between studies is due to heterogeneity of samples. Adults with
depression and early abuse have greater dysregulation of the HPAA (in particular elevated HPAA
response to stress (Heim, et al., 2000)) and so it may be that only adults with depression and
36
early abuse have greater CRH; depressed-comparison differences would then be diluted within a
non-selected depression sample. Another source of heterogeneity could be the presence of
anxiety disorders (a very common co-morbid disorder in depression). As stated earlier, animal
models suggest CRH may lead to anxiety rather than depressive symptoms, so any depressedcomparison differences in CRH in human studies may be due to high levels of anxiety disorders
in those studies. And of course genetic heterogeneity may lead to differing results: it may be
that only subtypes of depression with a certain genetic profile have raised CRH.
As stated earlier, CSF CRH only leads to a crude estimation of CRH levels in the HPAA, and
indeed at the receptor level in the whole brain. The best methodology to test human CRH
neuronal neurotransmission is post-mortem studies. There are higher levels of both CRH and
CRH-expressing neurones in the brain in the post-mortems of depressed patients than nondepressed comparison subjects (Austin, Janosky, & Murphy, 2003; Bissette, Klimek, Pan,
Stockmeier, & Ordway, 2003; Raadsheer, Hoogendijk, Stam, Tilders, & Swaab, 1994). CRH1 (but
not CRH2) receptors/binding sites are reduced in post-mortem brains of people who have
committed suicide (many of whom were depressed in the studies) (Merali et al., 2004;
Nemeroff, Owens, Bissette, Andorn, & Stanley, 1988). This is likely to be in response to high
levels of CRH.
Support for the hypothesis of raised CRH in depression is provided by the fact that CSF CRH is
reduced by successful treatment of depression, by antidepressants (De Bellis, Gold, Geracioti,
Listwak, & Kling, 1993; Heuser et al., 1998) and ECT (Nemeroff, Bissette, Akil, & Fink, 1991).
Tricyclic antidepressants also lead to a reduction in CSF CRH in healthy individuals (Heuser, et al.,
1998), suggesting that they directly reduce CRH as a mechanism of action, rather than this being
an epiphenomenon of depression improvement. High CSF CRH after antidepressant treatment
is associated with greater risk of relapse (Banki, Karmacsi, Bissette, & Nemeroff, 1992).
37
ACTH increases less after administration of exogenous CRH in depressed patients than healthy
comparisons, although there is no difference in cortisol levels following CRH (Amsterdam,
Maislin, Winokur, Kling, & Gold, 1987; Gold et al., 1984). This suggests reduced pituitary
sensitivity to CRH, supporting a theory of CRH receptor down-regulation secondary to
chronically high CRH. Cortisol levels rise more after ACTH administration and adrenal glands are
larger in depressed patients than non-depressed comparison subjects (Amsterdam, Marinelli,
Arger, & Winokur, 1987). This may compensate for or be in direct response to the lower ACTH;
or may be an independent source of HPAA over-activity in depresion.
Cortisol and ACTH levels are higher after both the dexamethasone suppression test (Pfohl, et al.,
1985; Rubin, Poland, Lesser, Winston, & Blodgett, 1987; Stetler & Miller, 2011) and the more
sensitive dexamethasone/CRH test (Heuser, et al., 1994; Stetler & Miller, 2011) in depressed
patients than healthy comparisons. This suggests downregulation of glucocorticoid receptors in
depression, which leads to higher cortisol through escape from negative feedback. High
baseline cortisol and reduced cortisol diurnal variation are correlated with high cortisol after the
DST, suggesting that GR downregulation partly causes these baseline cortisol level abnormalities
in depression (Pfohl, et al., 1985; Poland, Rubin, Lesser, Lane, & Hart, 1987). Cortisol levels
after the DEX/CRH test in depressed patients do reduce significantly after successful treatment,
suggesting that GC downregulation is at least in part a depressive state-related phenomenon
(Baghai et al., 2002; Rybakowski & Twardowska, 1999).
Overall these studies imply that allostatic failure of the HPAA is prevalent in depressive
disorders, with a putative mechanism that involves a central deficit in feedback mechanisms.
Measuring cortisol may not of itself provide sufficient precision in understanding the
mechanistic aspects of escape from negative feedback. Such work requires a detailed
38
assessment of the axis at the level of at least CRH and ACTH and a greater understanding of the
cellular and molecular events that control negative feedback effectiveness within the cell. This is
clearly not a disease model as such given that the associations with depressive disorders refer to
higher levels within the normal range for these dysregulated components (cortisol, ACTH, CRH).
It would be misleading to equate allostatic overload and failure with pathophysiological
mechanisms per se.
Genetic variants within the HPAA and risk for depression
Genetic polymorphisms of the HPAA influence the risk for depressive disorder, adding further
evidence for the role of the HPAA in risk for depression. As stated earlier, polymorphisms of the
glucocorticoid receptor gene and FKBP5 (an immunophilin involved in the regulation of GR) are
associated with increased cortisol secretion at rest, after DST and after psychosocial stress
(Derijk & de Kloet, 2008). These (and other GR) polymorphisms are significantly more common
in depressed patients than non-depressed comparison subjects (van Rossum et al., 2006; van
West et al., 2006; A. Zobel et al., 2008; A. Zobel et al., 2010). This FKBP5 genotype also predicts
differential risk for suicidal events in treatment resistant depressed adolescents (Brent et al.,
2010). A polymorphism of the CRH binding protein is associated with both higher plasma ACTH
and poorer response to antidepressant treatment (Binder et al., 2010).
Two intronic single nucleotide polymorphisms (SNPs) in the CRH1 receptor gene (CRHR1) are
associated with lower cortisol response to the DEX/CRH test in healthy adults, but only in
individuals with a history of childhood adversity (Tyrka, et al., 2009). A haplotype of these two
SNPs and a further intronic SNP in CRHR1 also reduced the effects of retrospectively reported
childhood/adolescent adversity on risk for adult depressive symptoms and disorder in three
39
independent samples (Bradley et al., 2008; Polanczyk et al., 2009). However, no such gene x
environment association was found in a fourth sample (Polanczyk, et al., 2009). The authors of
this study hypothesised that the difference in results may be due to differences in ages at which
adversity was measured, or differences in the measures. The studies with positive results used a
measure that particularly identifies adversity that leads to strong emotional memories, while
the negative study used a measure that enquired about trauma in a more emotionally neutral
way and also measured some trauma prospectively. CRHR1 polymorphisms may therefore
moderate the effects of emotional memories of abuse, possibly due to effects on the amygdala,
which has a high density of CRH1 receptors and a strong role in emotional memory
consolidation (Polanczyk, et al., 2009). One study has now demonstrated that genetic
polymorphisms of the glucocorticoid receptor (23/23EK and 9beta) moderate the effects of
childhood adversity on depressive symptoms in adulthood (Bet et al., 2009).
HPAA and the clinical phenotype of depression
HPAA dysregulation is greater in some depressed patients than others. The rise in ACTH after
CRH administration is more attenuated in patients with melancholic depression than nonmelancholic depression (Amsterdam, Maislin, et al., 1987). Cortisol response to ACTH and after
the dexamethasone suppression test is higher in patients with melancholic than nonmelancholic depression (Amsterdam, Maislin, Abelman, Berwish, & Winokur, 1986; Carroll et al.,
1981; Stetler & Miller, 2011) and in psychotic as opposed to non-psychotic depression (Nelson &
Davis, 1997; Stetler & Miller, 2011). High evening cortisol is associated with greater risk for
depressive episodes persisting (Goodyer, Park, & Herbert, 2001), complementing results stated
40
earlier that high CSF CRH after antidepressant treatment is associated with greater risk of
relapse (Banki, et al., 1992). As described in an earlier section, adults with depression and a
history of childhood abuse have greater HPAA abnormalities than adults with depression and no
history of abuse, including greater cortisol in response to both a psychosocial stress test and the
DEX/CRH test (Heim, Mletzko, et al., 2008; Heim, et al., 2000). Cortisol has actually been found
to be lower in non-psychotically depressed patients than healthy comparison subjects, while
patients with psychotic depression had higher cortisol than healthy comparisons (Posener et al.,
2000). Patients with atypical depression have down-regulated HPAA and lower central CRH than
healthy comparisons (Gold & Chrousos, 2002; Kasckow, Baker, & Geracioti, 2001).
These studies indicate the dangers of lumping together all patients with depression into one
single homogenous disorder; there are likely to be multiple forms of depression with different
biological profiles. It may be that people with depression and a history of abuse are
characterized by a more abnormal HPAA. This may be associated with poorer prognosis
(Goodyer, et al., 2001). Different subtypes of depression, delineated by HPAA abnormalities,
may respond best to different treatments. Indeed, a large randomized controlled trial of
depressed adults demonstrated that psychological therapy is more effective than
antidepressants alone for depressed adults with childhood trauma, whereas there is no
difference for adults without early trauma (Nemeroff et al., 2003). However, there was no
measurement of HPAA activity in this study. Further research is needed to test these
hypotheses.
HPAA abnormalities and depression: causal or a state-dependent epiphenomenon?
41
The above studies indicate that the HPAA is more active in depressed individuals (particularly
those with melancholic and psychotic depression) than healthy comparisons. However, HPAA
abnormalities do improve with treatment (Baghai, et al., 2002; Heuser, et al., 1998). Therefore
it is possible that raised activity and loss of negative feedback regulation is simply a
consequence of the depressed state. Evidence that high HPAA activity is associated with future
risk of depression onset would increase the probability that allostatic load of the HPAA mediates
the association between early environmental adversity and depression.
The cortisol awakening response (CAR) is higher in patients recovered from depression than
healthy comparisons (Bhagwagar, Hafizi, & Cowen, 2003), suggesting a degree of biological
independence between illness and HPAA abnormalities. While this may indicate that the high
CAR was present before depression, it may of course be an effect of scarring from the
depressive episode. In a prospective study, CAR has been shown to predict new episodes of
major depression (Adam et al., 2010). High morning cortisol measured at 08.00hrs is also
associated with future risk of depression onset (Goodyer, et al., 2009; Goodyer, Herbert,
Tamplin, & Altham, 2000; Harris et al., 2000). In contrast higher cortisol at other time points
during the 24 hour cycle is not associated with future depression onset.
Of note, high CAR is also found in healthy relatives of depressed patients (Mannie, Harmer, &
Cowen, 2007). The implications of this finding are not straightforward. High CAR in first degree
relatives may be the result of depression susceptibility genes, exposure to the negative
environmental impact of being related to a depressed patient, or environmental adversity
shared with the depressed proband. In addition, the genes increasing the CAR may act by
moderating the effects of early environment on the HPAA, as described earlier (Alexander, et al.,
2009).
42
If actively intervening to improve HPAA overactivity led to an improvement in depressive
symptoms, we could be more confident that there is a causal link between the two.
Medications that directly target the HPAA have been shown to be effective antidepressants.
The CRH1 antagonist drug, R121919, leads to improvement in depressive symptoms, which is
reversed when the drug is stopped (Kunzel et al., 2003; A. W. Zobel et al., 2000). This occurs at
doses that do not affect peripheral cortisol levels, suggesting the effects are directly due to
reduced central CRH effects rather than reduced effects of cortisol. However, a subsequent
randomized controlled trial of a different CRH1 antagonist, CP-316,311, was terminated early
due to non-efficacy (Binneman et al., 2008). The lack of significant results here suggests that
improvement in earlier non-controlled studies may have been a placebo effect or regression to
the mean. However, it remains possible that R121919, but not CP-316,311, is an effective
antidepressant; or that clinical heterogeneity between samples accounted for the differences in
results, and CRH1 antagonists are effective for a subtype of depression.
The steroid dehydroepiandrosterone (DHEA) may act as a natural antagonist to cortisol. The
cortisol:DHEA ratio is higher in depressed patients than healthy comparisons (Young, Gallagher,
& Porter, 2002). High cortisol:DHEA ratio is associated with longer duration of depressive
episode, both retrospectively up until sampling (Young, et al., 2002) and persistence of episode
after sampling (Goodyer, Herbert, & Altham, 1998). DHEA has been shown in randomized
controlled trials to be significantly better than placebo at treating depression, either as a
monotherapy (Schmidt et al., 2005) or combined with antidepressants (Wolkowitz et al., 1999).
The steroid synthesis inhibitor metyrapone is more effective than placebo as an adjunctive
therapy in treating depression (H. Jahn et al., 2004). The corticosteroid antagonist mifepristone
is more effective than placebo in the treatment of bipolar and psychotic depression (Belanoff,
Flores, Kalezhan, Sund, & Schatzberg, 2001; Young et al., 2004). The fact that these studies used
randomized designs means that it is less likely that confounders led to the differences between
43
groups, making it more likely that there is a true causal link between HPAA overactivity and
depression.
The above studies suggest that HPAA abnormalities are associated with risk of depression onset
and persistence, rather than just being state-dependent epiphenomena. However, it is also
possible that early adversity leads to both HPAA abnormalities and depression through
independent mechanisms, and that the HPAA abnormalities that are associated with depression
onset are simply markers of the earlier adversity, and themselves are not causal for depression
onset. Studies are needed that demonstrate in the same sample that early adversity is
associated with HPAA dysfunction, that is itself then associated with future depression risk, and
that there is true statistical mediation.
HPAA dysregulation and depression – possible mechanisms
Biological plausibility for the link between HPAA abnormalities and risk for depression would
increase our confidence that there is a true causal association. We have argued that early
environmental adversity leads to high secretion of CRH within the brain and high production of
cortisol by the adrenal glands, some of which enters the brain. We shall now argue that both
high CRH and cortisol may increase the risk for depression.
Evidence for the depressogenic effects of CRH mainly comes from the animal studies cited
above, that demonstrate that direct intra-ventricular infusion of CRH leads to depressive and
anxiety symptoms, even if peripheral cortisol levels are normal (Dunn & Berridge, 1990); and
that CRH1 receptor knockout reduces anxiety behavior (Keck, et al., 2004). This suggests that
CRH neural pathways may directly mediate depressive symptoms, and so greater activity in
44
these pathways may lead to greater depressive symptoms. However, intervention studies of
CRH1 antagonists in humans have had contradictory results, as described earlier (Binneman, et
al., 2008; Kunzel, et al., 2003; A. W. Zobel, et al., 2000).
Increased cortisol (in animals and humans, exogenously administered or as an endogenous
result of stress) mediates and facilitates consolidation, but impairs recall of, new memories
(Buchanan, Tranel, & Adolphs, 2006; Kuhlmann & Wolf, 2005; Wolf, 2008). Some studies have
demonstrated that high levels of arousal are needed for these effects of cortisol to be found
(Herbert, et al., 2006; Wolf, 2008). This suggests an interaction between the HPAA and the
amygdala; in particular cortisol may increase noradrenergic stimulation of the amygdala
(Herbert, et al., 2006; Wolf, 2008). The hippocampus plays an important role in episodic
memory. Chronic stress, and chronic exposure to glucocorticoids, leads to atrophy of
hippocampal cells and reduced hippocampal neurogenesis, which is reversed by SSRI
antidepressants (Herbert, et al., 2006); and reduced hippocampal volume (Herbert, et al., 2006).
Interestingly, adults with childhood abuse and current depression have lower hippocampal
volume than depressed adults with no abuse or healthy comparisons (Vythilingam et al., 2002).
However, the effects of cortisol on memory are not simply global. There is a mnemonic bias to
impaired recall memory: in healthy individuals, there is less of a deterioration in recall for
negative compared to neutral or positive words after cortisol administration (Domes, Heinrichs,
Rimmele, Reichwald, & Hautzinger, 2004; Wolf, 2008). A consistent cognitive correlate of
depression is overgeneral autobiographical memory: providing a summary of prior experience
rather than a specific event when prompted to recall a specific event in response to a cue word
(Williams et al., 2007). In adolescents overgeneral memories are associated with more severe
depressions and somewhat lower general intelligence but not with comorbid anxiety or conduct
disorder (Park, Goodyer, & Teasdale, 2004). Exogenous cortisol reduces the specificity of
45
memories in the autobiographical memory test (Buss, Wolf, Witt, & Hellhammer, 2004). A
mood-related ruminative response style (MRRS) is defined as ‘repetitive and passive thinking
about one’s symptoms of depression and the possible causes and consequences of these
symptoms’ (Nolen-Hoeksema, 2004). MRRS is associated with the onset and persistence of
major depression in young people and adults (Goodyer, Herbert, & Tamplin, 2003; NolenHoeksema & Morrow, 1991; Spasojevic & Alloy, 2001). Ruminating on negative cognitions about
the self increases the use of over general autobiographical memory and lowers mood and has a
deleterious effect on memory retrieval processing.
Prolonged higher cortisol levels within the normal range are likely to block retrieval of
consolidated positive memories so it may be difficult when depressed to recall positive
experiences and distract working memory from ruminating on negative thoughts. This
mnemonic block hypothesis may account in part for persisting cognitive features and treatment
resistance in depressed cases. Higher morning cortisol may also interfere with emotion
perception and consolidation: perhaps events and experiences are perceived, and consolidated,
as more negative in such individuals. They are later retrieved at times of stress preferentially
simply because there are more negatively stored memories even if they were misperceived at
the time of real experience. This is a theoretical a example based on the presented evidence of
how allostatic overload may occur within a physiological system, the HPAA, and exert
pathological effects on a cognitive process that would result in clinical symptoms.
There is a need to further test the effects of variations in cortisol levels both at rest and at times
of stress on affective and cognitive processing Such experimental studies would likely aid in
unraveling the corticoid mediated mechanisms that lead to cognitive vulnerabilities for
depressions (Goodyer, 2008).
46
HPAA dysregulation and depression - Conclusions
Human adults have greater HPAA activity during episodes of depression than healthy
comparisons. In particular, they produce more cortisol over the day and may have higher levels
of CRH in the brain. These may be caused by reduced sensitivity of glucocorticoid receptors.
HPAA abnormalities are also associated with increased risk of future onset of depression and
experimental manipulation of the HPAA leads to an improvement in depressive symptoms,
suggesting that these are not simply depressed state effects. However, this HPAA dysregulation
is not seen in all depressed patients, and is more likely to be found in a putative depressive
subtype with past childhood environmental adversity and greater risk for future persistence.
Conclusions
From all the available evidence we can conclude that environmental adversities that occur in the
preschool, and perhaps the early school age, years lead to increased risk for onset and
persistence of depressive disorder in humans. The mechanisms by which such statistical risks
translate to causal mechanisms within an individual remain poorly characterized. Early
environmental adversity is associated with both short-term adaptive activation of the HPAA
(allostasis) and long-term dysregulation of the HPAA (allostatic overload). HPAA abnormalities
present in people who have suffered early adversity have been demonstrated in people with
current depressive disorder and crucially with risk for future depression onset in healthy
individuals. There is indirect evidence that getting environmental factors ‘under the skin’ is
partially mediated by allostatic overload of the hypothalamic-pituitary-adrenal axis. This is likely
to lead to alterations in central neural control of resting state cortisol levels and differential
47
responses to subsequent environmental demands. It is crucial to remember that the risk for
activating a depressive episode is associated with higher resting morning cortisol levels within
the normal physiological range. This indicates a biomarker effect with a latent mechanism that
remains to be fully revealed. This is likely to involve variations in genetic control of HPAA in
concert with tonic changes in serotonergic and neurotrophic genes and their protein products
arising in part as a consequence of early childhood adversities. In contrast cortisol response at
times of acute demand reveals high levels that may lie outside the expected normal range
(Gotlib, et al., 2008) in genetically vulnerable individuals, indicating perhaps a peripheral
component of a central neural mechanism likely to involve neural systems subserving emotion
processing, memory encoding and retrieval, and reward and punishment mechanisms (Goodyer,
2008).
These preliminary conclusions reflect an early phase in the investigations and understanding of
how the HPAA contributes to the onset and recurrence of affective disorders and may inform
treatment decisions. Whilst this review has focused exclusively on the HPAA it is crucial to bear
in mind that environmental pathways and other physiological systems may influence the risk for
affective disorders, and corticoid-mediated pathways are unlikely to be the only source of
metabolic risk. For example, early adversities may exert their effects through a different
biological pathway that is independent of the HPAA, such as contributing to sub-optimal
inflammatory and immune systems (Danese et al., 2009).
Overall however we believe that the evidence presented is in favour of a causal contribution
with at least two plausible biological mechanisms: increased central CRH neurotransmission and
neurotoxicity in limbic-frontotocortical circuits; and a cortisol-induced negative mnemonic bias
to cognitive processing, which may occur due to atypical neurogenesis in the hippocampus.
These mechanisms may operate at basal levels and/or at time of stress, as HPAA activity is
48
elevated in both. There is experimental evidence that reducing HPAA overactivity treats
depression, providing important clinical proof of principle that there is a pathophysiology
involving the HPAA that is amenable to intervention.
More evidence is clearly needed. First prospective research is needed to demonstrate that
HPAA dysregulation truly mediates the association between early adversity and adult depression
within the same individuals. Second neuroimaging studies should examine in developmentally
sensitive designs whether growth in white matter tracts in neural systems that subserve
emotion and cognitive processing vary by individual differences in childhood adverse
experiences and if these are mediated by variations in HPAA.
And could this be clinically useful? When we go to a physician with shortness of breath, the
professional approach is to take a history, examine us and perform some investigations. The
clinical diagnosis is underpinned by physical investigations that tell the physician whether this is
heart failure, asthma, pneumonia or renal failure (or another diagnosis). All of these will lead to
very different treatment plans. When we go to a mental health professional such as psychiatrist
or clinical psychologist with feelings of sadness and loss of concentration, they would ask us
about all of our symptoms and see if they meet DSM-IV criteria and make a diagnosis with no
recourse to independent validation through further investigations. If so, we would get the
simple diagnosis of depression. The professional may then decide to offer us antidepressants,
or psychotherapy, or both, or neither, depending on local treatment availability and personal
opinions. However, there is virtually no evidence to guide her as to which type of depression
this is, and which treatment will work best.
It is possible that a deeper understanding of the role of the HPAA in depression will help us to
better delineate clinical subtypes and so help clinicians to provide appropriate personalized
49
treatment for our depressed patients. One study has demonstrated that depressed adults who
were abused are more likely to need psychological therapy (Nemeroff, et al., 2003). However,
there is a three way association within depressed individuals between early adversity, HPAA
dysregulation and persistence of depression. As well as early adversity being associated with
HPAA dysregulation (Heim, Mletzko, et al., 2008), both HPAA dysregulation and early adversity
are associated with greater persistence of depression (G. W. Brown, et al., 2008; Goodyer, et al.,
2001).
Is it the HPAA dysregulation or the early abuse that mean people are more likely to need
psychological therapy? Does high cortisol lead to negative cognitive biases that require
psychological therapy? Or is HPAA dysregulation again simply a marker for abuse?
Alternatively, would depressed patients with HPAA dysregulation benefit most from
antidepressants that directly target the HPAA, such as cortisol or CRH antagonists? To answer
these questions, we require large scale randomized controlled treatment trials that incorporate
measures of HPAA activity and early environment, with adequate power to test whether early
environment or HPAA dysregulation is a stronger moderator of treatment.
In summary, we believe that allostatic overload of the hypothalamic-pituitary-adrenal axis
partially probably does partially mediate the association between childhood environmental
adversity and adult depression. Further research is needed to prove such a causal link. It is
possible that further research into the HPAA will help us to better identify sub-types of
depression that respond best to different treatments.
Acknowledgements
50
Paul Wilkinson is funded by the MRC (UK). Ian Goodyer is funded by the MRC (UK),
Welcome Trust and NIHR. This review was completed within the NIHR Collaborating
Leadership in Applied Health Research and Care (CLAHRC) within the University of
Cambridge and the Cambridge and Peterborough Foundation Trust.
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Figure 1. Alternative models of regulation. Homeostasis describes mechanisms that hold
constant a controlled variable by sensing its deviation from a ‘setpoint’ and feeding back to
correct the error. Allostasis describes mechanisms that change the controlled variable by
predicting what level will be needed and overriding local feedback to meet anticipated demand.
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