Salivary Cortisol and Psychopathology in Children Bereaved by the September 11, 2001 Terror Attacks

Salivary Cortisol and Psychopathology in Children Bereaved by the September 11, 2001 Terror Attacks Cynthia R. Pfeffer, Margaret Altemus, Moonseong Heo, and Hong Jiang Background: Studies suggest that stressful events increase risk for childhood anxiety and depression and hypothalamic-pituitary-adrenal (HPA) axis dysregulation. This prospective longitudinal study evaluated relationships among severe psychosocial stress, psychiatric morbidity, and HPA axis function in children. Methods: Forty-five children (mean age: 8.9 ⫾ 2.9 years) suffering parent death from September 11, 2001 terror attacks and 34 nonbereaved children (mean age: 9.3 ⫾ 2.5 years) were evaluated prospectively at 6-month intervals in this 2-year study. Assessments involved diagnostic interviews (Child Schedule for Affective Disorders and Schizophrenia [K-SADS]) for psychopathology and 3 days of baseline salivary cortisol and a salivary dexamethasone suppression test for HPA axis function. Results: Bereaved children, but not nonbereaved children, had significantly increased rates of psychiatric disorders involving anxiety disorders, especially posttraumatic stress disorder (PTSD), after September 11, 2001 compared with retrospective assessments before September 11, 2001. Morning (AM) and 4:00 PM baseline cortisol were significantly and persistently higher for bereaved than nonbereaved children. Compared with bereaved children without psychopathology, bereaved children with PTSD had significantly lower 4:00 PM baseline cortisol and significantly greater 4:00 PM cortisol suppression. Children with generalized anxiety disorder had significantly less AM cortisol suppression than children without psychopathology. Conclusions: Children bereaved by sudden, unexpected parent death had persistent psychological dysfunction and HPA axis dysregulation in this study. Key Words: Bereavement, children, cortisol, HPA axis, psychopathology

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pidemiological and empirical studies suggest that severe childhood stressors, including parent death, increase risk for anxiety and mood disorders in childhood (Goodyer et al. 1993; Radke-Yarrow et al. 1993; Schwartz et al. 1990) and adulthood (Arborelius et al. 1999; Breier et al. 1988; Brown and Harris 1993; Kendler et al. 1992, 1993a, 1993b, 1999; Kessler and Magee 1993; Robins and Regier 1991; Rutter 1972; Tennant 1988). Few empirical studies of childhood bereavement exist. Some indicate that children who are bereaved prior to adolescence, compared with nonbereaved healthy children, have higher rates of anxiety and depressive symptoms within a year after a loved one’s death (Kranzler et al. 1990; Lutzke et al. 1997; Van Eerdeweigh et al. 1982; Weller et al. 1991) and in adolescence and young adulthood (Barnes and Prosen 1985; Brown and Harris 1993; Kendler et al. 1993a; Kessler and Magee 1993; Mireault 1992; Zall 1994). Even higher rates of psychiatric morbidity have been identified among bereaved children who suffered sudden, unexpected parent deaths during military combat (Elizur and Kaffman 1982), peer or sibling suicide (Brent et al. 1992, 1994), or parent suicide (Cain and Fast 1972; Mullarky and Pfeffer1992; Pfeffer 1981; Pfeffer et al. 1997, 2000; Shepherd and Barraclough 1974) compared with nonbereaved healthy children. Animal and human studies suggest that childhood stresses, including parent death (Petitto et al. 1992), produce acute and long-term dysregulation of the hypothalamic-pituitary-adrenal From the Department of Psychiatry, Weill Medical College of Cornell University, New York, New York. Address reprint requests to Cynthia R. Pfeffer, M.D., Professor of Psychiatry at Weill Medical College of Cornell University, New York Presbyterian Hospital, Westchester Division, Department of Psychiatry, 21 Bloomingdale Road, White Plains, NY 10605; E-mail: [email protected]. Received September 28, 2005; revised June 14, 2006; accepted July 28, 2006.

0006-3223/07/$32.00 doi:10.1016/j.biopsych.2006.07.037

(HPA) axis (Chrousos and Gold 1992; Hinde et al. 1978; Kaufman et al. 2000; Ladd et al. 1996; Lyons and Levine 1994; Meyer et al. 1975; Munck et al. 1984; Rilling et al. 2001; Soumi et al. 1973; Weiss et al. 1999). Hypothalamic-pituitary-adrenal axis hyperactivity has been associated with psychiatric symptomatology in nontraumatized children (Flinn and England 1997; Goodyer et al. 2000a; Gunnar 1998; Susman et al. 1997), sexually abused and maltreated children (De Bellis et al. 1999; Hart et al. 1996; Kaufman et al. 1997), children exposed to marital violence (Saltzman et al. 2005), and children with major depressive disorder (Birmaher et al. 1996; Dahl et al. 1991; Herbert et al. 1996; Pfeffer et al. 1989) and suicidal acts (Pfeffer et al. 1991). Cortisol hypersecretion was reported to precede onset of major depression among adolescents at risk for major depression (Goodyer et al. 2000b) and to be associated with chronicity (Goodyer et al. 2001) and recurrence (Rao et al. 1996) of major depressive disorder. Studies of HPA axis activity in adolescents and adults with posttraumatic stress disorder (PTSD) have produced mixed results. Some studies suggest HPA axis hyperactivity (Carrion et al. 2002; De Bellis et al. 1999; Lipschitz et al. 2003) but others reported an enhanced feedback sensitivity of the HPA axis, manifest as lower cortisol levels after administration of low dose dexamethasone, among recently sexually abused adults (King et al. 2001) and adolescents with posttraumatic stress disorder (Duval et al. 2004). Empirical longitudinal information about effects of severe stress among children not selected for psychiatric disorders or abuse is sparse. This prospective study aimed to evaluate longitudinal relationships among severe psychosocial stress, psychiatric morbidity, and HPA axis function in children over a 2-year period. Parent death was studied as a severe and often persistent psychosocial stress. Bereaved children were compared with children selected from the community without history of death of a close relative. Both groups of children were evaluated prospectively at 6-month intervals for an average of 2 years. It was hypothesized that after parent death, bereaved children, comBIOL PSYCHIATRY 2007;61:957–965 © 2007 Society of Biological Psychiatry

958 BIOL PSYCHIATRY 2007;61:957–965 pared with nonbereaved children, would have persistently higher rates of anxiety and mood disorders and HPA axis dysregulation, evident as increased baseline salivary cortisol levels and decreased inhibition of salivary cortisol secretion after dexamethasone administration. It was hypothesized also that development of affective disorders after parent death would be associated with HPA axis hyperactivity.

Methods and Materials Subjects Seventy-nine children (45 bereaved from 23 families, 34 nonbereaved from 25 families) were recruited from the community near New York City metropolitan area after the terrorist attacks on September 11, 2001. Bereaved children suffered sudden, unexpected death of one parent during the September 11, 2001 terrorist attacks. To compare rates of psychopathology before and after September 11, 2001 in a representative sample of bereaved and nonbereaved children, those with psychopathology prior to September 11, 2001 were not excluded. Recruitment occurred within schools, police and fire departments, and corporations for bereaved children and in schools for nonbereaved children utilizing talks and letters to parents and staff and fliers on bulletin boards. No nonbereaved children’s families lived or worked at or near the World Trade Center preceding or after September 11, 2001. This study was approved by the Institutional Review Board of Weill Medical College of Cornell University. Written informed consent from parents and assent from children were obtained prior to study entry. Mean study entry was 19.3 ⫾ 8.5 months after September 11, 2001, with earliest entry at 4 months and latest at 3 years after September 11, 2001. Bereaved and nonbereaved children were evaluated concurrently every 6 months. Average time of last assessment after September 11, 2001 was similar for bereaved (26.2 ⫾ 10.2 months) and nonbereaved (25.5 ⫾ 6.7 months) children [t (75.6) ⫽ .39, p ⫽ .70]. Bereaved and nonbereaved children were matched on distributions of age [bereaved: 8.9 ⫾ 2.9 years, range: 4.8 –13.0 years; nonbereaved: 9.3 ⫾ 2.5 years, range: 4.8 –13.8 years; t (76) ⫽ .66, p ⫽ .51], gender (bereaved: 48.9% female subjects, nonbereaved: 55.9% female subjects; p ⫽ .65), and ethnicity/race [bereaved: 82.2% White, 0% Black, 4.4% Hispanic, 6.7% Asian, 6.7% mixed race; nonbereaved: 64.8% White, 14.7% Black, 2.9% Asian, 8.8% mixed race; X2(4) ⫽ 8.65, p ⫽ .07] at September 11, 2001, and family social status (Hollingshead and Redlich 1958) within the month prior to September 11, 2001 [bereaved: 71.1% high, 13.3% middle, 15.6% low; nonbereaved: 67.7% high, 17.7% middle, 14.6% low; X2(2) ⫽ .28, p ⫽ .87]. Mean body mass index Z scores (BMI-z) (Knczmarski et al. 2002) in the year prior to September 11, 2001, calculated from pediatric records of height and weight, were similar for bereaved (.5 ⫾ 1.1) and nonbereaved (.8 ⫾ 1.0) children [t (59) ⫽ ⫺1.14, p ⫽ .26]. Scores of lifetime stressful events before September 11, 2001, evaluated from retrospective parent reports at the initial assessment using the Social Readjustment Rating Questionnaire for Children (Coddington 1972), which ascribes weighted scores for each type of life event, were similar for bereaved (mean: 195.9 ⫾ 123.7) and nonbereaved (mean: 184.4 ⫾ 127.5) children [t (57) ⫽ .35, p ⫽ .72]. In the year before September 11, 2001, no children received psychotherapy but two nonbereaved children with attention-deficit/hyperactivity disorder were treated with stimulant medication. www.sobp.org/journal

C.R. Pfeffer et al. Assessment of Children’s Psychiatric Disorders and Body Mass Index Presence of children’s current psychiatric disorders was evaluated at each assessment at 6-month intervals with the Child Schedule for Affective Disorders and Schizophrenia (K-SADS) (Ambrosini and Dixon 1996) during separate parent and child interviews. Retrospective assessments of history of children’s psychiatric disorders prior to September 11, 2001 and prior to study entry after September 11, 2001 were conducted at the initial assessment with the K-SADS. As is standard technique with the K-SADS, a consensus of parent and child reports of children’s psychiatric symptoms was used to determine the presence of children’s past and current psychiatric disorders. Children’s current BMI-z (Knczmarski et al. 2002) was calculated from children’s height and weight evaluated at each 6-month assessment after September 11, 2001. Cortisol Assays and Measurement Baseline and postdexamethasone cortisol samples were collected at initial and each follow-up assessment. A dexamethasone suppression test provided an estimate of glucocorticoid receptor feedback sensitivity. At each assessment, salivary cortisol samples were collected at home on 4 consecutive days starting Monday morning (day 1) and ending Thursday evening (day 4) to reflect children’s standard naturalistic routines involving school and after school activities. Samples were collected at 30 to 60 minutes after awakening in the morning (AM) (approximately 8:00 AM) and at bedtime (approximately 9:00 to 10:00 PM). To increase compliance in collecting cortisol samples and dexamethasone administration, research staff telephoned parents each day of cortisol collection to discuss completion of procedures. Parents assisted children in collecting saliva samples, administered dexamethasone to their children, and documented times of cortisol collection and dexamethasone administration. Three baseline cortisol collection days were utilized to minimize impact of day-to-day variability in cortisol secretion and influence of unusual stressors or activity preceding saliva collection. Mean baseline salivary cortisol levels for each subject were computed for 8:00 AM and 8:00 PM over the 3 days of baseline salivary cortisol collection. On Wednesday (day 3) and Thursday (day 4), salivary cortisol was collected also in the afternoon at 4:00 PM. Prior to bedtime on day 3, a .5 mg dexamethasone dose was given orally after collecting the evening cortisol sample. A psychiatrist (C.R.P.) interviewed parents at each assessment to identify children’s health problems or medications that may interfere with hypothalamic-pituitary-adrenal (HPA) axis function. No children were excluded for medical reasons. Seven (15.6%) bereaved and 7 (20.6%) nonbereaved children did not participate in the dexamethasone suppression test (p ⫽ .57) because their parents did not want them to take dexamethasone. If a child was taking a short-term medication, such as an antibiotic, or had acute cold symptoms or injury, assessment was delayed by 2 to 3 weeks to avoid distortion of cortisol measures and the dexamethasone suppression test. Dexamethasone dose of .5 mg was chosen because it was more sensitive in prior studies than a .25 mg dose (Young et al, in press) or a 1.0 mg dose (Pfeffer et al. 1989) for detecting differences among stressed and nonstressed children. Salivary cortisol samples were collected at children’s homes using the Salivette device (Sarstedt, Inc., Newton, North Carolina). Children were instructed not to eat for at least 15 minutes prior to sample collection and to gently chew on a cotton swab for approximately 1 minute to saturate it with as much saliva as

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C.R. Pfeffer et al. possible and then place the swab in the tube. Samples were placed in a refrigerator in the children’s home during the collection period and then frozen at ⫺80oC upon delivery to the investigator’s research office within 7 days of collection start. Cortisol was assayed using high-sensitivity Enzyme-Linked ImmunoSorbent Assays (ELISAs) developed specifically for use with saliva (Salimetrics, State College, Pennsylvania). Samples were run in duplicate and mean values were calculated for each sample. The detection limit for cortisol was .01 ␮g/dL. More than 98% of salivary cortisol measures were above the assay detection limit (.01 ␮g/dL) under naturalistic conditions. However, occasional postdexamethasone cortisol values were below the assay detection limit and were assigned the value of the detection limit. Statistical Analyses Descriptive statistics are provided as means and standard deviations. For comparative cross-sectional analyses, chi-square or Fisher exact tests were used for comparison of categorical variables and Student t tests were used for continuous variables. For analysis of longitudinal continuous outcomes, such as cortisol levels, mixed effects linear models (Laird and Ware 1982) were used, yielding Wald t test statistics for a continuous estimate of cortisol levels across the 2 years of study. Cortisol suppression after dexamethasone was evaluated as the difference between baseline and postdexamethasone cortisol levels at AM, 4:00 PM, or evening (PM), while controlling for baseline cortisol levels at each of these times. The result was reported as percent cortisol suppression. In models evaluating effects of psychiatric disorders on cortisol, specific psychiatric disorders were modeled as time-varying independent variables, i.e., the psychiatric assessments were made at the same time points as cortisol. Effects of specific psychiatric disorders were compared among children with a specific psychiatric disorder without versus with comorbid psychiatric disorders versus children without psychiatric disorders. For analysis of longitudinal categorical outcomes, such as current psychiatric disorders, mixed effects logistic regression models were applied (Hedeker and Gibbons 1994). In mixed effects modeling, the random intercept per family unit was modeled to take account of the correlation among serial observations of outcomes as well as among family members. The effect of bereavement status was modeled as fixed. Additionally, the continuous time span from September 11, 2001 to each assessment was included as an independent variable to model the trajectory of outcomes over the course of follow-up by means of the regression lines. Cortisol levels were log-transformed due to high right-skewedness of their distribution. Although the observed Wald t statistics and their p-values are reported based on the log-transformed cortisol levels, estimated effects are reported after application of antilog transformations. For graphical presentations, log-odds based on the estimated regression lines from mixed effects logistic models were converted to probability of having diagnoses during the time since September 11, 2001. Statistical analyses were performed using SAS vol 8.2, PROC MIXED, and NLMIXED (SAS Institute Inc., Cary, North Carolina) for repeatedly measured continuous and dichotomous outcomes, respectively (Littell et al. 1996). Statistical significance was declared at two-sided p-values ⱕ.05. Degrees of freedom (df ) in analyses varied depending on the number of observations appropriate for specific research questions or available for specific variables. In constructing models to test hypotheses, variables that may influence cortisol levels, such as age, gender, race/ ethnicity, and BMI-z after September 11, 2001 (Rosmalem et

al. 2005) were evaluated for their relationships with baseline salivary cortisol and salivary cortisol suppression in response to dexamethasone. Body mass index Z score after September 11 was significantly negatively associated only with AM baseline cortisol for the combined group of bereaved and nonbereaved children [t (115) ⫽ ⫺2.27, p ⱕ .02]. Body mass index Z score was included as a time-varying covariate to test hypotheses of AM baseline cortisol. Compared with analyses without BMI-z as a time-varying covariate, results were unchanged when BMI-z was controlled for in testing models of relationships between 4:00 PM or PM baseline or AM, 4:00 PM, or PM cortisol suppression after dexamethasone and bereavement status or effects of psychiatric disorders. Age, gender, and race/ethnicity were not significantly associated with baseline cortisol levels or cortisol suppression after dexamethasone and were not included as covariates. Seventy-one percent bereaved and 13% nonbereaved children received psychotherapy at some time after September 11, 2001. There were no significant relations between receiving psychotherapy and baseline cortisol levels or cortisol suppression after dexamethasone or rates of mood or anxiety disorders. Therefore, psychotherapy was not included as a time-varying covariate. Medication treatment was not included as a time-varying covariate because the number (0% bereaved, 5.9% nonbereaved) of children receiving medication after September 11, 2001 was low.

Results Psychiatric Disorders Prior to September 11, 2001, 31.8% of bereaved children had at least one lifetime psychiatric disorder, a rate similar to that for nonbereaved children (35.3%). Most frequent psychiatric disorders were anxiety and attention-deficit/hyperactivity disorder for bereaved (13.6% and 13.6%, respectively) and nonbereaved (17.7% and 17.7%, respectively) children (Table 1). After September 11, 2001, during the 2-year study, significantly more bereaved (72.7%) compared with nonbereaved (35.3%) children had at least one psychiatric disorder (p ⱕ .001) (Table 1). Significantly more bereaved than nonbereaved children had at least one current anxiety disorder (56.8% bereaved, 23.5% nonbereaved) (p ⱕ .005), especially posttraumatic stress disorder (29.6% bereaved, 2.9% nonbereaved) (p ⱕ .002). The probability of having a current anxiety disorder for the two groups of children decreased slowly throughout the study [t (30.6) ⫽ ⫺.84, p ⫽ .41]. There was no time by group interaction, suggesting that rates of decline for bereaved and nonbereaved children’s probabilities of having a current anxiety disorder were not significantly different and decreased in parallel throughout the study (Figure 1). There was a time by group interaction for probability of having PTSD [t (47) ⫽ 67.57, p ⱕ .0001]. Probability of bereaved children having PTSD remained high and declined throughout the study [t (18.6) ⫽ ⫺.96, p ⫽ .35], in contrast to nonbereaved children [t (38.9) ⫽ 1.69, p ⫽ .10] (Figure 1). Rates of current mood disorders and major depressive disorder (MDD) were higher among bereaved (29.6% and 13.6%, respectively) compared with nonbereaved (11.8% and 5.9%, respectively) children, but differences were not significant (p ⫽ .10 and p ⫽ .45, respectively). There was a parallel decrease in probability of having a current mood disorder [t (47) ⫽ ⫺1.37, p ⫽ .18] or current major depressive disorder [t (47) ⫽ ⫺1.18, p ⫽ .07] for bereaved and nonbereaved children in the 2 years of study (Figure 1). www.sobp.org/journal

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Table 1. Rates of Psychiatric Disorders Among Bereaved and Nonbereaved Children Pre-September 11, 2001 and During the Two-Year Study Post-September 11, 2001 Pre-September 11, 2001 Bereaved

Nonbereaved

Psychiatric Disorder

n

%

n

%

Any Psychiatric Disorder Mood Disorder Major Depressive Dysthymic Depressive NOS Bipolar Anxiety Disorder Separation Anxiety Generalized Anxiety Panic Social Phobia Simple Phobia Obsessive Compulsive Posttraumatic Stress Anxiety NOS Disruptive Disorder Attention Deficit Hyperactivity Conduct Oppositional Defiant Psychotic Disorder NOS Alcohol/Substance Abuse Other Disorders Elimination Adjustment

14 0 0 0 0 0 6 1 2 0 0 4 1 0 0 6 6 0 1 0 0 2 2 0

31.8 0 0 0 0 0 13.60 2.27 4.55 0 0 9.09 2.27 0 0 13.60 13.60 0 2.77 0 0 4.55 4.55 0

12 2 1 0 1 0 6 4 1 0 0 2 0 1 0 6 6 1 1 0 0 4 3 1

35.30 5.90 2.94 0 2.94 0 17.70 11.80 2.94 0 0 5.88 0 2.94 0 17.70 17.70 2.94 2.94 0 0 11.80 8.82 2.94

Post-September 11, 2001 Fisher’s Exact Test: p ⱕ .81 .19 .44 .44 .75 .16 1.00

.69 1.00 .44 .75 .75 .44 1.00

.39 .65 .44

Bereaved

Nonbereaved

n

%

n

%

32 13 6 0 7 0 25 12 11 2 0 6 3 13 2 11 10 0 4 0 0 8 6 3

72.70 29.55 13.64 0 15.90 0 56.82 27.30 25.00 4.60 0 13.60 6.82 29.55 4.55 25.00 22.70 0 9.10 0 0 18.20 13.64 6.82

12 4 2 0 3 1 8 4 4 3 1 2 0 1 0 9 9 1 3 2 0 4 1 3

35.30 11.80 5.88 0 8.80 2.94 23.50 11.80 11.80 8.80 2.94 5.90 0 2.94 0 26.40 26.50 2.94 8.80 5.88 0 11.80 2.94 8.82

Fisher’s Exact Test: p ⱕ .001 .10 .45 .50 .44 .005 .16 .16 .65 .44 .45 .25 .002 .50 1.00 .80 .44 1.00 .18 .53 .13 1.00

After September 11, 2001, bereaved children, compared with nonbereaved children, had significantly higher rates of at least one psychiatric disorder, an anxiety disorder, and posttraumatic stress disorder. Before September 11, 2001, bereaved and nonbereaved children had similar rates of psychiatric disorders. NOS, not otherwise specified.

Relationships Between Baseline Salivary Cortisol and Bereavement Status Bereaved compared with nonbereaved children had significantly higher AM baseline salivary cortisol that persisted throughout the study [t (44.9) ⫽ 2.05, p ⱕ .05] (Figure 2). Morning (AM) baseline cortisol for the combined sample of bereaved and nonbereaved children significantly decreased [t (126) ⫽ ⫺2.79, p ⱕ .006] throughout the study. There was no time by group interaction, suggesting that declines in bereaved and nonbereaved children’s AM baseline cortisol were not significantly different and decreased in parallel throughout the study. Bereaved compared with nonbereaved children had significantly higher 4:00 PM baseline salivary cortisol that persisted throughout the study [t (45.7) ⫽ 2.23, p ⫽ .03] (Figure 2). The 4:00 PM baseline cortisol for the combined groups of bereaved and nonbereaved children declined slowly but not significantly throughout the study [t (28.9) ⫽ ⫺1.14, p ⫽ .26]. There was no significant time by group interaction. In contrast, there was no significant difference between bereaved and nonbereaved children’s PM baseline cortisol [t (44.8) ⫽ .06, p ⫽ .95] (Figure 2). Circadian rhythm for bereaved [F (2,253) ⫽ 322.26, p ⱕ .0001] and nonbereaved [F (2,130) ⫽ 156.31, p ⱕ .0001] children’s baseline salivary cortisol was preserved (Figure 2). Relationships Between Salivary Cortisol Suppression and Bereavement Status Bereaved children’s salivary cortisol suppression after dexamethasone was less than for nonbereaved children at AM [t (35.6) ⫽ www.sobp.org/journal

⫺1.49, p ⫽ .15], 4:00 PM [t (24) ⫽ ⫺1.50, p ⫽ .15], and PM [t (27.9) ⫽ ⫺.96, p ⫽ .35], but the differences were not significant (Figure 3). During the study, cortisol suppression decreased at AM [t (8.27) ⫽ ⫺1.39, p ⫽ .20] and PM [t (10.9) ⫽ ⫺.71, p ⫽ .49] but increased at 4:00 PM [t (20.6) ⫽ .30, p ⫽ .77]; these changes were not significant (Figure 3). There were no group by time interactions. Relationships Between Salivary Cortisol and Psychiatric Disorders Relationships between children’s psychiatric disorders and baseline salivary cortisol or cortisol suppression after dexamethasone were evaluated while controlling for bereavement status and time from September 11, 2001 to each assessment. Analyses of AM baseline cortisol controlled also for effects of BMI-z. Psychiatric disorders that were most frequent after September 11, 2001 were examined, including PTSD, separation anxiety disorder, generalized anxiety disorder (GAD), and attention-deficit/ hyperactivity disorder. Posttraumatic stress disorder and separation anxiety disorder were present longitudinally only among the bereaved children. Each of these four disorders also had comorbid rates of least one of the following disorders: major depressive disorder; depressive disorder, NOS; separation anxiety disorder; generalized anxiety disorder; PTSD; and attention-deficit/hyperactivity disorder. Significant relationships were identified between PTSD and 4:00 PM baseline cortisol [F(2,18.9) ⫽ 7.49, p ⱕ .004] and 4:00 PM cortisol suppression [F(2,71.4) ⫽ 8.03, p ⱕ .007] and between GAD and AM cortisol suppression [F (2,48) ⫽ 3.11, p ⱕ .05]. Specifically,

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Figure 1. Probability for bereaved (B) and nonbereaved (C) children of having an anxiety disorder, current posttraumatic stress disorder, current mood disorder, or major depressive disorder after September 11, 2001. Note: Probability of having a current anxiety disorder was significantly greater for bereaved (B) than nonbereaved (C) children and decreased significantly throughout the study for both groups of children. Rates of decline in probability of having a current anxiety disorder for bereaved and nonbereaved children were not significantly different and decreased in parallel throughout the study. Probability of having current PTSD for bereaved children was higher than for nonbereaved children and declined rapidly over the course of the study. Bereaved and nonbereaved children had similar probabilities of a current mood disorder and current major depressive disorder with parallel decreases in probabilities of having these disorders. PTSD, posttraumatic stress disorder; MDD, major depressive disorder.

throughout the study, PTSD without [t (69.5) ⫽ ⫺2.71, p ⱕ .01] and with [t (14.5) ⫽ ⫺3.10, p ⱕ .008] comorbid psychiatric disorders had significantly lower 4:00 PM baseline cortisol than no psychiatric disorders (Table 2, Figure 4). These relationships were independent of the result that the total group of bereaved children had significantly higher 4:00 PM baseline cortisol than

Figure 2. Longitudinal AM, 4:00 PM, and PM baseline salivary cortisol levels for bereaved (B) and nonbereaved (C) children after September 11, 2001. Note: Bereaved (B) children compared with nonbereaved (C) children had significantly higher AM and 4:00 PM baseline salivary cortisol levels throughout the study. Morning (AM) baseline cortisol levels for bereaved and nonbereaved children significantly decreased in parallel throughout the study. The 4:00 PM baseline cortisol levels for bereaved and nonbereaved children declined in parallel but not significantly throughout the study. Bereaved and nonbereaved children’s PM baseline cortisol levels were similar throughout the study. Circadian rhythm for bereaved and nonbereaved children’s baseline cortisol levels was preserved. AM, morning; PM, evening.

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Figure 3. Longitudinal percent suppression of AM, 4:00 PM, and PM salivary cortisol after dexamethasone for bereaved (B) and nonbereaved (C) children after September 11, 2001. Note: Although bereaved children had less AM, 4:00 PM, and PM salivary cortisol suppression after dexamethasone than nonbereaved children, the percent of salivary cortisol suppression of bereaved and nonbereaved children was not significantly different throughout the study.

nonbereaved children throughout the study [t (12.6) ⫽ 3.20, p ⱕ .007] (Table 2). Post hoc analyses suggested no significant differences between 4:00 PM baseline cortisol for PTSD without or with comorbidity [t (90.2) ⫽ ⫺.45, p ⫽ .65]. Additionally, PTSD without [t (69.5) ⫽ ⫺2.71, p ⱕ .008] or with [t (14.5) ⫽ ⫺3.10, p ⱕ .008] comorbid psychiatric disorders had significantly lower 4:00 PM baseline cortisol than bereaved children without psychiatric disorders. However, PTSD without [t (83.7) ⫽ ⫺1.38, p ⫽ .17] or with [t (40.5) ⫽ ⫺1.26, p ⫽ .21] comorbid psychiatric disorders had similar 4:00 PM baseline cortisol to nonbereaved children without psychiatric disorders. Baseline 4:00 PM cortisol for the combined groups of PTSD without and with comorbidity and no psychiatric disorders tended to decrease over the course of study [t (30.3) ⫽ ⫺1.95, p ⱕ .06]. There were no time by psychiatric disorder interactions [F (2,64.9) ⫽ 1.62, p ⫽ .21], suggesting that decreases in 4:00 PM cortisol throughout the study were parallel for PTSD without or with comorbidity and for no psychiatric disorders. Throughout the study, PTSD without [t (70.3) ⫽ 3.82, p ⱕ .0003] and with [t (77.4) ⫽ 2.37, p ⱕ .02] comorbidity had significantly greater 4:00 PM cortisol suppression than combined groups of bereaved and nonbereaved children without psychiatric disorders (Table 2, Figure 4). Post hoc analyses showed that PTSD without [t (70.3) ⫽ 3.82, p ⱕ .0003] or with [t (77.6) ⫽ 2.37, p ⱕ .02] comorbid psychiatric disorders had significantly greater 4:00 PM suppression than bereaved children without psychiatric disorders. Posttraumatic stress disorder without comorbid psychiatric disorders [t (76) ⫽ 2.78, p ⱕ .007] had significantly greater 4:00 PM cortisol suppression than nonbereaved children without psychiatric disorders. Posttraumatic stress disorder with comorbid psychiatric disorders had similar 4:00 PM cortisol suppression to nonbereaved children without psychiatric disorders [t (67) ⫽ .95, p ⫽ .34]. Posttraumatic stress disorder without comorbidity compared with PTSD with comorbidity had significantly greater 4:00 PM cortisol suppression [t (62) ⫽ 2.09, p ⱕ .04]. The combined groups of PTSD without or with comorbidity and no psychiatric disorders had significant increases in 4:00 PM cortisol suppression throughout the study [t (68.5) ⫽ 3.08, p ⱕ .003]. Generalized anxiety disorder without comorbidity had significantly less AM cortisol suppression throughout the study than no www.sobp.org/journal

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Table 2. Longitudinal Relationships Between Salivary Cortisol Levels and Posttraumatic Stress Disorder and Generalized Anxiety Disorder without or with Comorbid Psychiatric Diagnoses After September 11, 2001

Cortisol Time Baseline 4PM Suppression AM Suppression AM Suppression 4PM Suppression PM

Psychiatric Disorder

Disorder without Comorbidity Versus No Disorder Effect Wald t (df), p ⱕ

Disorder with Comorbidity Versus No Disorder Effect Wald t (df ), p ⱕ

Disorder without Comorbidity Versus Disorder with Comorbidity Wald t (df ), p ⱕ

Bereavement Effect Wald t (df ), p ⱕ

Time Effect Wald t (df ) p ⱕ

PTSD GAD PTSD PTSD PTSD

⫺2.71 (69.5), .01 ⫺2.15 (32.2), .04 2.20 (21.1), .04 3.82 (70.3), .0003 2.30 (42.1), .03

⫺3.10 (14.5), .008 ⫺1.42 (76.9), .16 .11 (15), .91 2.37 (77.4), .02 .19 (35.5), .85

⫺.45 (90.2), .65 ⫺1.27 (37.4), .21 2.15 (64.1), .04 2.09 (62), .04 1.90 (61.8), .05

3.20 (12.6), .007 ⫺1.14 (20.6), .27 ⫺1.53 (22.4), .14 ⫺1.71 (30.1), .10 ⫺.91 (25), .37

⫺1.95 (30.3), .06 ⫺1.16 (17.9), .26 ⫺.40 (41.9), .69 3.08 (68.5), .003 .25 (72.1), .80

PTSD, posttraumatic stress disorder, GAD, generalized anxiety disorder.

psychiatric disorders [t (32.2) ⫽ ⫺2.15, p ⱕ .04] (Table 2, Figure 4). Post hoc analyses suggested that bereaved children with GAD without comorbid psychiatric disorders had significantly less AM cortisol suppression throughout the study than bereaved [t (33.7) ⫽ ⫺2.17, p ⱕ .03] and nonbereaved [t (31.5) ⫽ ⫺2.57, p ⱕ .02] children without psychiatric disorders. Bereaved children with GAD with comorbid psychiatric disorders tended to have less AM cortisol suppression throughout the study than nonbereaved children without psychiatric disorders [t (45) ⫽ ⫺1.81, p ⱕ .08]. Morning (AM) cortisol suppression slowly decreased, but not significantly, throughout the study for the combined groups of GAD without or with comorbidity or no psychiatric disorders [t (17.9) ⫽ ⫺1.16, p ⫽ .26]. There were no psychiatric disorder by time interactions [F (2.31) ⫽ .15, p ⫽ .86]. Trends were identified for PTSD to have greater AM cortisol suppression [F (2,18.8) ⫽ 2.74, p ⫽ .09] and PM cortisol suppression [F (2,37.5) ⫽ 2.66, p ⫽ .08] (Table 2).

Discussion This prospective longitudinal study identified significant differences in HPA axis function and prevalence of psychiatric disorders throughout this 2-year study among children who experienced sudden, unexpected parent death during the terrorist attacks on the World Trade Center on September 11, 2001 compared with nonbereaved children. This is among the few studies that empirically evaluated longitudinal relationships between bereaved children’s salivary cortisol and psychiatric disorders. Bereaved children (72.7%) had significantly higher rates of psychiatric disorders than nonbereaved children (35.3%), consistent with other studies of bereaved children (Van Eerdeweigh et al. 1982; Weller et al. 1991). Prior to the terrorist attacks on September 11, 2001, rates of specific psychiatric disorders were similar for bereaved and nonbereaved children. After September 11, 2001, there were significant increases in psychiatric disorders only among bereaved children. After September 11, 2001, rates of anxiety (56.8%) and mood disorders (29.6%) among bereaved children were higher than among nonbereaved children (anxiety disorders 23.5%, mood disorders 11.8%). The most significant difference was that approximately 30% of bereaved compared with 3% of nonbereaved children had PTSD. That the majority of bereaved children in this 2-year longitudinal study had an anxiety disorder was in marked contrast to findings of no anxiety disorders among bereaved children studied 8 weeks after parent deaths from a variety of causes (Sanchez et al. 1994). Similar to another longitudinal study of children bereaved from parent death (Cerel et al. 2006), children in this study showed gradual improvement in psychiatwww.sobp.org/journal

ric symptoms over the 2-year period of study. However, Worden and Silverman (1996), using the Child Behavior Checklist to assess psychiatric symptoms, reported no differences in psychiatric symptoms between bereaved and nonbereaved children up to a year after parent death but significantly higher rates of anxiety and depression 2 years after parent death compared with rates among nonbereaved children. Although not statistically significant, bereaved children (13.6%) in the present study had higher rates of MDD than nonbereaved children (5.9%). Major depressive disorder rates among bereaved children in this study were comparable with those of other longitudinal studies of bereaved children (Van Eerdeweigh et al. 1982). However, they were lower than a rate of 37% among bereaved children assessed 8 weeks after parent death resulting from varied causes (Weller et al. 1991). Lower rates of MDD than anxiety disorders among bereaved children in this study may be related to the unique cause of parent death, later assessment time, or to public sharing of grief and ritual after September 11, 2001. As hypothesized, this study demonstrated persistent dysregulation in HPA axis functioning among children who were severely stressed by sudden, unexpected parent death. Bereaved compared with nonbereaved children had significantly higher AM and 4:00 PM baseline salivary cortisol throughout this study. While there was a significant decline in AM cortisol for bereaved and nonbereaved children throughout the study, the decline was small. It is unclear whether nonbereaved children’s AM cortisol decline was a consequence of their own reactions to the September 11 disaster. Circadian rhythm of salivary cortisol was preserved among bereaved and nonbereaved children throughout the study. As hypothesized, HPA axis dysregulation longitudinally was associated with specific psychiatric disorders. Bereaved children with PTSD, compared with bereaved children without psychiatric disorders, had significantly lower 4:00 PM baseline and greater 4:00 PM suppression of salivary cortisol during the time they had this diagnosis. These findings were similar to studies of children (Goenjian et al. 1996), adolescents (Duval et al. 2004), and adults (King et al. 2001) with PTSD. Greater 4:00 PM salivary cortisol suppression among bereaved children with PTSD is similar to findings for children and adults experiencing severe chronic psychosocial stress (Fries et al. 2005; Gunnar and Vazquez 2001; Raison and Miller 2003) and may reflect sensitization of the glucocorticoid receptor resulting from severe stress (Yehuda et al. 2004). Low baseline salivary cortisol among bereaved children with PTSD is consistent with the concept of “adrenal exhaustion” involving tonic HPA axis inhibition as a chronic adaptation to a stressor (Yehuda 2000). However, bereaved

C.R. Pfeffer et al.

children with PTSD did not have lower baseline cortisol than the nonbereaved children without psychiatric disorders. Since there are no data on this sample preceding September 11, 2001, the possibility that cortisol dysregulation was present before the study cannot be ruled out. Decreased AM salivary cortisol suppression among children with generalized anxiety disorder suggests HPA axis hyperactivity among children with this diagnosis. Clinical and Research Implications Findings that children had persistent aberrations in HPA axis and psychological functioning during this 2-year study following parent terror-related deaths imply that additional longer-term studies are needed to determine when, if ever, children recover from these physiological and psychological consequences. Referrals for psychiatric treatment were suggested to parents for children who were identified as having psychiatric disorders. However, children’s morbid consequences were observed even though the majority of bereaved children received psychotherapy at some time in this 2-year study. Future research should

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Figure 4. Longitudinal 4:00 PM baseline salivary cortisol for bereaved children (B) with posttraumatic stress disorder compared with bereaved and nonbereaved (C) children without psychiatric disorders, 4:00 PM salivary cortisol suppression after dexamethasone for bereaved children with posttraumatic stress disorder compared with bereaved and nonbereaved children without psychiatric disorders, and AM salivary cortisol suppression after dexamethasone for bereaved and nonbereaved children with generalized anxiety disorder compared with bereaved and nonbereaved children without psychiatric disorders. Note: Longitudinal relationships between children’s PTSD and GAD without and with psychiatric comorbidity and salivary cortisol were evaluated while controlling for bereavement status and time from September 11, 2001 to each assessment. Analyses of AM baseline salivary cortisol controlled also for the effects of BMI-z. Posttraumatic stress disorder and GAD had high rates of comorbidity with at least one of the following disorders: major depressive disorder; depressive disorder, NOS; separation anxiety disorder; generalized anxiety disorder; PTSD; and ADHD. Analyses involved PTSD only among bereaved children because the one nonbereaved child with PTSD did not have cortisol assessments. All nonbereaved children with GAD had comorbid psychiatric disorders. Bereaved children with PTSD without and with comorbidity had significantly lower 4:00 PM baseline cortisol than the combined group of bereaved and nonbereaved children without psychiatric disorders throughout the study. As shown in this figure, bereaved children with PTSD without or with comorbid psychiatric disorders had significantly lower 4:00 PM baseline cortisol than bereaved children without psychiatric disorders. There were no significant differences in 4:00 PM baseline cortisol for bereaved children with PTSD without or with comorbid psychiatric disorders and nonbereaved children without psychiatric disorders. There were no significant differences in 4:00 PM baseline cortisol for bereaved children with PTSD without or with comorbidity. Bereaved children without psychiatric disorders had significantly higher 4:00 PM baseline cortisol than nonbereaved children without psychiatric disorders. Baseline cortisol at 4:00 PM for children with PTSD without and with comorbidity and no psychiatric disorders tended to decrease throughout the study. Salivary cortisol suppression at 4:00 PM was significantly greater for bereaved children with PTSD without and with comorbid psychiatric disorders than for the combined group of bereaved and nonbereaved children without psychiatric disorders. As shown in this figure, bereaved children with PTSD without or with comorbid psychiatric disorders had significantly greater 4:00 PM cortisol suppression than bereaved children without psychiatric disorders. Bereaved children with PTSD without comorbid psychiatric disorders had significantly greater 4:00 PM cortisol suppression than nonbereaved children without psychiatric disorders. Bereaved children with PTSD with comorbid psychiatric disorders had similar 4:00 PM cortisol suppression to nonbereaved children without psychiatric disorders. Cortisol suppression at 4:00 PM was significantly greater for bereaved children with PTSD without comorbid psychiatric disorders, compared with bereaved children with PTSD with comorbid psychiatric disorders. Cortisol suppression at 4:00 PM significantly increased throughout the study for bereaved children with PTSD without or with comorbidity and no psychiatric disorders. Children with GAD without comorbid psychiatric disorders had significantly less AM salivary cortisol suppression throughout the study than the combined group of bereaved and nonbereaved children without psychiatric disorders. As shown in this figure, bereaved children with GAD without comorbid psychiatric disorders had significantly less AM cortisol suppression throughout the study than bereaved and nonbereaved children without psychiatric disorders. Bereaved children with GAD with comorbid psychiatric disorders tended to have less AM cortisol suppression throughout the study than nonbereaved children without psychiatric disorders. Morning (AM) cortisol suppression slowly decreased, but not significantly, throughout the study for children with GAD without or with comorbidity and for children without psychiatric disorders. B-PTSD, bereaved children with posttraumatic stress disorder without comorbid psychiatric disorders; B-PTSD-Co, bereaved children with posttraumatic stress disorder with comorbid psychiatric disorders; B-GAD, bereaved children with generalized anxiety disorder without comorbid psychiatric disorders; B-GAD-Co, bereaved children with generalized anxiety disorder with comorbid psychiatric disorders; C-GAD-Co, nonbereaved children with generalized anxiety disorder with comorbid psychiatric disorders; B-No Psych Dis, bereaved children without psychiatric disorders; C-No Psych Dis, nonbereaved children without psychiatric disorders; AM, morning; PTSD, posttraumatic stress disorder; GAD, generalized anxiety disorder; BMI-z, body mass index Z scores; NOS, not otherwise specified; ADHD, attention-deficit/hyperactivity disorder.

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964 BIOL PSYCHIATRY 2007;61:957–965 focus on developing effective treatments to reduce these types of morbidities among bereaved children. The results that salivary cortisol levels were persistently elevated in bereaved children while the rates of psychiatric disorders declined suggests that traumatic bereavement may cause more lasting changes in HPA axis regulation that persist even as psychiatric disorders resolve. Furthermore, HPA axis functioning among bereaved children was found to be associated with specific psychiatric disorders, such as PTSD and GAD. For example, low baseline and greater suppression of salivary cortisol were observed during the course of study among bereaved children with PTSD. The low number of children with other psychiatric disorders, such as MDD, limited further evaluation of diagnosis-specific associations with cortisol levels. Because dexamethasone levels were not measured, the possibility cannot be excluded that compliance with taking dexamethasone and dexamethasone levels differed between bereaved and nonbereaved children. Future research involving effects of severe stress of parent death on children should evaluate types of parent death, psychiatric disorders, and psychosocial changes among children on psychological and HPA axis outcomes. Empirical studies are needed to determine whether early identification and intervention offered to bereaved children with varied psychopathologies may prevent persistence of abnormal neuroendocrine and psychological functioning and risk for future morbidities, such as cognitive impairment, reduced bone density, and insulin resistance.

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