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NEUROBIOLOGICAL SEQUELAE OF CHILDHOOD TRAUMA:
Post-traumatic Stress Disorders in Children
Bruce D. Perry, M.D., Ph.D.
The ChildTrauma Academy
www.ChildTrauma.org
*This is an Academy version of
a chapter originally published in Catecholamine
Function in Post Traumatic Stress Disorder: Emerging Concepts.
Official citation: Perry, BD Neurobiological
Sequelae of Childhood Trauma: Post traumatic Stress Disorders in Children.
In: Catecholamine Function in Post Traumatic
Stress Disorder: Emerging Concepts (M Murburg, Ed.) American Psychiatric Press,
Washington, DC, 253-276, 1994
Traumatic events can have a profound and lasting impact
on the emotional, cognitive, behavioral and physiological functioning of an individual.
These adverse effects have been described in combat veterans since the Civil War (DaCosta
1871, Bury 1918, Frazer and Wilson 1918, Dobbs and Wilson 1960 Birkhimer et al. 1985,
Bleich et al. 1986). Only recently, however, has the distinct trauma-associated syndrome
characterized by prominent affective symptoms (dysphoria, irritability, anxiety) and a
'hyperactive' sympathetic nervous system (Horowitz et al. 1980, Brende 1982 ) been called
Post-Traumatic Stress Disorder (DSM-III, PTSD). The symptoms of PTSD fall into three
clusters; 1) recurring intrusive recollection of the traumatic event such as dreams and
'flashbacks', 2) persistent avoidance of stimuli associated with the trauma or numbing of
general responsiveness and 3) persistent symptoms of increased arousal characterized by
hypervigilance, increased startle response, sleep difficulties, irritability, anxiety and
physiological hyperreactivity. While described originally in combat veterans, a high
percentage of rape victims, sexual abuse victims, survivors of natural or manmade
disasters, and witnesses to violence also experience symptoms of PTSD (e.g.,Terr 1983,
Blanchard et al. 1983, Boehlein et al. 1985, McLeer et al. 1988). The largest group of
victims of these traumatic events are children.
The present chapter will review childhood PTSD with
specific focus on neurobiological sequelae of childhood trauma and present some
preliminary evidence of altered functioning of brainstem catecholamine systems in
childhood PTSD. In specific, it is hypothesized that the abnormal patterns of
catecholamine activity associated with prolonged 'alarm reactions' induced by traumatic
events during infancy and childhood can result in altered development of the central
nervous system (CNS). Furthermore, it is hypothesized that this altered development
includes a 'dysregulated' brainstem which in turn results in a host of signs and symptoms
related to abnormal brainstem functioning, including altered cardiovascular regulation,
affective lability, behavioral impulsivity, increased anxiety, increased startle response
and sleep abnormalities. Finally, early life experience is discussed, in context of
childhood trauma, as an 'expresser of genetic predispositions.
THE SCOPE OF CHILDHOOD TRAUMA
PTSD has been described in survivors of sexual abuse
(Conte 1985, Browne and Finkelhor 1986), victims of violence (Boehnlein et al. 1985),
witnesses to violent acts (Eth and Pynoos 1985), survivors of natural disasters (McFarlane
1987), survivors of catastrophic accidents (Martini et al. 1990), and burn victims (Perry
et al. 1987) among others. While no epidemiological data regarding childhood PTSD are
available, conservative estimates can be made based upon the incidence of traumatic events
in the childhood population. Conservative estimates of childhood sexual abuse suggest an
incidence of 200,000 new cases each year (Finkelhor, 1984). Maltreatment of children
(physical, emotional or sexual abuse) is estimated to exceed 1.5 million children per year
(National Incidence Study, US Dept Health/Human Services, 1988). Prevalence values for
sexual (roughly 10-35 %) and physical abuse (5-15 %) vary (see Conte 1985, Greenwood 1990)
but even with conservative estimates (there are approximately 65 million children in the
United States below the age of 16), the number of children exposed to one of these severe
traumas is 9.5 million. In addition to being victims of, children are often witnesses to,
violence; Eth and Pynoos (1985) have estimated that approximately 3 million children each
year witness violence in their homes. Each year thousands of children survive natural or
man-made disasters and traumatizing medical problems such as burns. Taken together, a
conservative estimate of children currently at risk for PTSD exceeds 15 million, and
grows, as traumatized children carry their scars to adulthood and new children are
traumatized each year. It is estimated that 15 % of Vietnam Veterans (1.5 million people)
suffer PTSD (Helzer 1987), yet if one assumes that only 10 % of the children traumatized
since 1964 develop symptoms (a very conservative estimate) there would be 4.5 million
'veterans' of childhood with PTSD. Despite the scope of this serious public health problem
relatively little research has been dedicated to this area. Some critical initial steps
towards understanding the effects of childhood trauma, descriptive and clinical studies,
have been carried out, however.
THE CLINICAL PICTURE: CHILDHOOD PTSD
Clinical descriptive studies of PTSD in children have
been pioneered by Dr. Lenore Terr (Terr 1983). While fitting roughly into the three main
clusters described above, the symptoms of PTSD in children present a more confusing
diagnostic picture for the clinician, often appearing as Attention Deficit Hyperactivity
Disorder, Conduct Disorders, anxiety disorders and affective disorders (Terr 1991).
Over the last two years childhood PTSD has been the
focus of study at the Center for the Study of Childhood Trauma in Chicago. A number of
interesting observations have been made regarding the clinical picture of childhood PTSD.
In the population at the Center, co-morbid DSM III-R diagnoses were seen in 85 % of the
children with PTSD. In many cases the only clear distinguishing features of PTSD were 1)
documented history of a severe traumatic event(s), 2) exacerbation of symptoms with
re-exposure to trauma-specific stimuli and 3) autonomic nervous system hyperarousal. These
three features were noted in children that exhibited psychotic, anxiety and affective
symptoms as well as symptoms of disordered conduct (often aggressive or sexualized,
dependent upon the original trauma). One of the more interesting groups we have identified
is a set of children severely traumatized during the first 3 years of life, resulting in
an apparent post-traumatic pervasive developmental delay. In almost all cases the children
do not understand their symptoms as being related to their history of trauma and often,
especially in the children abused before age 4, cognitive recall of the trauma is not
present. In this regard, it is easy to see how the diagnosis of PTSD is under reported in
children -- a child presents with any array of psychiatric symptoms with no understanding
or recall of traumatic events in their early life, often with an adult caretaker who is
unaware of (e.g., sexual abuse), or unwilling (e.g., physical abuse) to give, history
regarding the trauma. A very consistent physical finding in these children, however, is
autonomic nervous system (ANS) hyperarousal.
Many factors appear to be important in the development
of PTSD following trauma -- the nature of the trauma, the degree to which body integrity
is threatened, the family support system following a trauma, among others (see Eth and
Pynoos 1985). We observed two important factors which appeared to play a role in the
specific set of symptoms a given child will exhibit following trauma: 1) family history of
psychiatric disorder and 2) age at which trauma occurred. Consistent with diathesis-stress
models of mental illness, we observed that, in general, if an individual had a family
history of schizophrenia, the symptoms expressed following childhood trauma included some
pre-psychotic and psychotic range symptoms, if affective or anxiety disorders were in the
family history, the expressed symptoms were mood and anxiety disordered, and if there was
a strong history of alcoholism and sociopathy, symptoms were more conduct disordered. All
of this was superimposed on a developmental matrix such that severe trauma occurring
before age 4 resulted in a much higher probability of pre-psychotic and psychotic
symptomatology. On the other hand, children with a stable first three years of life but
traumatized later in childhood tended to have more affective and anxiety symptoms similar
to those observed in adult PTSD (Perry et al, submitted). These observations may shed
light on recent studies suggesting a relationship between childhood sexual and physical
abuse and borderline personality disorder (Ogata et al. 1990). In this regard we have
found the same ANS hyperarousal and down-regulated platelet alpha-2 adrenergic receptors
in borderline personality disorder (Southwick et al., 1990a, 1990b) as we observed in
adult PTSD (Perry et al. 1987, Perry 1988, Perry et al. 1990).
This complex clinical picture complicates
neurophysiological research in childhood PTSD. Indeed, most of the useful clinical
research which informs the future directions of this field has not been performed within
the conceptual framework of PTSD, a DSM III-R diagnostic entity. Much of the important
descriptive work comes from studies of the effects of sexual or physical abuse (e.g.,
Browne and Finkelhor 1988, Dodge et al. 1991) and of early life loss as a predisposing
feature for affective disorders (e.g., Brier et al. 1987; 1988). Despite a relative
abundance of clinical descriptive studies from these areas, we know very little about the
pathophysiology underlying the many physical signs and symptoms of childhood PTSD (Ornitz
and Pynoos 1990). Studies of the neurobiology of PTSD in adults which suggest altered
functioning of catecholamines (this volume) provide direction for studies in children.
Involvement of CNS catecholamines in the pathophysiology of childhood PTSD is not
surprising considering the key role they play in the stress response (Murberg 1990).
CATECHOLAMINES AND STRESS
In 1914 Walter B. Cannon first coined the phrase
"fight or flight" to describe the body's appropriate response to a stressful
stimuli. When an individual is exposed to real or perceived danger, a series of complex,
interactive neurophysiological reactions occur in the brain, the autonomic nervous system,
the hypothalamic-pituitary adrenocortical (HPA) axis and the immune system. These
responses evolved to provide the critical total body mobilization required for the
individual to survive a life-threatening danger. In the initial phases, first labeled 'the
alarm reaction' and the 'stage of resistance' by Hans Selye in 1936, portions of the brain
involved in arousal, attention and concentration become activated, resulting in
hypervigilance to the danger with a decrease in attention to less pressing environmental
stimuli -- a soldier in the midst of a fire fight, for example, may not know he has been
wounded until the end of the fight.
The neurophysiology of the 'alarm reaction' has been
studied extensively in man and in animal models (see Selye 1936, Stone 1975, Stone 1988,
Murberg et al. 1990). Acute 'stress' is associated with a variety of physiological
responses including the activation of the HPA axis with a concomitant peripheral release
of ACTH, epinephrine and cortisol, a significant increase in centrally-controlled
peripheral sympathetic nervous system tone, and the 'activation' of a variety of
neurochemical systems in the CNS. One of the most critical of these systems is the
noradrenergic nucleus in the locus coeruleus (Korf 1976). This region controls
noradrenergic tone and activity throughout the midbrain and in important forebrain areas
including the cortex (Foote et al. 1983). The LC has been shown to be critical in many
regulatory functions including the regulation of affect, 'irritability', locomotion,
arousal, attention and startle (Korf 1976, Foote et al. 1983, Andrade and Aghajanian 1984,
Bhasharan and Freed 1988). Another key neural system in the brain, also an
adrenergic/noradrenergic system is the ventral tegmental nucleus (V.T.N.) which is
involved in regulation of the sympathetic nuclei in the pons/medulla (Moore and Bloom
1975). Both the L.C. and the VTN nuclei have adrenergic receptors which are involved in
modulation of the adrenergic or noradrenergic afferentation and efferent outflow (Perry et
al. 1983, Vantini et al. 1984). The critical role of CNS catecholamines and their
receptors is discussed in detail elsewhere (Giller et al. 1990, Murberg 1990, Perry 1988,
Perry et al. 1990), for the present discussion it is sufficient to know that acute stress
results in an increase in LC and VTN activity.
The neurophysiological activation seen during acute
stress is usually rapid and reversible. When the stressful event is of a sufficient
duration, intensity, or frequency, however, these changes are not reversible. Stress
induced 'sensitization' occurs-- the neurochemical systems mediating the stress response
(e.g., LC noradrenergic systems) change, becoming more 'sensitive' to future stressful
events. The molecular mechanisms underlying this phenomenon are not well understood but
likely are related to changes in receptor sensitivity following transiently increased
neurotransmitter activity, similar to what is seen in cocaine sensitization (Kalivas and
Duffy 1989, Kleven et al. 1990) The major increases in catecholamine activity seen during
the stress response result in increased receptor stimulation and intracellular
receptor-mediated signals. In turn, these changes in intracellular second and third
messenger result in altered gene expression of a variety of important structural and
regulatory proteins including receptor/effector systems (see Kandel and Schwartz 1982,
Goelet and Kandel 1986). Finally, the altered expression of these proteins alters the
responsivity of the catecholamine systems mediating stress. It is this altered
responsivity which can be related to the hypervigilance, increased startle, affective
lability, anxiety, dysphoria, increased SNS activity and reactivity seen in PTSD (see
Krystal et al. 1989; Perry et al. 1990a).
CATECHOLAMINES AND DEVELOPMENT
In the adult, with a mature brain, the increases in
catecholamine activity associated with the stress response may result in sensitization. In
the developing brain, however, neurotransmitters and hormones play key roles in neuronal
migration, differentiation, synaptic proliferation and overall brain development (Lauder
1988) and, therefore, the tremendous increases in neurotransmitter activity seen with
severe or prolonged stress would be expected to have a significant impact on brain
development.
While each neuron, indeed each cell, in an individual's
brain contains the same genetic material, each expresses a slightly different portion. As
the brain develops, neurons divide, migrate, and differentiate in response to
'microenvironmental' cues, which confer information to, and direct specific
differentiation of, the cell. Each neuron's unique structural, biochemical and functional
character, then, is a function of the its unique environmental history -- the specific
pattern, timing and quantity of these microenvironmental cues. Some of the most important
of these cues are receptor-mediated signals from neurotransmitters and hormones. Indeed,
catecholamine cues during development are important in determining critical functional
properties of mature neurons, including the density of neurotransmitter receptor (e.g.,
Miller and Friedhoff 1988, Perry et al. 1990b). Alterations in the pattern, timing and
quantity of catecholamine (or any critical neurotransmitter system) activity during
development might be expected to result in altered development of catecholamine
receptor/effector systems and the functions mediated, in part, by these systems. A
trauma-induced prolonged stress response is likely to result in an abnormal pattern,
timing and intensity of catecholamine activity in the developing brain. The development of
the human brain continues beyond birth and its development remains vulnerable to the
abnormal patterns of neurotransmitter and hormone activity seen following trauma. Young
children victimized by trauma are at risk for developing permanent vulnerabilities --
permanent changes in neuronal differentiation and organization. In this regard, childhood
PTSD is a developmental disorder.
It appears that there are developmental phases during
which an individual is most vulnerable to traumatic stressors. This most vulnerable period
occurs during the development of the complex stress-mediating CNS systems, including the
catecholamines. It is likely that the functional capabilities of the CNS systems mediating
stress in the adult are determined by the nature of the 'stress' experiences during the
development of these systems, i.e., in utero, during infancy and childhood (Perry, 1988;
Perry et al., 1990). A number of fascinating studies in animals demonstrate the exquisite
sensitivity of the developing CNS to stress (see Suoumi 1986). In rats exposed to
perinatal handling stress major alterations in the ability of the rat to 'learn' and to
respond appropriately to stressors are seen later in life (Weinstock et al. 1988). The
most interesting aspect of these studies is that exposure to unpredictable stress resulted
in deficits while exposure to consistent, daily stress resulted in 'improved' or superior
behavior -- these animals were 'resilient'. One can speculate on equivalent 'controlled'
or daily stress and uncontrollable, non-scheduled stressors in the development of a human.
An infant who is allowed to have an 'optimal' degree of frustration, one who can control,
during rapprochement, his own optimal degree of 'tension, anxiety' (i.e., stress) and
return to mother for comfort, is one whose developing CNS is establishing an appropriate
neurochemical milieu for the development of a flexible, maximally-adaptive physiological
apparatus for responding to future stressors. A child who is reared in an unpredictable,
abusive or neglectful environment (see Spitz and Wolfe 1946) will likely have evoked in
his developing CNS a milieu which will result in a poorly organized, 'dysregulated' CNS
catecholamine system. One would hypothesize that such an individual would be susceptible
to the development of more severe signs and symptoms when exposed to psychosocial
stressors through the course of their life.
Some studies in humans suggest this is the case.
Increased psychiatric symptoms and disorders are observed in adults who have severe,
unpredictable early life stressors (Brown and Harris 1977, Lloyd 1980, Rutter 1984). A
provocative study by Breier and co-workers (1988) reported the effects of parental loss
during childhood on the development of psychopathology in adulthood. They examined a
number of adults who had suffered a parental loss during childhood and found that the
subjects with psychiatric disorders and symptoms had significant biological and
immunological changes related to early parental loss relative to control groups. The
authors concluded that early parental loss (a traumatic event) accompanied by the lack of
a supportive relationship subsequent to the loss (an external stress reducing factor) is
related to the development of adult psychopathology.
If the early life trauma results in an abnormal pattern
of stress-mediating neurotransmitter and hormone and this abnormal set of cues alters
development of CNS catecholamine systems in an adverse fashion, this should be manifest
when examining functions putatively mediated by these CNS catecholamines (see Moore and
Bloom 1989). In specific, one would predict a host of abnormalities related to
catecholamine regulation of affect, anxiety, arousal/concentration, impulse control,
sleep, startle, and autonomic nervous system regulation, among others. Clearly the
clinical symptoms of PTSD support altered functioning in many of these domains. The next
sections of this chapter will review some of our preliminary investigations of the
pathophysiology of severe chronic childhood PTSD.
STUDIES IN CHILDHOOD PTSD
Over the last two years, a variety of studies have been
in progress at the Center for the Study of Childhood Trauma. While multiple groups of
children with PTSD have been studied, the present chapter will discuss our studies with
the severe chronic PTSD group. All of the children in this group have been victims of
severe, repeated trauma (usually physical or violent sexual abuse or both) typically
occurring during the first five years of life. Diagnosis was made using a modification of
the Structured Interview for Post Traumatic Stress Disorder (Davidson et al 1990). It was
hypothesized that since this group experienced trauma early in development, major
disruptions of brainstem organization/development would be more easily observed.
PLATELET ALPHA-2 ADRENERGIC RECEPTORS IN
CHILDHOOD PTSD
Alpha-2 adrenergic receptors, both pre- and
postsynaptic, play important roles in meditating the effects of the catecholamine systems
of the LC and VTN (Perry et al. 1983, Vantini et al. 1984) and thereby mediating both
acute and chronic stress (see U'Prichard and Kvetnansky 1980, Stone et al. 1975, Stone
1988). Over the last few years, we have demonstrated down-regulated and desensitized
platelet alpha-2 adrenergic receptors in combat veterans with PTSD (Perry et al. 1987,
Perry 1988, Perry et al 1990). We have been able to demonstrate that, using this marker,
we can track the overall 'tone' of the sympathetic nervous system (Perry 1988, Perry et
al. 1990, Southwick et al 1990a, 1990b). This indirect method has been useful in examining
regulation and dysregulation of the brainstem catecholamine systems involved in the
regulation of the SNS.
Figure 1
Figure 1. Platelet
alpha-2 adrenergic receptor binding sites in childhood PTSD. Alpha-2 receptor
sites were measured using standard methods (Perry 1988) and comparison of these values
were made across a variety of disorders. These values are all from our laboratory and
adult values summarize findings reported previously (Perry 1987; Perry 1988; Perry et al.
1990, Southwick et al. 1990a, 1990b). Groups include; adult control (n=24), major
depression (MDD, n=8), borderline personality disorder (BPD, n=14), adult PTSD (n=25),
congestive heart failure (CHF, n=23), children control (n=14), childhood PTSD (n=8).
We performed an initial pilot study using these
peripheral receptor measures in childhood PTSD (Perry et al, submitted). Platelet alpha-2
adrenergic binding sites were measured in a small group (n = 8) of children (mean age =
11.1, range 9-13) with PTSD using standard methodologies (Perry 1988). When compared with
an age comparable control group, the PTSD group had fewer total binding sites (Fig 1). This is similar to our observations in adult
PTSD. Down regulated peripheral adrenergic receptors is not unexpected. This likely
reflects down regulation in the presence of 'higher than control' circulating
catecholamine associated with the hyperreactive SNS seen in PTSD (Kosten et al. 1986).
These receptor measures are relatively invasive and
difficult to employ for longitudinal studies in already traumatized children. We elected
to seek other measures for our larger studies. Since the goal was to examine potential
dysregulation of brainstem catecholamines, we elected to utilize simple measures which, in
part, are regulated by brainstem catecholamines -- autonomic regulation of heart rate. We
first demonstrated a relationship between a baseline heart rate measure and platelet
alpha-2 receptor density. Using the children with PTSD and the controls from the
preliminary receptor studies (Fig 1), an estimate of
resting heart rate (obtained by the mean of two baseline periods on either side an
orthostatic challenge, see below) was found to be correlated with the density of platelet
alpha-2 adrenergic receptors (r=-0.839; p<0.001). This correlation is not surprising
considering that overall sympathetic tone is a major determinant of both heart rate and
platelet alpha-2 receptor density.
CARDIOVASCULAR LABILITY IN CHILDHOOD PTSD
A prominent feature of the children we have studied
with PTSD is significant cardiovascular lability. This is manifested in a variety of ways.
First of all, the majority of our PTSD population has a resting tachycardia. Of the 34
children meeting PTSD diagnostic criteria, 85 percent had a resting heart rate greater
than 94 bpm, (the value for an age-comparable group of normal children is 84: Matthews et
al. 1987). Forty percent had resting rates above 100 bpm.
Figure 2
Figure 2. Heart
rate changes following orthostatic challenge in children with PTSD. Examples of
the two major patterns of change in heart rate observed in children with severe chronic
PTSD. Heart rate was monitored each 2 minutes for 20 minutes. During the first 4 time
intervals children were resting quietly in a supine position; after 9 minutes (4.5 time
intervals) children stood up and remained standing for the duration of the challenge
period. A control pattern is illustrated by the open squares (non-PTSD, psychiatric
disordered child, age 11.4). The two PTSD patterns are generally described by higher than
control basal rate and 1) a dramatic overshoot of heart rate with a slow return to a
baseline (closed squares) or 2) a more normal increase in heart rate but a sluggish return
to a baseline rate (closed diamonds).
This lability was even easier to see following a simple
orthostatic challenge (Fig 2). In this simple
procedure, a child was supine for 9 minutes, during which time a baseline heart rate was
established. At 9.5 minutes, the child stood up and remained standing for another 10
minutes. Heart rate was monitored throughout this procedure. Two general patterns of heart
rate change following orthostatic challenge were seen (see Fig 2 legend). In general, the two PTSD patterns are
generally described by higher than control basal rate and 1) a dramatic overshoot of heart
rate with a slow return to a baseline (closed squares in Fig
2) or 2) a more normal increase in heart rate but a sluggish return to a baseline rate
(closed diamonds in Fig 2).
Clearly these simple studies reflect abnormal
regulation of simple autonomic nervous system reflexes mediated, in part, by brainstem
catecholamines. Central regulation of autonomic function, including cardiovascular
reflexes, is very complex (see Loewy and Spyer 1990) but the power of these findings
suggest poorly integrated brainstem functioning. Cardiovascular afferentation influences
the activity of the LC (Elam et al 1984, Svensson 1987) -- this would suggest that, in
addition to any primary dysfunction of the LC related to altered developmental
afferentation, these children with overactive and poorly regulated cardiovascular systems
may also give overactive and poorly regulated afferentation to the LC. This in turn may be
related to some of the symptoms observed in PTSD.
The cardiovascular findings above are from one end of
the spectrum of abused and traumatized children. While caution should be used in
generalizing the findings to other populations with childhood PTSD, it is likely that
similar pathophysiological mechanisms may also be important in other traumatized children.
Our preliminary studies in other children with PTSD suggest that this is the case.
CLONIDINE TREATMENT OF CHILDHOOD PTSD
The receptor and cardiovascular evidence above
suggested that one of the key features of our PTSD population were overactive (increased
sympathetic tone) and over-reactive, poorly regulated (exaggerated orthostatic responses)
brainstem catecholamine systems. For this reason, an open trial of clonidine was carried
out. Clonidine is an alpha-2 adrenergic receptor partial agonist. It acts via a
combination of pre-synaptic inhibition and post-synaptic alpha-2 receptors, some on
important sympathetic nuclei, which may be the mechanism by which it is an effective
antihypertensive medication. In limited open trials, clonidine has been found to be
effective in adult PTSD (Kolb et al. 1984) .
Seventeen children with PTSD (13 male, 4 female; mean
age 10.4, range 6.0 -14.2) were drug free for at least four weeks during which time
baseline symptoms were assessed by using the Psychiatric Symptom Assessment Scale, a 23
item modification of the Brief Psychiatric Rating Scale. As part of the clinical program,
a weekly PSAS was performed, independently, by each child's teacher, individual therapist
and primary child care worker. For the four week, drug-free period prior to starting
clonidine these PSAS scores were meaned. Clonidine was started after appropriate physical
exam, lab work and consents had been obtained. Initial dosage was 0.05 mg bid and rapidly
titrated up to 0.1 mg bid as tolerated. The only side effect of any significance was
sedation, which was typically transient. Altering schedule to 0.05 qid significantly
decreased sedation.
Figure 3
Figure 3. The
effects of clonidine on psychiatric symptoms in childhood PTSD. Seventeen children
with severe chronic PTSD received clonidine (dose range: 0.05 bid to 0.1 mg tid) for a
four week period. Prior to and during this time weekly assessments of symptoms were made
independently by teacher, individual therapist and primary child care worker using the
Psychiatric Symptom Assessment Scale (PSAS). Values represent means of these three
independent assessments from the two weeks prior to (open squares) and the fourth week
(closed squares)of clonidine treatment.
The effects of clonidine on psychiatric symptoms were
profound (Fig 3). This group of children had a wide
range of presentations (see descriptions above). Largest degree of improvement was in the
areas of behavioral impulsivity, anxiety, arousal, concentration and mood. Interestingly,
in the few children that had pre-psychotic or psychotic symptoms, improvement was seen in
these symptoms as well as the more 'traditional' PTSD symptoms. In addition to improvement
in psychiatric symptoms, there appeared to be a decrease in physiological 'lability',
likely underlying the improvement in the other symptoms. Basal heart rate of this group
prior to clonidine treatment was 110 + 12 (as compared to 88 + 10 in an age comparable
non-PTSD psychiatric population). Following four weeks of clonidine, the group mean
dropped to 96 + 8. In addition, the D-scale (autonomic arousal) score of the SI-PTSD
(Davidson et al 1990) prior to medication, 15.3 + 4, dropped to 6 +3. Overall, clonidine
treatment, in this population, significantly improved the signs and symptoms of childhood
PTSD.
This observed pharmacologically-induced decrease in
arousal symptoms suggests that alpha-2 adrenergic receptors play a pivotal role in
mediating the signs and symptoms of PTSD in this group of severely traumatized children.
The role of the alpha-2 receptor in regulating the LC and VTN is well known (Perry et al.
1983, Vantini et al. 1984). The capacity of clonidine to modulate and 'buffer' LC and VTN
activity is related to its special qualities as a partial agonist. In physiological
systems, a partial agonist can act as both an agonist and as an antagonist depending upon
the system's tonic activity -- if the tonic activity falls below a certain level, the
partial agonist will act by stimulating unoccupied receptors thereby increasing agonism;
when the tonic activity becomes too high, the partial agonist will compete with the
endogenous agonist for the receptor sites and decrease activity of the system by
virtue of lower intrinsic activity than the full agonist neurotransmitter. In this way,
clonidine activates some parts of the noradrenergic terminal areas and prevents over
reactivity in others. The summed effect is to help poorly regulated brainstem
catecholamine systems work in a more organized, efficient fashion, thereby decreasing
symptoms related to dysregulation of the brainstem.
IMPLICATIONS AND FUTURE DIRECTIONS
Severe trauma during childhood can have a devastating
effect on the development the brain and all functions mediated by this complex organ --
emotional, cognitive, behavioral and physiological. In many cases the sequelae of
childhood trauma present with signs and symptoms similar to adult PTSD, often they present
with very different symptoms. The concept of childhood PTSD must be considered within the
broader concept of the diathesis-stress model of mental illness. The diathesis-stress
model suggests that a predisposition (genetic or developmental) for a specific psychiatric
disorder exists which can be differentially expressed in an individual depending upon the
degree of 'biopsychosocial' stressors. The concept of PTSD loses meaning if we consider
all of the effects of childhood trauma as part of this 'disorder'. Indeed, it is clear
that early life trauma/stress plays an important role an expresser of
genetically-determined vulnerabilities to a variety of neuropsychiatric disorders,
including schizophrenia (e.g. Garmezy 1978), major depression (Lloyd 1980) and Tourette's
syndrome (Leckman et al. 1990). It is important to study childhood trauma/stress as an
expresser of genetic vulnerabilities to medical conditions, as well, (Coddington 1972a,
1972b) including cardiovascular diseases such as essential hypertension, sudden cardiac
death or cardiac dysrhythmias. Associations between stress during childhood and
adolescence and the development of cardiovascular disease have been made for many years
(see Boyce and Chesterman 1990). It is interesting to note that associations have also
been made between vulnerability to affective disorders and cardiovascular disease. Early
life stress/trauma is a common link between many associated medical and psychiatric
conditions -- including neuroimmunological, cardiovascular and neuroendocrine. This is not
surprising considering the critical role of development in determining final phenotype
(and therefore function) of all physiological functioning in the adult.
For a number of reasons, the long term effects of
childhood trauma remain relatively unexplored. In part this has been due to a variety of
complex clinical and social issues, some of which are being addressed at present by
multipdisciplinary research teams working closely with the state and local social agencies
involved in providing services for these unfortunate children. With the high incidence of
sexual abuse, physical abuse and violence in our society, the need to understand these
complex issues is ever pressing. The study of traumatized children and the long term
effects of trauma provides an important conceptual starting point from which to study the
developmental nature of all psychiatric illness and, hopefully, to develop new and
effective therapeutic and preventative interventions.
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ACKNOWLEDGEMENTS
The author would like to thank the staff, residents and
students of St. Joseph's Carondelet Child Center and the members of the Laboratory of
Developmental Neurosciences. These studies were supported in part by the Center for the
Study of Childhood Trauma, the Brain Research Foundation of Chicago and the Harris Center
for Developmental Studies.
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