Developmental traumatology part I: biological stress systems∗

A.E. BENNETT RESEARCH AWARD Developmental Traumatology Part I: Biological Stress Systems* Michael D. De Bellis, Andrew S. Baum, Boris Birmaher, Matcheri S. Keshavan, Clayton H. Eccard, Amy M. Boring, Frank J. Jenkins, and Neal D. Ryan Background: This investigation examined the relationship between trauma, psychiatric symptoms and urinary free cortisol (UFC) and catecholamine (epinephrine [EPI], norepinephrine [NE], dopamine [DA]) excretion in prepubertal children with posttraumatic stress disorder (PTSD) secondary to past child maltreatment experiences (n 5 18), compared to non-traumatized children with overanxious disorder (OAD) (n 5 10) and healthy controls (n 5 24). Methods: Subjects underwent comprehensive psychiatric and clinical assessments and 24 hour urine collection for measurements of UFC and urinary catecholamine excretion. Biological and clinical measures were compared using analyses of variance. Results: Maltreated subjects with PTSD excreted significantly greater concentrations of urinary DA and NE over 24 hours than OAD and control subjects and greater concentrations of 24 hour UFC than control subjects. Post hoc analysis revealed that maltreated subjects with PTSD excreted significantly greater concentrations of urinary EPI than OAD subjects. Childhood PTSD was associated with greater co-morbid psychopathology including depressive and dissociative symptoms, lower global assessment of functioning, and increased incidents of lifetime suicidal ideation and attempts. Urinary catecholamine and UFC concentrations showed positive correlations with duration of the PTSD trauma and severity of PTSD symptoms. Conclusions: These data suggest that maltreatment experiences are associated with alterations of biological stress systems in maltreated children with PTSD. An improved psychobiological understanding of trauma in childhood may eventually lead to better treatments of childhood PTSD. Biol Psychiatry 1999;45:1259 –1270 © 1999 Society of Biological Psychiatry

From the University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania (MDDB, ASB, BB, MSK, NDR); Developmental Traumatology Laboratory, Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania (MDDB, CHE, AMB); University of Pittsburgh, Pittsburgh, Pennsylvania and Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania (ASB, FJJ). Address reprint requests to Michael D. De Bellis, Director, Developmental Traumatology Laboratory, Western Psychiatric Institute and Clinic, University of Pittsburgh Medical Center, 3811 O’Hara Street, Pittsburgh, PA 15213. Received June 18, 1998; revised December 15, 1998; revised February 16, 1999; accepted February 19, 1999.

© 1999 Society of Biological Psychiatry

Key Words: Child maltreatment, posttraumatic stress disorder (PTSD), urinary catecholamines, cortisol, overanxious disorder (OAD), sexual abuse *See accompanying Editorial, in this issue.

Introduction

T

he diagnosis of posttraumatic stress disorder (PTSD) is made after a person experiences one or more overwhelming traumatic event(s) and reacts with fear or disorganized behavior; followed by complaints of three clusters of categorical symptoms for at least one month: 1) intrusive re-experiencing of the trauma(s), 2) persistent avoidance of stimuli associated with the trauma, and 3) persistent symptoms of increased physiological arousal (Frances 1994). The clinical picture of PTSD in children is similar to that of adults (for review see Pynoos and Eth [1985] or De Bellis [1997]) with the exception of children less than age 4 years where more objective criteria based on observable behaviors are warranted (Scheeringa et al 1995). Children seem to be less resilient to trauma than adults. Results from a recent meta-analysis suggest that children and adolescents are about 1.5 times more likely to be diagnosed with PTSD, once traumatized, than their adult counterparts (Fletcher 1996). Maltreatment of children is defined as neglect, physical abuse, sexual abuse, and emotional maltreatment (that includes verbal threats to the child and witnessing domestic violence). It is a serious public health problem, and may be one of the most common causes of interpersonal traumas and of PTSD in children and adolescents (De Bellis 1997). In 1996, the incidence rate of alleged maltreatment cases were reported to be 44 out of every 1000 children (U.S. Department of Health and Human Services 1998). Maltreatment in childhood is both a cause and a risk factor for PTSD (De Bellis and Putnam 1994). PTSD occurs in 42%–90% of individuals exposed to sexual abuse (McLeer et al 1994), 50%–100% among those witnessing domestic violence (Pynoos and Nader 1989), and 11%–50% (Pelcovitz et al 1994; Green 1985) among physically abused children. Famularo et al (1993) showed that 62 out of 156 (39.7%) children, who were 0006-3223/99/$20.00 PII S0006-3223(99)00044-X

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removed from their parent’s physical and legal custody secondary to maltreatment, had PTSD within the initial disclosure period. Of those children who disclosed sexual abuse, 63% had a diagnosis of PTSD. Seventeen of the 52 (32.7%) re-examined from the original sample of 62 continued to meet PTSD criteria, although 67.3% no longer met full PTSD criteria at 2-year follow-up (Famularo et al 1996). Subjects with chronic PTSD also had much co-morbidity. Thus, the chronic stress of maltreatment experiences in childhood, especially sexual abuse, is a risk factor for acute and chronic PTSD as well as other negative developmental consequences (De Bellis 1997; National Research Council 1993). Several neurotransmitter and neuroendocrine systems are activated during acute stress (reviewed by Charney et al 1993). Traumatic stress may have negative effects on the development of these systems (De Bellis and Putnam 1994). There is little research on the neurobiological effects of trauma and PTSD in developing children. Studies of the neurobiological effects of overwhelming stress in animal models and of the psychobiology of adult PTSD provide our only comparative models. To date, most investigators have focused on two of the body’s major stress systems, the catecholamine system (the locus ceruleus-norepinephrine [NE]/sympathetic nervous system [SNS]) and the hypothalamic-pituitary-adrenal (HPA) axis. Animal studies show that traumatic stress activates the locus ceruleus, the major catecholamine (specifically NE) containing nucleus in the brain (Simson and Weiss 1988) and the SNS leading to the biologic changes of the “fight-or-flight reaction” (Aston-Jones et al 1991). Direct and indirect effects of this activation include increases in catecholamine turnover in the brain, the SNS, and adrenal medulla leading to increases in heart rate, blood pressure, metabolic rate, alertness, and in the circulating catecholamines (epinephrine [EPI], NE, and dopamine [DA]) (for review see De Bellis and Putnam 1994). During stress, the brain’s hypothalamic corticotropin-releasing hormone (CRH) is released. CRH activates the HPA axis by stimulating the pituitary to secrete adrenocorticotropin (ACTH). These events, in turn, promote cortisol release from the adrenal gland, stimulate the SNS, and centrally cause behavioral activation and intense arousal (Chrousos and Gold 1992). The locus ceruleus also indirectly stimulates the HPA axis via connections through the limbic system (for review see De Bellis and Putnam 1994). Cortisol, via negative feedback inhibition on the hypothalamus, pituitary, and other brain structures (hippocampus), suppresses the HPA axis leading to restoration of basal cortisol levels (homeostasis). In animal models, activation of the catecholamine system and CRH results in behaviors consistent with anxiety and hypervigilance, the core symptoms of PTSD in humans.

M.D. De Bellis et al

In adult PTSD, it is hypothesized that the catecholamine system and HPA axis responses to stress become maladaptive, causing long-term negative consequences (reviewed by Charney et al 1993). Results from adult combat-related PTSD studies suggest increased sensitivity of the catecholamine system evident under experimental conditions of stress or challenge (for review see Southwick et al 1998). These findings include increased heart rate, systolic blood pressure, skin conductance, and other SNS responses to adrenergic or traumatic reminder challenge (reviewed by Charney et al 1993, Pittman 1993, Southwick et al 1998), and decreased sleep latency and efficiency (Ross et al 1989) in adult PTSD compared to healthy combat or non-combat controls. Although most baseline studies of single or multiple time point plasma catecholamines found no significant differences between adult PTSD and controls (Southwick et al 1995), elevated 24-hour urinary catecholamine excretions were seen in 3 of 5 studies (for review see Southwick et al 1995). Single time point measures of catecholamines and cortisol may not provide an accurate measure of baseline functioning because of circadian influences. Further, the stress of a single-stick venipuncture may result in elevations of cortisol and catecholamine concentration, obscuring any baseline differences. Thus, in adult PTSD, elevated 24-hour urinary excretion of catecholamines provides evidence of an increase in baseline functioning of the catecholamine system. Unlike the increased sensitivity of the catecholamine system to stress seen in adult PTSD, baseline and challenge studies show that the HPA axis functions in a more complicated manner (Southwick et al 1998). In adult combat-related PTSD, elevated levels of central CRH were found (Bremner et al 1997). Infusion studies of metyrapone, that blocks the conversion of 11-deoxycortisol to cortisol and allows for the direct measure of pituitary release of ACTH, suggested that there is downregulation of anterior pituitary CRH receptors presumably secondary to elevated central CRH and enhanced negative feedback inhibition of the pituitary for cortisol (Yehuda et al 1996). Further evidence for enhanced negative feedback inhibition includes findings of increased number of glucocorticoid receptors on lymphocytes presumably secondary to decreased circulating cortisol, suppression of cortisol with low dose dexamethasone, and lower 24-hour urinary free cortisol (UFC) concentrations in 3 of 4 studies of adult combat related PTSD compared with controls (Mason et al 1986; Yehuda et al 1991; Yehuda et al 1992). Low urinary cortisol was also found in one study of male and female adults with PTSD who survived the Holocaust as children and adolescents compared to survivors without PTSD (Yehuda et al 1995). In two other studies, 24-hour UFC concentrations were higher in male combat veterans with PTSD compared to combat veterans without PTSD

Biological Stress Systems in Childhood PTSD

(Pittman and Orr 1990) and in women with PTSD secondary to childhood sexual abuse compared to women abused as children without PTSD and healthy non-abused control women (Lemieux and Coe 1995). These discrepant findings may be related to the confounding effects of assay methodology, differences in body weight between groups, current life stressors (Kaufman et al 1997b), an independent contribution of other stress systems on the HPA axis (Chrousos and Gold 1992), or as a reflection of chronic HPA adaptation axis long after trauma exposure. Because there are few psychobiological studies on childhood PTSD, we will review this area broadly, also focusing on studies of traumatized children with anxiety or depressive disorders. Findings of elevated baseline 24hour urinary concentrations of catecholamines from the few investigations in traumatized children to date suggest that the psychobiology of child maltreatment may be similar to that of combat-related adult PTSD (De Bellis and Putnam 1994) because there is evidence of an increase in baseline functioning of the catecholamine system in these children. For example, in a pilot study, we showed that sexually abused girls, 58% of whom had histories of severely depressed mood with suicidal behavior (but only one of whom had PTSD), exhibited significantly greater 24-hour urinary concentrations of catecholamines and their metabolites compared with demographically matched non-abused controls (De Bellis et al 1994b). Noradrenergic function as measured by 24-hour urinary catecholamine excretion has been found to be high in male, but not female, children with severe clinical depression having a history of parental neglect (Queiroz et al 1991). Perry (1994) found decreased platelet adrenergic receptors and increased heart rate after orthostatic challenge in physically and sexually abused children with PTSD, suggesting an enhancement of SNS tone in childhood PTSD. Further support for an increase in baseline functioning of the catecholamine system in childhood PTSD is provided by two separate, open-label treatment trials of clonidine, a central alpha2-adrenergic partial agonist, and propranolol, a beta-adrenergic antagonist, both of which dampen catecholamine transmission. Clonidine treatment was associated with general clinical improvement, and decreases in the arousal cluster of PTSD symptoms and in basal heart rate (Perry 1994), while propranolol treatment was associated with decreases in aggressive behaviors and insomnia (Famularo et al 1988). The few investigations to date on the HPA axis and childhood trauma have led to somewhat discrepant results. When examined as a function of the subjects being studied after a duration of time elapsed since trauma exposure, results may fall into a predictable pattern of response; elevated central CRH and resultant hypersecretion of cortisol is seen initially, and enhanced negative feedback

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inhibition of the pituitary for cortisol leading to lower 24-hour UFC findings is seen as a long term, and possibly a developmental (post-pubertal) consequence, of trauma (De Bellis et al 1994a). For example, in two separate studies, maltreated young children with a diagnosis of major depression failed to show the expected diurnal decrease in cortisol secretion from morning to afternoon (Hart et al 1996; Kaufman 1991). Maltreated prepubertal depressed children undergoing current psychosocial adversity have increased human CRH induced ACTH response, but normal cortisol secretion compared to depressed children with prior histories of maltreatment, depressed non-abused children, and healthy children (Kaufman et al 1997b). In an NIMH longitudinal study, augmented mean morning serial plasma cortisol levels were found in sexually abused girls recruited within six months of disclosure compared with non-abused sociodemographically matched controls, suggesting morning hypersecretion of cortisol secretion in the former (Putnam et al 1991). We reported attenuated plasma ACTH responses to ovine CRH in a subsample of these sexually abused girls studied several years after disclosure (De Bellis et al 1994a); the majority of these children had histories of severely depressed mood with suicidal behavior, but only one of whom had a diagnosis of PTSD. The abused girls exhibited reduced evening basal, ovine CRHstimulated, and time integrated total plasma ACTH concentrations compared with matched control subjects. Plasma total and free cortisol responses to ovine CRH stimulation did not differ between the two groups. Twenty-four-hour UFC excretion were nonsignificantly greater in the abused group. These results show that sexually abused girls manifest a dysregulatory disorder of the HPA axis, associated with hyporesponsiveness of the pituitary to exogenous CRH and normal overall cortisol secretion to CRH challenge. Central CRH hypersecretion may have occurred in these sexually abused girls during the emotional and physical stress associated with the traumatic sexual assault(s). CRH hypersecretion may have led to an adaptive down regulation of CRH receptors in the anterior pituitary, similar to the mechanism suggested in adult PTSD (Bremner et al 1997). Another study also found blunted ACTH responses, but normal cortisol secretion to human CRH challenge, in children with major depression and a past history of abuse compared to healthy controls (Kaufman et al 1993). Armenian adolescents who lived close to the epicenter of the 1988 earthquake and experienced a significant direct threat to life had greater PTSD and co-morbid depressive symptoms, lower baseline mean salivary cortisol levels, and greater afternoon suppression of cortisol by dexamethasone, five years after exposure, compared to Armenian adolescents who lived 20 miles from the epicenter (Goenjian et al 1996). The

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Table 1. Demographic Characteristics of Maltreated Children with PTSD, Non-Maltreated Children with OAD and Control Subjects

n Age (years) Age range (years) Race (White/AfricanAmerican/biracial) Weight (kg) Height (cm) BMI (kg/m2) SES Gender (female/male) 24-hour urine (volume) Tanner stage I/II

PTSD

OAD

Control

Statistic

p

18 10.4 6 1.4 8 to 13 10/4/4

10 10.9 6 1.3 9 to 13 10/0/0

24 10.5 6 1.1 8 to 12 20/1/3

— F2,49 5 .56

— NS

FET

.06

40.9 6 11.9 145.9 6 11.2 1.29 6 .21 31.8 6 7.7 8/10 626.8 6 170 9/9

36.2 6 15.7 142.3 6 16.8 1.20 6 .31 41.3 6 10.9 6/4 655.5 6 249.4 6/4

35.5 6 8.7 143.1 6 10.2 1.20 6 .17 48.8 6 11.0 9/15 751.5 6 277.8 13/11

F2,49 5 1.24 F2,49 5 .39 F2,49 5 1.20 F2,49 5 14.9 x2 5 1.5 F2,49 5 1.51 x2 5 .2

NS NS NS ,.001a NS NS NS

PTSD, posttraumatic stress disorder; OAD, overanxious disorder; SES, socioeconomic status; BMI, body mass index; FET, Fisher’s Exact Test. a PTSD . OAD 5 Controls.

results of this latter study are similar to the HPA findings in adult PTSD. Thus, these studies show that elevated secretion of ACTH or cortisol is seen initially, and enhanced negative feedback inhibition of the pituitary for cortisol is seen as a long term, and possibly a developmental consequence, of trauma. The objective of this investigation was to non-invasively examine biological stress response systems in maltreated children with PTSD and to compare these measures to two non-traumatized groups, anxious children with DSM-III-R overanxious disorder (OAD) and healthy controls. We were not only interested in studying maltreated children with PTSD from past traumas, but also children who were not currently experiencing overwhelming stress, to ascertain if traumatic experiences were associated with long lasting biological stress system changes during development. We recruited non-traumatized OAD children to disentangle PTSD from other non-trauma related anxiety disorders. Because this investigation is cross sectional, it is difficult to separate out the effects of heterogeneous sources of trauma and other confounding factors, e.g., poverty, substance abuse, low educational levels, poor parenting skills, and legal and social service entanglements (De Bellis and Putnam 1994). In the emerging field of developmental traumatology, measures of trauma (type, age of onset, and duration of trauma) as well as other mediating factors such as social support and demographic measures are regarded as independent variables and behavioral, cognitive, emotional, and biological measures as dependent variables. Because PTSD in maltreated children is hypothesized to be associated with global deficits in behavioral, cognitive, and emotional functioning, and alterations of biological stress systems, a cross sectional study showing an association between abuse and the dependent variables is the first scientific step in evaluating these issues. Although cross

sectional investigations do not establish cause-effect relationships, they are undertaken to generate likely hypotheses that can be tested in more expensive prospective longitudinal studies of child abuse. Baseline activity of the HPA axis and the catecholamine system can be measured by sampling concentrations of UFC and the catecholamines, NE, EPI, DA and their metabolites in body fluids. In humans, cortisol and essentially all catecholamines and their metabolites are excreted into urine and have a 24-hour diurnal rhythm (Maas et al 1987) (Chrousos and Gold 1992). Timed measures of 24-hour UFC and catecholamine concentrations reflect daily baseline functional activity. Therefore, we hypothesized that prepubertal children with PTSD will manifest increased 24-hour UFC and urinary catecholamines concentrations when compared to the non-traumatized groups. We also hypothesized that children with PTSD will have greater anxiety as well as co-morbid depressive and externalizing symptoms than OAD and control subjects and that clinical symptoms will positively correlate with 24-hour UFC and urinary catecholamine concentrations.

Methods and Materials Subjects Medication naive prepubertal children with PTSD (n 5 18), with OAD (n 5 10) and healthy non-abused controls (n 5 24) were recruited (Table 1). Subjects were group matched on age, gender, Tanner Stage, height, and weight. Fourteen of the 18 maltreated subjects with PTSD had co-morbid psychiatric disorders, major depressive disorder (n 5 8), dysthymic disorder (n 5 5), oppositional defiant disorder (n 5 10), and attention-deficit hyperactivity disorder (n 5 3). Ten of 18 subjects met criteria for more than 3 DSM-III-R Axis I diagnoses (mean number of diagnoses 2.4 6 1.0). The majority of maltreated subjects (15 of 18) experienced PTSD secondary to sexual abuse. For these children, the average age of

Biological Stress Systems in Childhood PTSD

onset of sexual abuse was 4.7 6 3 years with an average duration of 2.4 6 1.8 years before disclosure. All perpetrators of sexual abuse were male and included father or step-father (6 of 15), older brother (5 years senior to victim) (5 of 15), uncle or other close family friend or relative whom served as a regular caregiver (4 of 15). Of the sexually abused subjects, many experienced other interpersonal traumas including physical abuse (2 out of 15) with average age of onset of physical abuse of 2.5 6 0.7 years and an average duration of 1.5 6 0.7 years; and witnessing domestic violence (11 of 15) from the average age of onset of witnessing domestic violence of 2.1 6 2 years with an average duration of 5.3 6 2.2 years. One subject experienced PTSD from chronic physical abuse (age of onset of 7 years with duration of 4 years before disclosure) and two from witnessing domestic and community violence (age of onset of 1.3 6 0.4 years with an average duration of 4 6 0.7 years before disclosure of neglect). Thus all maltreated subjects with PTSD had experienced chronic adversity throughout their development and had a diagnosis of chronic PTSD. During this study, all maltreated subjects were living in stable home environments (permanent placements) with a non-abusing caregiver: 11 were living with their mother, 1 with a grandmother, 2 with a legally adoptive mother, and 1 with an aunt. Eight of the ten OAD subjects had co-morbid psychiatric disorders, major depressive disorder (n 5 1), dysthymic disorder (n 5 4), oppositional defiant disorder (n 5 2), attention-deficit hyperactivity disorder (n 5 1), and other anxiety disorders (separation anxiety disorder, social phobia, (n 5 2). Eight of 10 met criteria for two or more DSM-III-R Axis I diagnoses (mean 1.9 6 0.6). The PTSD group had a non-significantly greater number of African-Americans. Maltreated subjects with PTSD were lower on socioeconomic status (SES), as measured by the Hollingshead four factor index (Hollingshead 1975) compared to control groups. All subjects underwent clinical evaluations as described below.

Clinical Evaluation Subjects were evaluated by the primary author (a board certified child psychiatrist [M.D.D.]) using a detailed trauma interview as described (De Bellis 1997) and again by a trained Master’s level clinician (who was blind to clinical status before the structured interview) using a modified version of the Schedule for Affective Disorders and Schizophrenia for School-Age, Present Episode (K-SADS-P) (Chambers et al 1985) and Lifetime Version (K-SADS-E) (Orvaschel and Puig-Antich 1987) interview with both child and parent(s) as informants. Questions concerning traumatic events and PTSD symptoms over the subject’s lifetime were incorporated into an expanded assessment of PTSD completed as part of the K-SADS. These additional questions involved the types of interpersonal and non-interpersonal traumas and the nature and circumstances of the such traumatic experiences are described (Kaufman et al 1997a). Consensus meetings were held after the structured interview (M.D.D.) with the clinician and all discrepancies were resolved with information written in the medical records or on re-interviewing the child or parent to clarify information. All subjects completed the Childhood Depression Inventory (CDI) (Kovacs 1985) during the initial screening. Parents of subjects completed the Child Behavior Checklist (CBCL) (Achenbach and

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Edelbrock 1983), and the Child Dissociative Checklist (CDC) (Putnam and Peterson 1994); and the clinician completed the Children’s Global Assessment Scale (GAF) (Shaffer et al 1983) and Hollingshead Four factor index of socioeconomic status (SES) (Hollingshead 1975). Maltreated children with PTSD were recruited from the outpatient clinic of Western Psychiatric Institute and Clinic, University of Pittsburgh and private mental health agencies that serve maltreated children in the City of Pittsburgh. Inclusion criteria were the following: 1. A primary DSM-III-R diagnosis of PTSD that resulted from child maltreatment (interpersonal violence) defined as physical abuse, sexual abuse, or witnessing domestic violence. Physical abuse was defined as physical maltreatment as a result of which serious injury was sustained or bruises were sustained on more than one occasion. Sexual abuse was defined as incidents of forced genital fondling or oral vaginal or anal intercourse, by an adult or adolescent caregiver/perpetrator (of greater than 5 years senior to the subject). Witnessing domestic violence was defined as the subject witnessing caregiver injured by a violent act. 2. Reported and substantiated child maltreatment experiences by Child Protective Services in the City of Pittsburgh, before initiation of treatment and this research study. 3. The availability of at least one non-abusing caregiver who could cooperate with this protocol. 4. Living in a stable home environment defined as not in danger from perpetrator(s) for at least a period of 3 months before this investigation. 5. Because child maltreatment experiences, as well as a prior diagnosis of PTSD, are associated with much psychiatric co-morbidity (De Bellis 1997), the DSM-III-R diagnosis of PTSD must predate the onset of other co-morbid psychiatric diagnoses and be the diagnosis for which the subject was primarily treated in psychotherapy. Co-morbidity was not an exclusionary criteria for this study. 6. Because the DSM-IV criteria for PTSD differed slightly from DSM-III-R, we required that all maltreated subjects with PTSD also met the DSM-IV PTSD criteria currently for inclusion in this study. Non-traumatized children with OAD were recruited from the outpatient clinic of Western Psychiatric Institute and Clinic, University of Pittsburgh. Inclusion criteria were the following: 1. A diagnosis of DSM-III-R OAD. 2. No lifetime episode(s) of trauma or maltreatment. 3. Because DSM-III-R diagnosis of OAD is also associated with psychiatric co-morbidity (Biederman et al 1993), OAD must predate the onset of other co-morbid diagnoses and be the most persistent diagnosis in time. Co-morbidity was also not an exclusion criteria for this group. 4. Because the DSM-IV dropped the diagnosis of OAD, all OAD subjects also met the DSM-IV criteria currently for generalized anxiety disorder (GAD) for inclusion in this study.

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Control children were at low risk for a major psychiatric disorder and had no lifetime episode of trauma or maltreatment or any other major psychiatric disorder assessed as described above, and were recruited by advertisement. First and second degree relatives were interviewed using the K-SADS-E for relatives, age 6 –18, and the Schedule for Schizophrenia and Affective Disorders-Life Time (SADS-L) (Spitzer et al 1978) for adult relatives. Unavailable adult first and second degree relatives were assessed using the Family History-RDC technique with the child’s parent(s) serving as the informant(s). Low familial risk for major psychiatric disorder was defined as having no first degree relative with a lifetime episode of any affective disorder, having no first or second degree relative with a lifetime episode of mania, schizoaffective disorder or schizophrenia, and having not more than 20% of second degree relatives with a lifetime episode of Major depressive disorder (MDD). Exclusion criteria were: 1. The use or presence of medication with central nervous system or HPA axis effects within the 2 weeks before 24-hour urine collection, including over the counter cold preparations that contain pseudoephedrine and related compounds. 2. Presence of a significant medical illness. 3. Gross obesity (weight greater than 150% of ideal body weight) or growth failure (height under 3rd percentile). 4. IQ lower than 70. 5. Anorexia nervosa, autism or schizophrenia by DSM-III-R criteria. 6. Tanner stage III or greater of either breast or genital development (Marshall and Tanner 1969; Marshall and Tanner 1970). 7. Current or past substance abuse or dependence disorder. 8. Current diagnosis of functional or nocturnal enuresis. 9. Positive trauma history in subjects in the OAD and healthy volunteer control groups. All subjects were naive to psychotropic medication(s) before this study and thus were not withdrawn from psychotropic medication(s) to undergo this investigation. Parent(s) or guardian(s) gave written informed consent and children assented before participating in this protocol. Confidentiality was maintained. Subjects received monetary compensation for participation. This protocol was approved by the University of Pittsburgh Institutional Review Board.

Sample Collections Subjects and their guardians were given detailed instructions. 24-hour urine collections started after the first morning void and ended after the next morning’s void. Subjects followed a low monoamine diet and kept a daily log of diet and activities for three days before and on the day of collection. Twentyfour hour urine collections were performed, for volume, cortisol, and catecholamine measures over a non-school day in which the subjects were not engaged in stressful activities (such as athletic competitions, studying for important exams, or involved in court proceedings). Urine samples were refrigerated during the 24-hour collection period without preserva-

tives. At the end of collection and after the evaluation of volume, aliquots were frozen at 280°C without preservatives by 11:00 hours until assayed.

Biochemical Measures CORTISOL. Twenty-four-hour urinary free cortisol (UFC) concentrations were determined by radioimmunoassay (RIA), MAGIC COR RIA kit (Ciba Corning) and calculated as mg/dl. Samples were centrifuged at low speed, 5C, to precipitate sediment. Twenty ml of urine was assayed in duplicate according to kit directions along with kit standards. CATECHOLAMINES. Biochemical analyses of the 24-hour urinary catecholamine concentrations (epinephrine (EPI), NE and DA)(reported as ng/day) were calculated as nanograms per milliliter (ng/ml) and analyzed by solid phase extraction (SPE), in duplicate, along with a calibrator and control (Bio-Rad) and determined by high pressure liquid chromatography (HPLC) with electrochemical detection. Three ml of urine/calibrator/control was pipetted into a tube along with 50 ml DHBA (internal standard, Bio-Rad), 5 ml dilution reagent (30 mM ammonium acetate, 2.7 MM EDTA; pH 7.5) and 100 ml M NaOH. The pH of each sample was adjusted to between pH 6–7 using 0.5 M NaOH or 1 M acetic acid. The sample solution was absorbed onto a SPE column filled with Bio-Rex 70 cation exchange resin, 50–100 mesh (Bio-Rad). When the samples had completely drained, they were washed with 8 ml dilution reagent followed by two 7.5 ml distilled water washes. When completely drained, the SPE columns were placed over clean vials containing 200 ml of 1 M acetic acid. The catecholamines were eluted using 6 ml of 3.6 mM ammonium pentaborate, 100 ml of the eluate was injected onto the HPLC. HPLC was performed using a Beckman Ultrasphere C18 ODS 5 mm column, 4.6 3 15 cm on a system consisting of a Beckman 125 pump and 507e refrigerated autosampler, an ESA 460 electrochemical detector equipped with an ESA 520 guard cell 9 1 400 mV) and 5011 analytical cell (E1: 2200 mV, E2: 1280 mV). The mobile phase consisted of 50 mM M NaH2PO4, 33.6 mM EDTA, 0.43 mM SOS, pH 4.0: MeOH; 88:12, flow was set at 1.2 ml/min. The coefficient of intra-assay variation were 3%, 4%, 5% for E, NE, DA respectively.

Statistical Methods Data distributions were examined for normality. Where significantly non-normal distributions were found, the data were log transformed to normalize the distributions before applying parametric tests. Demographic variables were compared using analysis of variance (ANOVA) or Pearson Chi Square or Fisher’s Exact Test as appropriate. PTSD symptoms were grouped into the DSM-IV criteria B (intrusive symptoms), C (avoidant symptoms), and D (increased arousal symptoms) clusters. The total number of symptoms, age of onset of PTSD trauma, duration of PTSD trauma, and clinical data were correlated with biological measures using Spearman correlations. Spearman correlations were used because of the non-normal distribution of trauma measures. ANOVA was used to detect significance diagnostic group differences in biochemical measures. To determine post hoc differences between individual groups the Tukey–Kramer

Biological Stress Systems in Childhood PTSD

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Table 2. Clinical Ratings of Maltreated Children with PTSD, Non-Maltreated Children with OAD and Controls Ratings CDI CDC Suicidal ideation Suicidal attempts GAF CBCL-competence T score CBCL-activities T score CBCL-social T score CBCL-school performance T score CBCL-withdrawn T score CBCL-somatic complaints CBCL-anxious/depressed T score CBCL-social problems T score CBCL-thought problems T score CBCL-attention problems T score CBCL-delinquent behaviors T score CBCL-aggressive behaviors T score CBCL-internal T score CBCL-external T score CBCL-total T score

PTSD

OAD

9.61 6 7.1 7.28 6 4.9a 12/18 8/18 52.39 6 11.4b 44.18 6 9.6b 47.44 6 6.1 44.50 6 10.6b 40.59 6 9.6b 61.94 6 12.35a 61.11 6 7.51a 64.00 6 11.2a 60.94 6 9.2a 61.61 6 10.0a 63.61 6 12.4a 62.39 6 10.6a 65.11 6 13.2a 63.22 6 12.2a 62.83 6 13.2a 64.28 6 12.2a a

Control

3.70 6 4.2 2.20 6 5.0b 3/10 1/10 59.80 6 5.1a,b 46.75 6 10.2b 48.13 6 5.4 45.75 6 9.4b 45.13 6 9.1b 60.30 6 9.3a 59.30 6 11.8a 66.00 6 9.0a 55.70 6 6.5b 55.40 6 9.3b 60.10 6 9.2a 53.90 6 7.1b 56.10 6 6.9b 63.80 6 11.2a 53.00 6 9.8a,b 57.30 6 10.4a b

2.08 6 2.4 0.65 6 0.9b 0/24 0/24 87.17 6 5.5a 54.17 6 11.6a 49.29 6 5.4 50.38 6 6.5a 50.75 6 4.7a 51.38 6 2.9b 52.17 6 4.4b 51.71 6 3.4b 51.21 6 2.4b 52.88 6 4.6b 51.38 6 4.2b 52.42 6 4.9b 51.17 6 3.2b 43.08 6 9.4b 43.54 6 9.9b 40.88 6 10.3b b

Statistic

p

F2,49 5 12.97 F2,49 5 16.85 x2 5 22.28 x2 5 14.66 F2,49 5 120.09 F2,49 5 4.62 F2,49 5 0.56 F2,49 5 2.58 F2,49 5 9.43 F2,49 5 8.96 F2,49 5 8.35 F2,49 5 17.35 F2,49 5 11.79 F2,49 5 6.59 F2,49 5 10.66 F2,49 5 9.15 F2,49 5 13.62 F2,49 5 22.96 F2,49 5 15.52 F2,49 5 24.66

p , .0001 p , .0001 p , .0001 p , .0007 p , .0001 p , .01 NS p , .09 p , .0005 p , .0005 p , .0008 p , .0001 p , .0001 p , .003 p , .0001 p , .0004 p , .0001 p , .0001 p , .0001 p , .0001

PTSD, posttraumatic stress disorder; OAD, overanxious disorder; CDI, Child Depression Inventory; CDC Child Dissociative Checklist; GAF, Children’s Global Assessment Scale; CBCL, Child Behavioral Checklist. a . b (q . 2.42; p , .05).

HSD method was used. In testing for covariate effect such as: age, gender, SES, and interaction (age by gender, age by diagnosis, gender by diagnosis), multivariate regression analysis was used. All significance testing was two-tailed with alpha 5 0.05 (p 5 .1 constituted a trend). All data are presented as mean 6 standard deviation (SD) unless otherwise specified. Bonferroni corrections were applied to correct for multiple comparisons.

Results Clinical Ratings Maltreated subjects with PTSD showed significantly lower levels of functioning on the GAF, greater ratings of depression on the Child Depression Inventory, more suicidal ideation and attempts, greater parent ratings for dissociation on the Child Dissociative Checklist (CDC), and more thought problems and externalizing symptoms (especially on social problems, aggressive and delinquent behavior subscales) on the Child Behavioral Checklist (CBCL), than OAD and healthy controls (Table 2). Maltreated subjects with PTSD also showed significantly lower social, school, and overall psychosocial competence, and more internalizing symptoms (including greater withdrawal, somatic complaints, anxiety and depression, and attentional problems subscale measures) on the Child Behavioral Checklist (CBCL) than healthy controls; but these measures were similar to non-traumatized OAD subjects. OAD subjects showed significantly lower levels of functioning on the GAF and more suicidal ideation than

healthy controls; but PTSD subjects showed significantly more psychopathology to OAD subjects in these same areas. The groups did not differ in participation in activities.

Urinary Cortisol and Catecholamines Measures Maltreated subjects with PTSD excreted significantly greater concentrations of urinary NE and DA over 24 hours than OAD and control subjects. Maltreated subjects with PTSD excreted significantly greater concentrations of 24-hour UFC excretion than control, but not OAD subjects. Maltreated subjects with PTSD showed a trend toward significantly greater concentrations of urinary EPI over 24 hours than OAD, but not control subjects. Post hoc analysis revealed that maltreated subjects with PTSD excreted significantly greater concentrations of urinary EPI than OAD subjects (Table 3).

Relationships Between Biochemical Measures and Demographic and Clinical Factors Duration of maltreatment experiences, but not age of onset of abuse, significantly correlated with UFC and all urinary catecholamine measures. The correlations for total 24hour NE and DA excretion persisted after Bonferroni correction. There were positive correlations between UFC and various urinary catecholamine measures with PTSD intrusive, avoidant and increased arousal symptoms as well as various measures of symptoms of depression and

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Table 3. Urinary Catecholamine and Cortisol Measures in Maltreated Children with PTSD, Non-Maltreated Children with OAD, and Controls

Epinephrine (ng/day) Norepinephrine (ng/day) Dopamine (ng/day) Urinary free cortisol (ug/day) (means adjusted for SES)

PTSD

OAD

Control

Statistic

p

8182.5 6 2880.9a 26782.8 6 8461a 264081 6 103237a 57.35 6 15.88a

5719.8 6 2767.7b 16496.2 6 7762.9b 163940 6 71199b 55.99 6 24.02

7086.3 6 2734.9 19945.5 6 7851.1b 191666 6 81175b 43.62 6 20.58b

F2,49 5 2.54 F2,49 5 6.40 F2,49 5 3.38 F2,48 5 3.94

,.09 ,.01 ,.05 ,.03

PTSD, posttraumatic stress disorder; OAD, overanxious disorder; SES, socioeconomic status. a . b (q . 2.42; p , .05).

anxiety, suicidal ideation, dissociation, inattention, and aggression. There were positive correlations between PTSD symptoms and UFC and total 24-hour NE excretion; and between history of suicidal ideation, history of suicide attempts, PTSD avoidant and increased arousal symptoms, and dissociation, and total 24-hour DA and total catecholamine excretion after Bonferroni correction (Table 4). Overall, urinary NE and EPI excretion was significantly higher in males than females (urinary NE, F 5 6.57, df 5 1, p 5 .01; urinary EPI, F 5 5.94, df 5 1, p 5 .02; males . females) except for urinary dopamine (F 5 1.33, df 5 1, p 5 .25). Overall, UFC concentrations showed a trend for higher levels in males (F 5 3.63, df 5 1, p 5 .06). Both diagnosis (F 5 4.36, p , .02) and SES (F 5 5.86 p , .02) significantly predicted UFC excretion; but SES did not predict catecholamine measures. Therefore, we reported UFC means adjusted for the effects of SES. African American subjects excreted significantly greater Table 4. Significant Correlations of Urinary Catecholamines and Cortisol with Clinical Measures

Duration of abuse Abuse age of onset History of suicidal ideation (yes/no) History of suicide attempts (yes/no) Children’s global assessment scale PTSD intrusive symptoms PTSD avoidant symptoms PTSD hyperarousal symptoms Child dissociative checklist CBCL-somatic complaints CBCL-anxious/depressed T score CBCL-Thought problems T score CBCL-Attention problems T score CBCL-Aggressive behaviors T score CBCL-Internal T score CBCL-External T score CBCL-Total T score

EPI

NE

DA

UFC

.29 NS NS NS NS NS .31 NS NS .29 NS .32 .29 NS .30 NS NS

.44a NS NS .36 NS .29 .40a .30 .27 NS NS NS .27 NS NS NS NS

.45a NS .40a .57a 2.29 .31 .45a .31 .41a NS .30 NS .34 .27 .27 NS .26

.28 NS NS .32 NS .35 NS .33 NS NS .27 NS .37 .34 .28 NS NS

CBCL 5 Child Behavior Checklist. All values are significant at the p , .05 level without Bonferroni correction. a For Bonferroni correction at p , .05 (individual test, p , .003 without Bonferroni correction).

concentrations of EPI (F 5 4.5(2,49) p , .02) and showed a trend for significantly greater concentrations of NE (F 5 2.8(2,49), p , .07) over 24 hours than Caucasian subjects. There were no gender or SES or race by diagnosis interactions for UFC and catecholamine measures.

Discussion Severely maltreated, but medically healthy children with the diagnosis of PTSD excreted significantly greater concentrations of baseline urinary NE and DA concentrations than non-abused anxious and healthy controls, greater concentrations of UFC than healthy controls, and greater concentrations of urinary EPI than non-abused anxious controls, years after disclosure of abuse. These measures positively correlated with duration of the PTSD trauma. We noted robust correlations with urinary NE and DA excretion and duration of maltreatment experiences after conservative Bonferroni corrections. PTSD cluster symptoms of intrusive thoughts, avoidance, and hyperarousal correlated positively with UFC, urinary NE, and DA excretion. Overall, maltreated children and adolescents with a diagnosis of PTSD exhibited significantly greater psychopathology and lower GAF scores than non-abused anxious and healthy controls. Maltreated children with PTSD differed from non-abused anxious children with OAD in that the former manifested more symptoms of thought problems and externalizing symptoms. PTSD in childhood, as it is in adults, is associated with many psychosocial, and cognitive consequences as well as much co-morbid psychopathology (De Bellis 1997). Our maltreated subjects with PTSD were similar to most studies of maltreated children that find significantly increased rates of internalizing disorders (especially major depression or dysthymia and suicidal behaviors) and externalizing disorders (oppositional behaviors) in abused children (National Research Council 1993). Maltreated children with PTSD excreted greater concentrations of baseline total 24-hour urinary catecholamine concentrations than non-traumatized children with

Biological Stress Systems in Childhood PTSD

OAD and control children. Urinary catecholamine concentrations reflect plasma and peripheral SNS activity, tonic stimulation of the adrenal medulla, and metabolic breakdown of catecholamines. These results agree with the few published studies to date showing elevated urinary catecholamine excretion in maltreated children (De Bellis et al 1994b; De Bellis and Putnam 1994; Queiroz et al 1991). These results also provide evidence suggesting an enhancement of SNS tone in childhood PTSD as suggested in other investigations (Famularo et al 1988; Perry 1994). These data are interesting in light of the clinical investigations on urinary catecholamine excretion in adult patients with PTSD. Vietnam combat veterans with PTSD were shown to excrete elevated concentrations of urinary EPI, NE, and DA (Kosten et al 1987; Yehuda et al 1992). Among catecholamine studies of Vietnam combat veterans who suffered from PTSD, measures of urinary 24-hour DA significantly correlated with overall severity of PTSD symptoms, particularly symptoms of intrusive flashbacks, avoidance, and hyperarousal in adult PTSD (Yehuda et al 1992). Taken together, our results suggest that maltreated children with PTSD show increased baseline catecholamine activity that may be similar to the psychobiology of adult PTSD. Our HPA axis findings differ from adults who suffer from PTSD in that maltreated children with PTSD show higher cortisol secretion rather than the lower UFC concentrations seen in adults (Yehuda et al 1995). We propose that elevated central CRH and resultant hypersecretion of cortisol is seen initially after traumatic experiences and enhanced negative feedback inhibition of the pituitary for cortisol leading to lower 24-hour UFC findings is seen as a long term, and possibly a developmental (post-pubertal) consequence of trauma (De Bellis et al 1994a). In this study, we found evidence for higher cortisol levels in prepubertal maltreated subjects with PTSD, a substantial percentage of whom had co-morbid mood disorders. Cortisol hypersecretion is not strongly associated with either major depressive disorder or dysthymia in children and adolescents (Casat and Powell 1988; Dahl et al 1989; Puig-Antich et al 1989) although one should note that like adults, some severely depressed and suicidal children and adolescents do manifest evidence of hypercortisolism (Birmaher et al 1995; Dahl et al 1991; Pfeffer et al 1991). Our data suggest that maltreated children manifest alterations of the HPA axis. The differences between child and adult PTSD may be explained by maturation effects or a long term adaptation of the HPA axis after the trauma experience. Thus, these results support the hypothesis of a higher baseline activity of the catecholamine system and HPA axis in childhood PTSD compared to controls. Our smaller sample of non-traumatized children with anxiety disorders

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did not show these findings. Altered catecholamine and cortisol activity have also been implicated in the pathophysiology of adult and childhood anxiety disorders (Black 1993). Behaviorally inhibited children (Kagan et al 1988) have increased sympathetic tone, increased excretion of urinary NE and its metabolites after completion of cognitive tasks, and higher levels of baseline and laboratory salivary cortisol measures compared to matched controls (Kagan et al 1988). Behaviorally inhibited children are at greater risk of developing anxiety disorders particularly OAD, social phobia or avoidant disorder, separation anxiety disorder (Biederman et al 1993) and PTSD (Davidson and Fairbank 1993). Kagan’s concept of behavioral inhibition is thought to be an extreme inherent temperamental trait (Kagan et al 1988). There is a substantial amount of data in primates (Higley et al 1993) and humans (Karl and Chrousos 1993) suggesting that genetic factors influence catecholamine and cortisol activity. In our study, maltreated subjects with PTSD showed higher catecholamine excretion than non-traumatized OAD and control subjects. Thus, severely stressful life experiences may also be associated with increased baseline activity of catecholamines as well as inherent temperamental traits. Non-traumatized anxious children may show increased arousal (catecholamine and cortisol responses) to novel or stressful stimuli (Pliska et al 1994), but may have relatively normal functioning of baseline biological stress systems. Because we did not find a difference in UFC between maltreated subjects with PTSD and non-abused anxious controls, our data did not allow us to disentangle the complexities of HPA axis regulation in anxiety disorders. Childhood trauma may change the baseline set point for catecholamine and cortisol activity in a positive fashion (De Bellis and Putnam 1994; Perry 1994). Due to the small sample of non-traumatized anxious subjects with OAD, lack of a match for clinical severity in the OAD group to the maltreated PTSD group, lack of a maltreated control group without psychopathology, and difficulty disentangling confounding factors associated with maltreatment, these ideas must be considered speculative. In conclusion, our data suggest that the overwhelming stress of maltreatment experiences in childhood is associated with alterations of biological stress systems. PTSD in maltreated children is also associated with increased psychiatric morbidity and poor psychosocial outcomes. Our intention in this study was to examine psychobiology in children who had experienced years of chronic and overwhelming stress, but were currently living in stable non-abusive environments. Therefore, this was not a psychobiological study of acute and current stress in childhood. Thus, trauma in childhood may be more detrimental than trauma experienced in adulthood secondary to interactions between trauma and neurodevelopment (De Bellis and Putnam 1994). In the developing brain,

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catecholaminergic neurotransmitters and steroid hormones are known to modulate the developmental processes of neuronal migration, differentiation, synaptic proliferation, and may affect overall brain development (for review see Part II of these papers [De Bellis et al 1999]). Psychopharmacologic treatments that dampen the activity of these biological stress systems such as clonidine (De Bellis 1997; Perry 1994), in conjunction with psychotherapy and social skills training, may provide an effective treatment strategy for maltreated children who suffer from PTSD, and may prevent the long term adverse consequences of traumatic stress in these patients (De Bellis et al 1994a; Patchev et al 1997). These data in preliminary parts were presented as in poster presentations at the 42nd Annual Meeting of the American Academy of Child and Adolescent Psychiatry in New Orleans, LA, Oct. 1995, the New York Academy of Sciences Conference on the Psychobiology of Posttraumatic Stress Disorder in New York, NY, Sept. 1996, and at the 50th Annual Meeting of The American Psychiatric Association held in San Diego, California, 1997. This work was supported in part by the 1994 Eli Lilly Pilot Research Award, “A Pilot Study of Urinary Catecholamine Excretion in Three Groups of Prepubescent Girls: Overanxious Disorder, Posttraumatic Stress Disorder, and Healthy Volunteers” (Principal Investigator: Michael D. De Bellis, M.D.), the 1995 NARSAD Young Investigators Award, “Attention and Concentration in Maltreated Children with Posttraumatic Stress Disorder” (Principal Investigator: Michael D. De Bellis, M.D.), by NIMH Grant # MH 41712 “The Psychobiology of Depression in Children & Adolescents” (Principal Investigator: Neal D. Ryan, M.D.), and by NIMH grants 5 T32 MH18951 (Clinical Research Training for Dr. De Bellis) and 5 K08 MHO1324-02 (Principal Investigator: Michael D. De Bellis, M.D.) The primary author thanks Frank W. Putnam, Jr., M.D., Director of the Unit on Developmental Traumatology at the NIMH and one of the founders of Developmental Traumatology Research for his invaluable mentorship throughout the years and the following staff of the Developmental Traumatology Laboratory: Rashida Dykes, Karin Frustaci, Adam Kersh, and Ester Saghafi, Med, MLS of the WPIC Health Sciences Library System, and Doug Williamson, B.S. and Satish Iyengar, Ph.D., for their statistical consultations, the staff of Family Resources and The Whale’s Tale, two non-profit community mental health clinics that serve maltreated children and their families for the clinical care of these maltreated subjects, and the parents and children who participated in this study.

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