The Role of Childhood Trauma in the Neurobiology ofMood and Anxiety Disorders: Preclinical and ClinicalStudies
Christine Heim and Charles B. Nemeroff
Epidemiologic studies indicate that children exposed toearly adverse experiences are at increased risk for thedevelopment of depression, anxiety disorders, or both.
Persistent sensitization of central nervous system (CNS)
circuits as a consequence of early life stress, which areintegrally involved in the regulation of stress and emotion,
may represent the underlying biological substrate of anincreased vulnerability to subsequent stress as well as tothe development of depression and anxiety. A number ofpreclinical studies suggest that early life stress induces
long-lived hyper(re)activity of corticotropin-releasing factor (CRF) systems as well as alterations in other neurotransmitter systems, resulting in increased stress responsiveness. Many of the findings from these preclinicalstudies are comparable to findings in adult patients withmood and anxiety disorders. Emerging evidence fromclinical studies suggests that exposure to early life stress is
associated with neurobiological changes in children andadults, which may underlie the increased risk of psychopathology. Current research is focused on strategies toprevent or reverse the detrimental effects of early life
stress on the CNS. The identification of the neurobiological substrates of early adverse experience is of paramount importance for the development of novel treatments
for children, adolescents, and adults. Biol Psychiatry
2001;49:1023–1039 © 2001 Society of BiologicalPsychiatry
Key Words: Stress, development, animal, human, depression, anxiety

IntroductionT

he past decades have witnessed an increasing societal
awareness of the presence and high incidence of childmaltreatment, which has now been pronounced a publichealth problem of epidemic dimensions (Margolin and
From the Department of Psychiatry and Behavioral Sciences, Emory University
School of Medicine, Atlanta, Georgia.
Address reprint requests to Charles B. Nemeroff, MD, PhD, Department of
Psychiatry and Behavioral Sciences, Emory University School of Medicine,
1639 Pierce Drive, WMRB, Suite 4000, Atlanta, GA 30322.
Received December 5, 2000; revised March 13, 2001; accepted March 30, 2001.

© 2001 Society of Biological Psychiatry

Gordis 2000). According to the National Center of Child
Abuse and Neglect, approximately 1.5 million verified
cases of child maltreatment are reported annually in the
United States; more than half of these cases represent
instances of neglect, and about 700,000 cases are incidents
of sexual, physical, or emotional abuse (Sedlack andBroadhurst 1996). In addition to child maltreatment, large
numbers of children experience the loss of a parent (Agidet al 2000) or live with a mentally ill parent likely unableof providing continuous parental care (Goodman and
Gotlib 1999). In view of estimates that 5% to 16% of
women are sexually or physically abused during pregnancy (Cokkinides et al 1999; Goodwin et al 2000; Hedin
and Janson 2000; McFarlane et al 1996), it can also be
assumed that a significant number of children are exposed
to prenatal stress.
Compelling evidence from a variety of studies suggeststhat early life stress constitutes a major risk factor for thedevelopment and persistence of mental disorders. Increased rates of major depression, posttraumatic stressdisorder (PTSD), attention-deficit/hyperactivity disorder,
and other behavioral disorders have been reported for
maltreated children (e.g., Famularo et al 1992; Pelcovitz etal 1994). Representative of many other studies, a community-based study of almost 2000 adult women revealed
that those with a history of childhood sexual or physicalabuse, but not adulthood rape or physical assault, exhibited more symptoms of depression and anxiety and had
more frequently attempted suicide than women without ahistory of childhood abuse (McCauley et al 1997). Syndromal major depression and anxiety disorders, including
panic disorder and PTSD, are frequent in adults with ahistory of childhood abuse (e.g., Felitti et al 1998; Mullen
et al 1996; Saunders et al 1992; Stein et al 1996). Similarfindings have been reported for other instances of earlylife stress. For example, early parental loss has been foundto be related to unipolar and bipolar depression, as well asanxiety disorders, beyond familial or genetic factors (Agidet al 1999; Kendler et al 1992, 1993). Moreover, prenatal
stress has been related to an increased risk for major
depression in adulthood (Hulshoff et al 2000). Early life
0006-3223/01/$20.00
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C. Heim and C.B. Nemeroff

excellent recent reviews on the neurobiological consequences of early developmental stress in animals (Francis
et al 1999; Kaufman et al 2000; Ladd et al 2000). This
review seeks to provide an update of preclinical findings
and summarizes available clinical data on the neurobiological consequences of early life stress in children andadults.

Neural Circuits Implicated in Stress,
Depression, and Anxiety
Figure 1. Proposed model of the interaction between genetic
disposition and early environment leading to a vulnerable phenotype. Subsequent exposure to stress or trauma throughout thelife span may induce exacerbation of pathology based on theunderlying vulnerability. Social support or coping styles may
buffer the effects of early life stress on vulnerability. Modified by
Dr. P.M. Plotsky from Ladd et al (2000) with permission.

stress has also been associated with increased risk forother disorders, including schizophrenia and substanceabuse (Agid et al 1999; Felitti et al 1998; Kendler et al2000) as well as diabetes, heart disease, and immune
disorders (Felitti et al 1998; Francis et al 1999; Wallace1987). The manifestation or worsening of these psychiatricand classical medical disorders in adulthood is often
related to acute life events or ongoing stress (Hammen etal 1992; Mooy et al 2000; Norman and Malla 1994; Twisk
et al 1999). Thus, it may be suggested that adverse
experience during development may induce a vulnerability
to the effects of stress later in life, predisposing these
individuals to develop a wide array mental and physicaldisorders that are known to manifest or worsen in relationto acute or chronic life stress.
Vulnerability to stress and disease is surely not theexclusive consequence of an adverse early environment,
but is well documented to be influenced by genetic factors(see Francis et al 1999). Thus, the concatenation ofgenetics, early life stress, and ongoing stress may ultimately determine individual stress responsiveness and the
manifestation of psychiatric disorders. Thus, an epidemiologic twin study indicated that the manifestation of major
depression occurs as a function of genetic disposition,
early trauma, and recent life stress (Kendler et al 1993).
Early adverse experiences may “shape” a preexisting
genetic vulnerability to stress and disease, resulting in astable phenotype, with a certain risk to develop one or
another syndrome in response to further stress exposure(see Figure 1). By what means can early adverse experiences shape a vulnerable phenotype? It is likely that early
adverse experiences induce a persistent sensitization ofstress-responsive neural circuits. There are a number of

The relationship between early life stress and the development of major depression and anxiety disorders, as wellas other mental and physical disorders, may be hypothesized to be mediated by persistent changes in corticotropin-releasing factor (CRF) neurotransmission and alterations in other neurotransmitter systems implicated in theregulation of the stress responses (e.g., Nemeroff 1999).
Because of its strategic distribution throughout the central
nervous system (CNS), the 41 amino acid peptide, CRF, isgenerally acknowledged to be the major coordinator of the
behavioral, autonomic, immune, and endocrine components of the mammalian stress response. The cell bodies in
the medial parvocellular region of the hypothalamic paraventricular nucleus (PVN) containing CRF form the central component of the hypothalamic-pituitary-adrenal(HPA) axis, which constitutes the major neuroendocrine
stress response system. Upon stress exposure, CRF isreleased from the median eminence nerve terminals into
the hypothalamo-hypophysial portal circulation and transported to the anterior pituitary, where it binds to CRF
receptors on the corticotropes, thereby stimulating the
production and release of the proopiomelanocortin(POMC)-derivatives, adrenocorticotropin (ACTH) and␤-endorphin. In turn, ACTH stimulates the synthesis andsecretion of glucocorticoids from the adrenal cortex (seeArborelius et al 1999). Circulating glucocorticoids exert awide range of metabolic and immune-modulating effects
and counter-regulate the neuroendcorine stress responseby negative feedback at pituitary, hypothalamic, andhippocampal levels. Negative feedback is mediated via
two types of adrenal steroid receptors: the high-affinity
mineralocorticoid receptors (MR) in the hippocampus andthe low-affinity glucocorticoid receptors (GR) widelydistributed throughout the brain. Although increased glucocorticoid secretion is critical to the adaptation of anorganism to stress, prolonged or excessive exposure to
glucocorticoids may be deleterious because of untoward
effects on the CNS and physical organs (see McEwen
1998).
It is now well established that CRF, beyond its role asa hypothalamic hypophysiotropic hormone, also serves asa neurotransmitter within the CNS, mediating autonomic

Childhood Trauma, Depression, and Anxiety

and behavioral stress responses. Thus, when administereddirectly into the CNS of laboratory animals, CRF produces
effects that are reminiscent of stress, depression, andanxiety, including increases in peripheral catecholamine
secretion, heart rate and arterial pressure, changes ingastrointestinal activity, decreased reproductive behavior,decreased appetite, disruption of sleep, increased grooming behavior, increased locomotor activity in a familiar
environment, suppression of exploratory behavior in anovel environment, potentiation of acoustic startle responses, facilitation of fear conditioning, and enhancement of shock-induced freezing and fighting behavior (seeDunn and Berridge 1990; Owens and Nemeroff 1991).
There is evidence that these effects are mediated via
binding of CRF to CRF1 receptors, whereas CRF2 receptors that bind with high affinity to urocortin, a relatedendogenous neuropeptide, appear to be involved in dampening stress and fear (see Arborelius et al 1999).
The capability of CRF to integrate the mammalianorganism’s responses to stress is founded on widespread
CRF neuronal circuitry connecting brain structures criticalto cognitive and emotional processing with autonomic
outflow centers and the hypothalamus. Thus, an abundantpresence of CRF neurons and its receptors is found in the
neocortex and the central nucleus of the amygdala, a key
brain site in the mediation of emotions (see LeDoux 2000).
The CRF neurons originating in the central nucleus of theamygdala project directly and indirectly, via the bed
nucleus of the stria terminalis, to the hypothalamic PVN
and likely influence pituitary-adrenal responses to stress.
Thus, electrical stimulation of the central nucleus of theamygdala results in increased neuroendocrine stress responses, whereas lesion of the same region results indecreased responses (see Feldman and Weidenfeld 1995).
The CRF neurons of the central nucleus of the amygdala
are also directly and indirectly connected to brain-stem
nuclei, including the locus coeruleus (LC) and the raphé
nuclei. The LC regulates autonomic outflow and is the
major source of the noradrenergic perikarya projecting to
the forebrain. The raphé nuclei contain the bulk of theserotonergic projections to the forebrain. Noradrenergicand serotonergic neurons themselves send projections tovarious brain regions that contain CRF neurons or areotherwise involved in the stress response (see Owens andNemeroff 1991). Consistent with these neuroanatomic
connections, on a functional level, stress results in increases of CRF concentrations in the central nucleus of theamygdala as well as the LC (Chappell et al 1986; Pich etal 1993). Microinjection studies have shown that CRF
induces many behaviors reminiscent of fear or anxiety
through actions on specific brain regions (Butler et al
1990; Liang and Lee 1988; Weiss et al 1994). Moreover,it has been shown that CRF increases the firing rate of

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noradrenergic neurons in the LC (Valentino et al 1983),
likely resulting in sympathetic nervous system activationand noradrenergic stimulation of CRF in the PVN. In
contrast, CRF predominantly inhibits serotonergic neurons
in the raphé nuclei (Kirby et al 2000; Price et al 1998),
which modulate stress responses through projections to the
PVN, amygdala, and the hippocampus. Increasing evidence suggests that ␥-aminobutyric acid (GABA)-containing neurons located in these brain structures exert inhibitory influences on central CRF neurons and stressresponsiveness (see Kaufman et al 2000). Another important structure involved in the regulation of emotion is theprefrontal cortex, which is believed to control behavioral
and pituitary-adrenal responses to stress through inhibitory
GABA-ergic projections to the amygdala and the hypothalamus (see Davidson et al 2000).
Taken together, there is a corpus of literature inferring
a role for CRF as a key mediator of the stress response.
Preclinical studies suggest that CRF possesses marked
depressogenic properties and is involved in the mediationof fear and anxiety, consistent with its neuroanatomic
distribution and its mutual interactions with other neurotransmitter circuits involved in the regulation of emotion.

Preclinical Findings on the NeurobiologicalConsequences of Early Life Stress
Given the preclinical evidence for a role of CRF in the
mediation of stress and emotion, it may be plausible thatearly adversities induce persistent changes in CRF neuralcircuits that are associated with the development of depression or certain anxiety disorders. Preclinical studies
using rodents or nonhuman primates are indispensable toimprove our understanding of the consequences of earlylife stress because experimental variation of early environment in humans is obviously precluded on ethical grounds.
Although a large number of studies have evaluated thelong-term neurobiological adaptations to perturbations of
the early environment in rodents or nonhuman primates,
few preclinical studies exist on the immediate effects ofearly developmental stress on the brain.
Among animal models of early life stress in rodents isrepeated separations of rat pups from their mothers during
the neonatal period. Although there is evidence for a stress
hyporesponsive period in neonatal rats, our group observed significant rises in plasma corticosterone levels
both on postnatal day (pnd) 10 and pnd 18 in rats subjected
to maternal deprivation. After 24 hours of maternal separation, we observed a reduction of CRF concentrations in
the median eminence in 10-day-old rats and a 50%
reduction of pituitary CRF receptors in 18-day-old rats,
likely reflecting sustained release of CRF (Pihoker et al1993). Another study reported that 12-day-old rats ex-

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Table 1. Findings on the Long-Term Neurobiological Consequences of Early Environmental Variation in Selected Animal Models
ModelSpecies

Timing

Neurobiological Changes
ACTH after stress
CORT after stress
CRF mRNA in PVN
CRF receptor binding in LC␣2 receptor binding in LC
CBZ in CeA, LnA, LC
GR mRNA in hippocampus
Synaptogenesis in hippocampus
ACTH after stress
CORT after stress
CRF in CSF, ME, LC
CRF receptor binding in LC
CRF mRNA in PVN, CeA, BNST
NE in PVNGABAA receptor binding in CeA, BnA, FC
CBZ in CeA, BnA, LC, NTS
GR in hippocampus
5-HT cell firing in NR after citalopram
ACTH basal and after stress
CORT basal and after stress
CRF in ME
Pituitary CRF receptor binding in NR
CRF receptor binding in NR
ACTH after stress
CORT after stress
CSF CRFCSF CORT
Behavioral response to yohimbine
GH response to clonidine
Behavioral response to m-CPP

Increased maternal caregiving behavior

Rats

Observed at pnd 1–10

Maternal separation

Rats

180 min/day pnd 2–14

Rats

4 – 6 hour/day pnd 2–14

Nonhuman primates

Separated after birth andpeer reared
12 weeks beginning at⬃17 weeks of age

Variable foraging demand

Nonhuman primates

2
2
2
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
1
3
1
2
1
1
1
1
2
1
2
2

ACTH ⫽ adrenocorticotropic hormone; BNST ⫽ bed nucleus of the stria terminalis; CBZ ⫽ central benzodiazepine receptor; CeA ⫽ central nucleus of the amygdala;
CORT ⫽ corticosterone or cortisol; CRF ⫽ corticotropin-releasing factor; CSF ⫽ cerebrospinal fluid; FC ⫽ frontal cortex; GABAA ⫽ gamma-aminobutyric acid A receptor;
GH ⫽ growth hormone; GR ⫽ glucocorticoid receptor; LC ⫽ locus coeruleus; BnA ⫽ basolateral nucleus of the amygdala; m-CPP ⫽ meta-chlorophenylpiperazine; ME ⫽median eminence; mRNA ⫽ messenger ribonucleic acid; NR ⫽ nucleus raphe; NTS ⫽ nucleus tractus solitarius; pnd ⫽ postnatal day; PVN ⫽ paraventricular nucleus.

posed to maternal deprivation exhibit increased ACTH
responses to restraint stress compared with rats not exposed to maternal separation (Dent et al 2000). Althougha rapid increase in CRFmRNA expression in the PVN was
observed in both groups, only the maternally separated rats
exhibited increased arginine vasopressin (AVP) mRNA
expression, suggesting that increased stress responsivenessmay be associated with the synergy of releasing effects of
CRF and AVP. There is, furthermore, important evidence
that there are critical developmental “windows,” in which
early life stress may have differential effects on neurobiological function. Thus, prolonged maternal separation
over 24 hours at pnd 3– 4 produces increased ACTH andnormal corticosterone responses to stress at pnd 20 in rats,
whereas prolonged maternal separation at pnd 11–12
produces blunted ACTH and normal corticosterone responses to stress at pnd 20 (van Oers et al 1998; Workel etal 1997). In a recent study, 6-month-old rhesus monkeys
who were reared without their mothers but with peers
showed increased cortisol responses to social separationcompared with mother-reared rhesus monkeys, with cor-tisol increases predicting alcohol preference of thesemonkeys in young adulthood (Fahlke et al 2000). A
magnetic resonance imaging (MRI) study found decreased
volumes of the posterior corpus callosum, but not of the
hippocampus, in prepubescent nonhuman primates reared
under social isolation from 2 to 12 months of age compared with primates reared in a social environment(Sanchez et al 1998), paralleling findings in maltreatedchildren (De Bellis et al 1999b, see below). Taken together, these findings suggest that intense neonatal stressinduces immediate neurobiological changes, likely resulting in long-term maladaptations. More developmentally
focused preclinical studies on the neurobiological impactof early life stress are strongly needed to elucidate themechanisms of early-onset depression and other mental
disorders after early life stress.
As for the long-term consequences of early life stress(see Table 1), adult rats separated from their dams for 180
min per day on pnd 2–14 demonstrate increased CRF
concentrations in the median eminence, portal blood, andCSF, as well as increased CRF mRNA expression in theChildhood Trauma, Depression, and Anxiety

hypothalamic PVN and decreased pituitary CRF receptor
binding under resting conditions compared with rats
reared under normal animal facility conditions. Rats separated from their dams for 180 min per day on pnd 2–14
also exhibited increased ACTH and corticosterone responses to a variety of stressors, including the exposure to
air-puff startle, novel environment, or restraint stress(Ladd et al 2000; Plotsky and Meaney 1993). Adult ratsthat were removed from their dams for 4 – 6 hours per day
on pnd 2–21 also exhibited increased ACTH but notably
normal corticosterone responses to foot-shock (Ladd et al1996), suggesting that more severe or extended postnatal
stress may promote adrenal dysfunction, which is also
observed in other models of early life stress (Coplan et al
1996, see below).
Rats exposed to maternal separation for 180 min per day
on pnd 2–14 also develop marked behavioral abnormalities, including reduced consumption of a sweetened solution reflecting anhedonia, as well as increased freezing inan open-field, decreased exploration of a novel environment, and increased acoustic startle responses, all indicative of fear (Caldji et al 2000; Ladd et al 2000). As
outlined above, the underlying substrate of these behaviors
may be increased CRF neurotransmission in corticolimbic
and brain-stem circuits. Accordingly, adult rats that wereseparated from their dams in the same model demonstrateincreased CRF mRNA expression in the central nucleus of
the amygdala and in the bed nucleus of the stria terminalis.
Moreover, discordant with the well-accepted concept ofligand-induced receptor regulation, increased CRF concentrations along with increased CRF receptor binding
density was measured in the LC (Plotsky et al, in press).
Consistent with the evidence that the LC-noradrenergic
neurons project to the hypothalamus, increased concentrations of norepinephrine (NE) have been measured in the
PVN of the hypothalamus of maternally separated rats
(Liu et al 2000a). Norepinephrine serves as major stimulus
for CRH release in the hypothalamus, suggesting that
increased CRF transmission in pathways connecting theamygdala with the hypothalamus and the LC may contribute to enhanced neuroendocrine stress reactivity after earlylife stress.
With respect to other neurotransmitter systems, increased CRF receptor binding has been measured in the
nuclei raphé (Ladd et al 1996). Corticotrophin releasing
factor neurotransmission in the nuclei raphé is associatedwith predominantly decreased firing rates of serotonergic
neurons (Kirby et al 2000; Price et al 1998). Indeed, adultrats separated from their dams for 180 min per day on pnd
2–14 exhibit decreases in serotonin (5-hydroxytryptamine[5-HT]) cell firing in the raphé nuclei in response toincreasing doses of the selective 5-HT reuptake inhibitor
citalopram, suggesting persistent alterations in 5-HT trans-

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porter, 5-HT1A autoreceptors, or both after maternal
separation (Arborelius et al 2000). As noted before,
serotonergic neurons originating in the raphé nuclei
project to various brain regions that are pivotal to thecontrol of the stress response, including the hippocampus
and the prefrontal cortex. Serotonergic dysfunction may
thus contribute to exaggerated neuroendocrine stress responsiveness after early life stress. In addition, it has
previously been shown that maternal separation is associated with a decrease in hippocampal GR, reflecting impaired feedback inhibition of the HPA axis. Changes inhippocampal GR as a consequence of early environmental
changes have been reported to be dependent on 5-HT (seeMeaney et al 2000).
Several brain regions involved in the control or inhibition of the stress response send inhibitory GABA-ergic
projections to various other brain regions involved in the
stress response. A recent study has evaluated GABAA andcentral benzodiazepine receptor (CBZ) levels in the brainof maternally separated rats (Caldji et al 2000). Central
benzodiazepine receptors are a component of the GABAA
receptor and enhance the affinity of the GABAA receptor
for GABA resulting in increased inhibition of fear andanxiety. For example, the anxiolytic actions of benzodiazepines are mediated by binding to the CBZ. Interestingly,
it was found that maternally separated rats exhibit adecreased density of GABAA or CBZ binding sites invarious brain regions, including the LC, several nuclei ofthe amygdala, and the frontal cortex. It may thus beassumed that dysfunction of GABA-ergic neurotransmitter
systems may contribute to enhanced stress responsivenessafter early life stress.
Opposite to the long-term consequences of prolonged
maternal separation, brief handling involving removal ofrat pups from their dams for 15 min per day on pnd 2–14
results in a phenotype, which is less sensitive to stress, lessfearful and thus better adapted compared with rats who
were left undisturbed during the postnatal period (Francis
et al 1999; Kaufman et al 2000; Plotsky and Meaney1993). Pivotal to the understanding of the determinants
involved in the mediation of the neurobiological consequences of early life stress in rodents are a series offindings showing that separation of rat pups from theirdams results in alterations in maternal behavior. Comparedwith normal animal facility conditions, removal of pups
from dams for 15 min/day has been shown to induceincreased maternal care-giving behavior, as evidenced byincreased licking, grooming, and arched-back nursing.
Several studies have assessed the neurobiological andbehavioral adaptations to naturally occurring variations inmaternal behavior, without actually removing the pups
from their dams (Caldji et al 1998; Liu et al 1997, 2000b).
Remarkably, these studies showed that increased licking,

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grooming, and arched-back nursing behavior is highly
correlated with decreased pituitary-adrenal responses tostress, increased GR binding and enhanced synaptogenesis
in the hippocampus, decreased CRF mRNA expression in
the hypothalamus along with decreased CRF receptor andincreased presynaptic ␣2 receptor site binding, as well as
increased CBZ receptors in the amygdala and LC. These
rats were also less fearful when behaviorally tested (Caldji
et al 1998; Liu et al 1997). The causal role of variations inmaternal caregiving behavior in shaping a phenotype moreor less vulnerable to stress has impressively been provenin a series of cross-fostering studies demonstrating thatmaternal behavior determines stress reactivity in the offspring and, moreover, that individual differences in maternal behavior are passed on the next generation throughnongenomic transmission (Francis et al 1999). Thesefindings are of paramount importance for our understanding of the long-term consequences of adverse parenting
behavior in humans, such as child abuse or neglect, and its
transition across generations. Interesting in this regard are
findings suggesting that the neurobiological systems thatare modified by early experience are also involved in the
mediation of aggressive and abusive behavior (Davidson
et al 2000).
Similar to findings in rodents, adult nonhuman primatesthat have been maternally deprived during infancy exhibit
increased pituitary-adrenal and behavioral responses toacute stress, as well as signs of behavioral despair (Suomi
1991). Some studies on the long-term consequences of
early life stress in nonhuman primates have also focusedon variations in maternal behavior during infancy. In one
model, mothers of infant bonnet macaques are exposed todifferent foraging demands over 12 weeks. Mothers withconstantly low foraging demand (LFD) can obtain foodwithout any effort, whereas mothers with constantly highforaging demand (HFD) have to complete a daily task to
obtain their food. In a variable foraging demand (VFD)
condition, mothers are exposed to unpredictable conditions with respect to food access, resulting in diminishedperception of security and a reduction of maternal care in
the infants. As adults, VFD-reared nonhuman primates
exhibit stable traits of anxiety as well as significantly
elevated CSF CRF concentrations when compared with
LFD- or HFD-reared primates (Coplan et al 1996). Therealso appears to exist an opposite dysregulation of increased CRF and decreased adrenal activity. Nonhuman
VFD-reared primates further exhibit exaggerated behavioral responses to the administration of the selective
␣2-receptor antagonist, yohimbine, and reduced growth
hormone responses to the ␣2 agonist, clonidine, suggesting
sensitization of the noradrenergic system as a consequenceof early life stress (Coplan et al 2000; Rosenblum et al1994). In addition, VFD-reared nonhuman primates ex-

C. Heim and C.B. Nemeroff

hibit decreased behavioral responsiveness to the 5-HT
agonist meta-chlorophenylpiperazine (m-CPP), suggestinga dysfunctional 5-HT system after early life stress (Rosenblum et al 1994).
Importantly, increasing evidence from preclinical studies suggests that environmental influences may shapestress vulnerability of the offspring even in the prenatal
period. Thus, adult rats exposed to prenatal stress show
marked increases in fear-related behaviors (Takahashi et al1992), along with increased ACTH responses to stress anddecreased hippocampal GR levels as well as increases of
CRF content and CRF receptor binding in the amygdala(see Cratty et al 1995; Maccari et al 1995; Ward et al2000). Similar changes have been observed after prenatal
alcohol exposure (Ogilvie and Rivier 1997). Some of thesechanges may be altered by postnatal maternal caregiving.
In view of the relative high prevalence of prenatal stress inhumans and its relationship to adult psychopathology, thisarea of investigation deserves further attention.
Taken together, there is considerable evidence frompreclinical studies suggesting that an adverse early environment is associated with marked behavioral changes
indicative of fear and anxiety, as well as with persistentalterations in CRF neural circuits, which may contribute toincreased vulnerability for the development of depression
or certain anxiety disorders.

Comparison of Preclinical Findings on the
Neurobiological Consequences of Early Life
Stress with the Neurobiology of Mood andAnxiety Disorders
The accumulating evidence from preclinical studies on
early life stress suggesting persistent changes in brain
regions pivotal to the mediation of stress and emotion has
raised the question of whether patients suffering fromdepression or anxiety disorders exhibit similar neurobiological alterations.
Although many of the long-term consequences of earlylife stress in animals bear significant similarities with theneurobiological changes observed in adult patients withdepression and some anxiety disorders, preclinical studies
on the consequences of early life stress appear to be a poor
heuristic for the neurobiology of child or adolescentaffective disorders. For example, disturbances of the HPA
axis, such as hypercortisolemia or blunted ACTH responses to CRF stimulation or other indices of HPA axis
hyperactivity, are rare in depressed children, contrastingfindings in adult major depression (Birmaher et al 1996;
Dorn et al 1996; Kaufman and Ryan 1999). It may beargued that peripheral measures of pituitary-adrenal activity may not reflect central CRF activity at extrahypothalamic sites and, moreover, that peripheral changes may

Childhood Trauma, Depression, and Anxiety

only develop over time with chronic or repeated depression (Martin et al 2000). Differential pathophysiology ofdepression at different developmental stages is further
reflected by differences in responses to pharmacologic
treatments in patients of different ages (Martin et al 2000);
however, there is evidence that CRH and serotonergic
alterations are present in depressed children with histories
of maltreatment, but not in depressed nonabused children(Kaufman et al 1997, 1998; see next section), suggestingthat preclinical studies on early life stress represent aheuristic specifically for understanding depression associated with early trauma. This subtype of depression may
also more frequently occur in comorbidity with anxiety
disorders. Some studies on the neurobiology of anxiety
disorders in children and adolescents have yielded findings similar to some findings on the effects of early life
stress in animals. For example, elevated ACTH but normal
cortisol levels have been reported for children with generalized anxiety disorder who anticipated a laboratorystress task (Gerra et al 2000). Altered behavioral andhormonal responses to central noradrenergic stimulation
have been observed in children with several anxiety
disorders (Sallee et al 2000). Neurobiological alterations
are also present in children with PTSD related to early
trauma (see next section). It may be that early life stressaffects neurobiological function in children with otheranxiety disorders as well, similar to findings in early-onset
depression.
As for studies in adults, increased CSF CRF-like immunoreactivity has been measured in untreated patientswith depression, PTSD, and obsessive-compulsive disorder (OCD), but not panic disorder (see Heim and Nemeroff 1999). Importantly, two recent studies using serial CSF
sampling techniques have provided evidence for sustained
increases in CRF activation in both major depression and
PTSD suggesting that CRF hypersecretion occurs independent of anxiety or stress related to the lumbar puncture(Baker et al 1999; Wong et al 2000). Concentrations of
CRF in CSF are derived from various brain regions. Thus,
these findings are consistent with findings of increased
CRF activity in corticolimbic structures of animals exposed to early life stress. In addition, increased CRF and
CRF mRNA levels have been measured in hypothalamic
tissue obtained postmortem from depressed patients(Raadsheer et al 1994, 1995). Blunted ACTH responses to
CRF injection have been reported for patients with depression, PTSD, and panic disorder, although increased responses to CRF also have been reported for panic disorder(see Heim and Nemeroff 1999). It may be that initial
sensitization evolves into blunted responses reflecting, inpart, down-regulation of pituitary CRF receptors as aconsequence of hypothalamic CRF hypersecretion. Thesefindings therefore parallel the findings indicative of in-

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creased hypothalamic CRF expression and release, as well
as reductions in pituitary CRF receptors in maternallydeprived rodents.
Although major depression and some anxiety disorders,
including PTSD, panic disorder, and OCD, appear relatively similar with respect to central or hypothalamic CRF
hypersecretion, findings at peripheral levels of the HPA
axis are discordant. Melancholic major depression and
OCD have been associated with hypercortisolism in somestudies, whereas panic disorder (in the absence of comorbid depression) has been associated with normal basal
cortisol secretion (see Heim and Nemeroff 1999). In
contrast, adult patients with PTSD were shown to exhibit
decreased adrenocortical activity in a series of studies (seeYehuda 2000), although this finding was not replicated inseveral other studies in adult PTSD patients (Lemieux andCoe 1995; Maes et al 1998). It has been suggested that
decreased cortisol secretion found in some PTSD patients
may reflect enhanced negative feedback inhibition of the
HPA axis; however alterations at the adrenal level may, inpart, contribute to altered cortisol concentrations. The
opposite dysregulation of central and peripheral components of the stress system in PTSD parallels findings insome animal models of early life stress.
Consistent with feed-forward actions between central
CRF and NE systems, recent evidence suggests sustained
increases in CSF NE concentrations of depressed patients(Wong et al 2000). Pharmacologic provocation studies andperipheral catecholamine measures also suggest increased
noradrenergic activity in several anxiety disorders, including PTSD and panic disorder (see Coplan et al 1996). In
addition, indices of serotonergic dysfunction have beenreported for patients with depression, PTSD, OCD, andsocial phobia (Hollander et al 1998; Newport and Nemeroff 2000; Owens and Nemeroff 1994; Stein et al 1999).
Regarding GABA-ergic systems, recent functional neuroimaging studies revealed decreased cortical GABA concentrations in depressed patients, as well as decreased
prefrontal CBZ receptors in patients with PTSD or panic
disorder (Bremner et al 2000a, 2000b; Sanacora et al1999). These findings parallel findings of noradrenergic,
serotonergic, and GABA-ergic changes in animal modelsof early life stress.
Evidence from neuroimaging studies suggests morphologic and functional changes in brain structures involvedin the control of the stress response in depression andsome anxiety disorders. Thus, a reduction in hippocampal
volume has been documented in several studies in adultpatients with depression or PTSD (e.g., Bremner et al
1995, 2000c; Sheline et al 1996), although reduced hippocampal volume was not observed in childhood PTSD
(De Bellis et al 1999b; see below). Reduced hippocampal
volume may be a long-term consequence of overexposure

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to excitatory amino acids or glucocorticoids, potentiallyleading to cell atrophy, loss, or decreased neurogenesis(see Duman and Charney 1999). Potential mechanisms
explaining the reductions in hippocampal size in potentially hypocortisolemic PTSD patients may include thecumulative effects of excessive adrenocortical responses
to repeated stress in these patients or increased glucocorticoid sensitivity of the target cells. Neuroimaging studies
have further documented alterations in the structure or
activity patterns of the prefrontal cortex, which is involvedin the inhibition of the stress response, in patients withdepression or PTSD (Drevets 1999; Mayberg et al 1999;
Newport and Nemeroff 2000; Rajkowska et al 1999).
Structural alterations of the amygdala also have been
noted in depression (Sheline et al 1998).
Although these findings provide evidence for increased
activation of the central stress response system closely
resembling findings in animal models of early life stress,a recent study reported reduced ␤-endorphin and normal
cortisol responses to psychosocial laboratory stress in
depressed patients (Young et al 2000). Although theauthors argue that the blunted response may reflect increased feedback inhibition at the pituitary level givenhigh basal cortisol levels in these patients, these findings
are in contrast to findings in animal models of early life
stress.

Does Early Life Stress Induce Similar
Neurobiological Alterations in Humans?
Given the rapidly increasing number of preclinical studies
on the consequences of early life stress and overwhelming
evidence of a close relationship between early life stressand affective or anxiety disorders, a number of studies
have evaluated neuroendocrine, neurochemical, andneurostructural-functional changes in children or adults
with histories of early adversities.

Studies in Children
Several studies recruiting children of different ages who
experienced different types of early life stress at different
developmental stages report decreased salivary cortisol
concentrations in the morning or a lack of decline ofcortisol toward the evening, suggesting a disturbed circadian rhythm of the HPA axis (Carlson and Earls 1997;
Goenjian et al 1996; Hart et al 1996; Kaufman 1991).
Cortisol concentrations were related to symptoms of depression or PTSD. The absent decline of cortisol in thesechildren may be due to higher numbers of stressful events
during the day or increased HPA responses to daily stress.
Thus, unlike findings in Vietnam veterans with PTSD, theC. Heim and C.B. Nemeroff

total 24-hour urinary cortisol excretion is unaltered orincreased in maltreated children, depending on the duration of the abuse and the severity of psychopathology (DeBellis et al 1994, 1999a).
In response to a CRF stimulation test, sexually abused
girls demonstrated a markedly blunted ACTH responsecompared with control subjects in one study (De Bellis etal 1994), reflecting in part pituitary CRF receptor downregulation due to hypothalamic CRF hypersecretion. Another study using the CRF stimulation test found enhanced
ACTH and normal cortisol responses in abused children
with current depression compared to nonabused depressedchildren and control subjects (Kaufman et al 1997). Abouthalf of these children were emotionally abused at the timeof the study. In a naturalistic stress study, maltreatedchildren did not show an increase of cortisol in a social
conflict situation, whereas control subjects showed increases (Hart et al 1995), but these results may reflect lackof novelty to such situations in maltreated children, rather
than decreased stress sensitivity. Two studies using thedexamethasone suppression test in children with acuteparental death (Weller et al 1990) and children who werein an earthquake 5 years before the study (Goenjian et al1996) yielded opposite results. Although bereaved children were depressed and did not adequately suppress
cortisol, the children exposed to the earthquake showed
symptoms of PTSD and enhanced suppression of cortisol,
similar to some findings in adult patients with PTSD.
Taken together, it is evident that neuroendocrine dysfunction in children with early life stress is highly variable andlikely influenced by multiple factors (i.e., type, age at
onset and duration of the stressful event, the time elapsed
since the event, concomitant stress and psychopathology).
Moreover, a stable phenotype of altered stress vulnerability related to early life stress may not yet have evolved inchildren.
Similar to findings in animal models of early stress andadult patients with depression or PTSD, elevated 24-hoururinary NE, epinephrine (E), and dopamine (DA) excretion as well as decreased platelet adrenergic receptors havebeen measured in abused children with PTSD (De Bellis etal 1999a; Perry 1994). Abused children with PTSD also
exhibit increased heart rate and blood pressure levels at
rest and after orthostatic challenge (Perry 1994). Elevatedcatecholamine secretion does not appear to be an exclusive
correlate of psychopathology because elevated levels werealso found in abused girls without PTSD (De Bellis et al1997) and children whose parents had marital problems(Gottman and Katz 1989). Notably, decreased levels of
NE and DA-␤-hydroxylase (D␤H), the rate limiting factor
in the synthesis of NE, were observed in children who
were neglected in infancy (see Rogeness and McClure
1996), indicating that the type and timing of early stressChildhood Trauma, Depression, and Anxiety

may determine the direction of biological changes, which
may be related to differential psychopathology.
Indicative of serotonergic dysfunction, abused children
with depression were shown to exhibit increased prolactin
but normal cortisol responses to the injection of L-5hydroxytryptophan, a precursor of 5-HT, compared withnonabused depressed children and control subjects (Kaufman et al 1998). Likewise, increased prolactin responses
to fenfluramine were observed in boys with adverse
rearing environment (Pine et al 1997). Since prolactin but
not cortisol release is mediated via 5-HT1A receptors,
these findings suggest sensitization of these receptors due
to early life stress. Another study recently reported thatchildren with traumatic brain injury (TBI) who had experienced abuse have dramatic increases in CSF concentrations of glutamate compared with nonabused TBI children(Ruppel et al 2001). Consistent with a role of glutamate in
the phenomenon of excitotoxicity during neural injury,
increased glutamate concentrations were related to pooroutcome in these children.
In contrast to findings in adult depression and PTSD,
normal hippocampal volumes were observed in maltreatedchildren with PTSD (De Bellis et al 1999b; also see
below); however, similar to findings in prepubescentprimates exposed to early stress (Sanchez et al 1998),
these children exhibited decreased volumes of the corpus
callosum. Furthermore, a proton magnetic resonance spectroscopy study found smaller ratios of N-acetylasparate tocreatine in the anterior cingulate of abused children with
PTSD compared with control subjects (De Bellis et al2000), which is thought to reflect decreased neural integrity in this brain region.

Studies in Adults
A limited number of retrospective studies have evaluatedthe long-term consequences of early life stress in adults.
Lemieux and Coe (1995) observed increased 24-hoururinary cortisol excretion in women with a history ofchildhood sexual abuse and PTSD, concordant to findings
in abused children with PTSD. These findings are opposite
to findings in Vietnam veterans and Holocaust survivors
with PTSD (Yehuda 2000). Increased plasma cortisol
concentrations were also measured in adults who experienced the death of a parent in childhood and had obtained
a lifetime psychiatric diagnosis (Breier et al 1988). Cortisol suppression after dexamethasone was normal in thesesubjects. In another study, women with a history ofchildhood sexual abuse were found to show hypersuppression of salivary cortisol concentrations in response
to a low dose of dexamethasone (Stein et al 1997a).
Basal morning cortisol concentrations and GR binding

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1031

were unaltered in these women; however, there was atrend for higher GR binding in abused women with
PTSD or dissociation. We found decreased basal plasma
cortisol concentrations in the morning in abused women(Heim et al, 2001). The variance in these data may inpart reflect methodologic differences. It may be that
increased 24-hour urinary cortisol excretion in partreflects enhanced fluctuation of cortisol release in
response to stress throughout the day in abused womenwith PTSD.
Given the clear preclinical evidence for long-term
sensitization of the stress response after early life stress, it
is important to evaluate neuroendocrine stress responsiveness in adult humans exposed to early life stress. We foundthat abused women with or without current depression
exhibit markedly increased plasma ACTH responses to
psychosocial laboratory stress compared with control subjects and depressed women without early life stress (Heimet al 2000). Abused women with depression also exhibited
increased cortisol responses to stress compared with allother groups. Similarly, an increase of cortisol during aspeech in front of a video camera was noted in adults withparental loss experience, whereas cortisol levels decreased
in control subjects (Luecken 1998). These findings are
remarkably consistent with findings from animal studies
suggesting sensitization of the neuroendocrine stress responses after early life stress in humans, which may in turnbe related to an increased risk for psychopathology.
Similar to findings in depressed children, our findings
suggest that there are subgroups of depression with differential pathophysiology depending on early trauma, explaining the inconsistency of findings in the literature, forexample, Young et al (2000).
To further explore the mechanism(s) of pituitary-adrenal dysfunction in these women, we used a standard CRF
stimulation test, which selectively stimulates pituitary
CRF receptors without involving higher levels of HPA
axis control (Heim et al 2001). Abused women without
depression, similar to their responses in the social stress
test, exhibited increased ACTH, but normal cortisol responses to oCRF. In contrast and opposed to their responses in the social stress test, abused women withdepression exhibited a blunted ACTH response to exogenous CRF. This finding compares with classical findings
in depression and was also observed in depressed women
without abuse. Abused women with depression women
also reported elevated levels of recent life stress. One may
thus assume that early life stress is related to sensitizationof the CRF neuronal circuits, resulting in high CRF
secretion whenever these women are stressed. At thepituitary, this eventually leads to CRF receptor downregulation, and, because of CRF actions at extrahypothalamic sites, to signs and symptoms of depression and1032

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2001;49:1023–1039

anxiety. The discrepancy between the responses in the
stress test compared with the CRF stimulation test inabused women with depression remains unexplained but
may involve activation of corticolimbic pathways. We
further reported that abused women without depression
release less cortisol during a standard ACTH1–24 stimulation test (250 ␮g) (Heim et al 2001), suggesting peripheral
adaptation to CNS hyperactivity, which parallels findings
in animal models of early life stress and abused children
with depression.
Parallel to findings in abused children with PTSD,
elevated 24-hour urinary NE excretion was reported inabused women with PTSD (Lemieux and Coe 1995). In
addition, increased heart rate or blood pressure responses
have been observed during stress induction in adults withearly parental loss and abused women with depression(Heim et al 2000; Luecken 1998) as well during mental
imagery of abuse experiences in abused women with
PTSD (Orr et al 1998), suggesting increased autonomic
reactivity. With respect to serotonergic function, a historyof severe childhood abuse was found to be highly correlated with blunted prolactin responses to m-CPP in adultwomen who suffered from borderline personality disorder(Rinne et al 2000). Because this finding is opposite tofindings in maltreated children but comparable with findings in VFD-reared adult nonhuman primates, these authors suggested that the 5-HT system may undergo adevelopmental “switch” after early stress.
Similar to findings in adult depression or combatrelated PTSD, decreased hippocampal volumes have beenmeasured in adults with perinatal trauma and adult womenwith child abuse and PTSD (Bremner et al 1997; McNeil
et al 2000; Stein et al 1997b). Because hippocampal
atrophy is not observed in abused children with PTSD (DeBellis et al 1999b), it may be hypothesized that repeatedly
increased cortisol secretion over the course of time induces hippocampal cell loss and impaired neurogenesis in
the dentate gyrus, which may further disinhibit cortisol
secretion, eventually resulting in measurably smaller hippocampi. Two positron emission tomography studies reported decreased activation of the anterior cingulate
during script-driven guided mental imagery of personal
abuse experiences in abused women with PTSD relative
to abused women without PTSD (see Newport and
Nemeroff 2000), a structure that is also abnormallydeveloped in maltreated children with PTSD. Thesestudies also found altered activation of several areas of
the frontal cortex, which are involved in the processingof emotion; however, because of the immanent difficulties in including nonabused control subjects whenreading trauma scripts, it cannot be decided whether
early life stress per se is associated with these neurobiological changes.

C. Heim and C.B. Nemeroff

Are the Neurobiological Consequences of
Early Life Stress Reversible?
As we have shown, accumulating evidence from preclinical and clinical studies suggests that early life stressinduces persistent sensitization of CRF neurocircuits, resulting in a phenotype with increased vulnerability tostress, depression, and anxiety. Pharmacologic agents thattarget central CRF systems may reverse the neurobiological consequences of early life stress and may therefore be
useful in the prevention and treatment of disorders related
to early life stress in children and adults.
A number of studies provide evidence that different
classes of antidepressants decrease CRF neuronal or HPA
axis activity in rodents and primates, including humans(Bánki et al 1992; Brady et al 1991, 1992; De Bellis et al
1993; Michelson et al 1997; Veith et al 1993). It would
appear that a decrease in the activity of one or more CRF
neural systems is one shared mechanism of action ofseveral classes of antidepressant drugs and may be relevant to their therapeutic efficacy. Many of the above
effects were produced by drugs that affect the central
serotonergic neurons, including the selective 5-HT reuptake inhibitors (SSRI). The SSRIs have been shown tobe effective in the treatment of several psychiatric disorders that have been associated with early life stress (e.g.,
depression and PTSD; Hidalgo and Davidson 2000).
Notably, in a randomized placebo-controlled trial, survivors of childhood abuse with PTSD were more responsive
to fluoxetine than combat veterans with PTSD (van der
Kolk et al 1994). Furthermore, SSRIs, including fluoxetineand paroxetine, show significant efficacy versus placeboin the treatment of early-onset depression in children andadolescents, whereas it appears to be resistant to tricyclic
antidepressants (Martin et al 2000). Other SSRIs, such as
sertraline or fluvoxamine, showed efficacy in open clinical
trials in early-onset depression (Martin et al 2000). Interesting in this regard are findings showing that treatment ofmaternally deprived rats as adults with the selective 5-HT
reuptake inhibitor paroxetine reverses the neurobiologicalconsequences of early life stress, resulting in unalteredvulnerability to stress, depression, and anxiety (Plotsky et
al in press). Tricyclic antidepressants have also been found
to reverse increased HPA axis reactivity to stress in adultprimates exposed to maternal deprivation (Suomi 1991). It
appears that several available drugs, but namely the
SSRIs, may be beneficial in the treatment of children andadults exposed to early life stress. Future preclinicalstudies will have to evaluate the efficacy of these drugs in
the prevention or reversal of the effects of early life stressduring development. Furthermore, the efficacy of otherclasses of available drugs known to decrease CRF activity,
including the 5-HT/NE reuptake inhibitor venlafaxine andChildhood Trauma, Depression, and Anxiety

benzodiazepines (Owens et al 1996; Skelton et al 2000), in
the prevention or reversal of the effects of early life stressshould be studied. Clinical trials evaluating the efficacy ofthese available drugs in reversing neurobiological andpsychological maladaptation in children and adults withhistories of early life stress are urgently needed.
There are also promising novel drugs that may beefficient in the treatment of disorders related to early life
stress. Thus, considerable attention has been directed
toward the development and evaluation of CRF receptor
antagonists. Given the integral role of CRF and its
receptors in the mediation of stress and emotion, the CRF1
receptor antagonists are being discussed as novel antidepressants and anxiolytics as well as potentially preventive
treatments for PTSD (Martin et al 2000). Oral administration of the CRF1 receptor antagonist antalarmin significantly decreased CSF CRF, pituitary-adrenal and autonomic responses to stress and inhibited behaviors
indicative of fear and anxiety in adult primates (Habib et
al 2000). The antidepressant and anxiolytic properties ofthe selective CRF1 receptor antagonist R121919 wasrecently demonstrated in a clinical trial of depressed
patients (Zobel et al 2000). Interestingly, treatment of rats
exposed to prenatal stress with CRF antagonists reverses
the characteristic increases of fearful behavior observed inthese animals (Ward et al 2000). In 9- to 11-day-old rat
pups, the CRF1 receptor antagonist CP 154,526 diminishes
vocalizations indicative of anxiety in response to separation from their litters (Kehne et al 2000). Given the factthat early life stress is related to substantial alterations incentral CRF systems, it is plausible that CRF1 receptor
antagonists, once they are available, will represent themost direct treatment of symptoms related to early life
stress in children and adults.
Finally, the intriguing evidence that the neurobiologicaleffects of handling and maternal separation may be reversed by cross-fostering of the pups gives rise to the
hypothesis that improvement of parental or foster care
may help prevent or reverse the neurobiological andpsychopathologic consequences of early life stress inhumans. Thus, a recent study found that maltreated preschool children who were placed in an Early Intervention
Foster Care program, which uses the foster-care setting fortherapeutic intervention promoting positive parenting
strategies, showed improved behavioral adjustment andoverall decreases in salivary cortisol levels compared withchildren in normal foster care (Fisher et al 2000).

Conclusion
An unacceptably large number of children in our society
are subjected to early adverse experiences, exposing thesechildren to an increased risk for the development of

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2001;49:1023–1039

1033

depression or anxiety disorders, as well as other disorders,that may persist throughout adulthood. We have summarized findings from preclinical and clinical studies
suggesting that early life stress induces long-lived hyperactivity and sensitization of CNS CRF and other neurotransmitter systems, resulting in enhanced endocrine, autonomic, and behavioral stress responsiveness. With
repeated exposure to life stress, this vulnerability may
result in symptoms of depression and anxiety disorders, aswell as in other physiologic abnormalities frequently
observed in adult survivors of abuse. Researchers havenow begun to identify factors that moderate or reverse theeffects of early life stress on neurobiological systems.
Most preclinical studies have examined the long-term
impact of early life stress on brain development in adultanimals, whereas a limited number of studies have evaluated the impact of early experiences in developing animals; however, neurobiological findings in children withearly life stress differ in several aspects from findings inadults. There are also differences in the neurobiology ofearly-onset and adulthood depression, and early life stressappears to be a crucial factor in explaining these differences. Thus, preclinical studies focusing on developmental
aspects of the effects of early life stress are urgently needed.
These studies may help to understand time patterns in thedevelopment of neurobiological changes in relation to earlylife stress, to identify critical developmental periods sensitive
to the effects of stress or intervention, and to help elucidate
the mechanisms of early-onset depression.
It should be noted, however, that it is generally difficult
to infer from animal studies on the effects of early life
stress on human development. First, the length of periodsof plasticity in various brain regions differs between ratsand humans. Second, there are immanent difficulties inmodeling typical stressful experiences of human infants orchildren in animal paradigms: maternal separation and
VFD may best parallel instances of neglect of humanchildren, whereas the human experiences of sexual or
physical abuse include a commission, which may havedifferential neurobiological effects (Glaser 2000). Moreover, human early life stress is characterized by great
variety with respect to age at onset, severity, frequency,
and chronicity of the stressor, and additional environmental variations, such as the general family environment andthe availability of coping resources, which contribute to
the effects of the stress in humans. Fourth, different
research methods to assess neurobiological systems inanimals and humans complicate the direct comparison offindings.
Therefore, more studies in humans exposed to early life
stress are needed. These studies will have to meet thechallenge to identify differential immediate and long-term
effects of great varieties of early life stress experienced at

1034

C. Heim and C.B. Nemeroff

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2001;49:1023–1039

different developmental stages. Although difficult to realize, it will be indispensable to conduct longitudinal clinicalstudies, which will enhance our understanding of the criticaldevelopmental phases that are particularly sensitive to theeffects of stress as well as pharmacologic or social
buffering and that will provide unequivocal knowledge on
a causal relationship between early life stress and thedevelopment of pathology in humans. The development of
new techniques allowing for the assessment of central neurotransmitter and receptor changes, including CRF receptors,
will considerably advance this clinical research and will
increase the comparability of clinical and preclinical findings.
Future studies should further elucidate the role ofpredisposing factors in the manifestation of a vulnerable
phenotype as a consequence of early life stress. For
example, there may be genetic vulnerability to the neurobiological effects of early life stress. Thus, twin studies areneeded for the prediction of neurobiological stress responsiveness as a function of genes, early life stress, andongoing stress, among other factors. Although national
epidemiologic studies suggest a similar incidence of childhood abuse in girls and boys, the role of gender in thedevelopment of neurobiological alterations after early life
stress is a neglected area of research. And although theprevalence of early-onset depression is similar in girls andboys, adult women more often develop depression thanmen (Martin et al 2000). Gender differences in children’sand adolescents’ adaptation to sexual abuse have beenreported (Feiring et al 1999), as well as differences in HPAaxis reactivity in male and female healthy subjects anddepressed adolescents (Dorn et al 1996; Kirschbaum et al1999). Thus, future preclinical and clinical studies should
evaluate the interaction between stress and gender in inducing neurobiological vulnerability to depression and anxiety.
Taken together, a pivotal role of early environmental
variation in the development of long-term (mal)adaptations to stress has been documented in an impressive seriesof studies. The current database suggests that early adverse
experiences should be addressed in the clinical care ofchildren, adolescents, and adults with psychiatric disorders, a need that is often unmet in clinical practice.

Supported by The Conte Center for the Neurobiology of Mental
Disorders and NIH MH Grant No. 42088.
Aspects of this work were presented at the conference, “The Unmet
Needs in Diagnosis and Treatment of Mood Disorders in Children andAdolescents,” October 17–18, 2000, in Washington DC. The conference
was sponsored by the National Depressive and Manic-Depressive Association through unrestricted educational grants provided by Abbott
Laboratories, AstraZeneca, Bristol-Myers Squibb Company, Forest Laboratories Inc., Glaxo Wellcome Inc., The Henry Foundation, Janssen
Pharmaceutica, Eli Lilly and Company, Merck & Co., National Instituteof Mental Health, Pfizer Inc., Pharmacia, SmithKline Beecham, Solvay
Pharmaceuticals Inc., and Wyeth-Ayerst Laboratories.

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