EMPIRICAL ARTICLE
Childhood Trauma and Cortisol Awakening Response in Symptomatic Patients with Anorexia Nervosa and Bulimia Nervosa Alessio Maria Monteleone, MD1 Palmiero Monteleone, MD1,2* Ismene Serino, PhD3 Pasquale Scognamiglio, MD1 Monica Di Genio, MD1 Mario Maj, MD, PhD1
ABSTRACT Objective: Exposure to trauma during childhood is a risk factor for eating disorders (EDs) in adulthood. The biological mechanisms underlying such increased risk seem to involve the endogenous stress response system (i.e., the hypothalamic-pituitary-adrenal [HPA] axis), which undergoes trauma-induced functional changes that may persist later in life. In the present study, we examined the effects of childhood trauma experiences on HPA-axis activity, comparing saliva cortisol awakening response (CAR) in adult patients with anorexia nervosa (AN) or bulimia nervosa (BN) with CAR in adult healthy controls. Method: Twenty-three patients with symptomatic AN, 21 patients with symptomatic BN, and 29 healthy women collected saliva samples at awakening and again after 15, 30, and 60 min. Participants also completed the Childhood Trauma Questionnaire and eating-related psychopathological rating scales.
Introduction Available data suggest that childhood maltreatment, such as abuse, neglect, or loss, increases the risk of developing a wide range of psychological and behavioral problems in adulthood, including depression, anxiety, posttraumatic stress disorder (PTSD), bulimia nervosa (BN), and substance
Accepted 20 November 2014 The authors declare no biomedical financial interests or potential conflicts of interest. *Correspondence to: Palmiero Monteleone, Neuroscience Section, Department of Medicine and Surgery, University of Salerno, via Allende, 84081 Baronissi, Salerno, Italy. E-mail: [email protected] 1 Department of Psychiatry, University of Naples SUN, Naples, Italy 2 Neurosciences Section, Department of Medicine and Surgery, University of Salerno, Salerno, Italy 3 Department of Experimental Medicine, University of Naples SUN, Naples, Italy Published online 23 March 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/eat.22375 C 2014 Wiley Periodicals, Inc. V
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Results: According to the Childhood Trauma Questionnaire, 13 individuals with AN and 12 individuals with BN, but none of the healthy women, reported childhood maltreatment. Compared with the control group, the non-maltreated AN patient group exhibited an enhanced CAR, whereas the group of nonmaltreated BN patients showed a normal CAR. Moreover, both AN and BN patient groups with childhood maltreatment exhibited statistically significant blunting of CAR compared with non-maltreated groups. Discussion: The present findings add to the evidence supporting the concept that there is a dysregulation of HPA-axis activity in symptomatic patients with EDs and suggest that childhood trauma exposure may contribute to such dysreC 2014 Wiley Periodicals, Inc. gulation. V
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abuse,1–3 as well as the risk of cardiovascular diseases,4 HIV, and herpes virus type 2 infection5 and several other major causes of death.6 Therefore, childhood trauma exposure is a documented risk factor for adult psychopathology in general, although the biological mechanisms that mediate such increased risk are not fully understood. Both animal and human studies support the idea that the endogenous stress response system, including the hypothalamic-pituitary-adrenal (HPA) axis, is probably involved, and that early traumatic events can induce persistent changes in HPA-axis activity.7,8 HPA-axis dysregulation has been documented in both normal adults and adult psychiatric patients9–14 exposed to early traumatic experiences, although the direction of such dysregulation is not consistent across the studies. In particular, hyperresponsiveness of the HPA axis to the combined dexamethasone/corticotrophin-releasing factor (DEX/CRF) test has been detected in depressed adult patients with 615
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early trauma exposure, as compared with those without childhood trauma exposure; this effect was not explained by concomitant PTSD.10 Oppositely, in the same study, participants without depression but with PTSD exposed to early traumatic events had a decreased HPA-axis response to the combined DEX/CRF test. Results that were similar were also reported by Rinne et al.11 Moreover, women with PTSD who had been abused during childhood had lower afternoon cortisol levels than abused women without PTSD,12 and a hypoactivity of the HPA axis has been repeatedly reported in patients with PTSD.13 These data suggest the need to control for the presence of PTSD in studies assessing HPAaxis activity in subjects exposed to trauma. Moreover, regardless of the presence of PTSD, a hypoactivity of the corticosteroid axis has also been reported in adult subjects exposed to childhood trauma.14 An association has been reported between stressful life events and the onset or the course of anorexia nervosa (AN) and BN15; therefore, a role for the endogenous stress response system in the pathophysiology of eating disorders (EDs) seems likely. Actually, an increase of plasma and salivary and urinary cortisol levels as well as an increase of plasma and cerebrospinal fluid CRF concentrations and a reduced or absent suppression of cortisol to DEX suppression test have been detected in both patients with AN and patients with BN, although in the latter, such alterations were generally milder (see, for review16). All HPA-axis changes have been ascribed mainly to ED-induced malnutrition, because most of them receded or were not found in recovered patients with AN and BN (see, for review16). In the past several years, the cortisol awakening response (CAR) has received increasing attention as a useful method of assessing HPA-axis functioning.17 We recently reported an increased CAR in adult patients with symptomatic AN but not in patients with BN.18,19 However, to the best of our knowledge, the effects of childhood trauma exposure on the CAR of adult ED patients have not been explored yet. This area seems worthy of investigation, because patients with EDs report childhood trauma experiences more frequently than matched healthy controls.20,21 Therefore, in the present exploratory study, we examined possible associations between childhood traumatic experiences and HPA-axis functioning in adult patients with AN or BN and in healthy adult women. We hypothesized that adult patients with AN and adult patients with BN who were exposed 616
to early traumatic experiences would have a different CAR from adult ED patients without childhood trauma exposure.
Methods Patients consecutively attending the outpatient facilities of the Eating Disorders Center of the Department of Psychiatry of the University of Naples SUN were screened for inclusion in the study. They were required to meet DSM-IV diagnostic criteria for current AN or BN. Exclusion criteria were age less than 18 years, use of hormones or drugs, history of psychosis, diabetes mellitus, psychoactive substance use or head trauma, presence of severe physical diseases, or current comorbid Axis I psychiatric disorders, including depression and PTSD. According to these criteria, 12 patients with AN and 8 patients with BN with current major depression, and 7 patients with AN and 5 patients with BN with concomitant anxiety disorders were excluded. Moreover, five patients with AN and seven patients with BN who were eligible for the study refused to participate. The final patient sample included 23 women with the diagnosis of AN (8 were of the binge-purging subtype and 15 were of the restrictive subtype) and 21 women with the diagnosis of BN. Three patients with BN had a lifetime diagnosis of major depression. Diagnostic assessment was made by a trained interviewer by using the Structured Clinical Interview for Axis I DSM-IV Disorders2Patient Edition (SCID-IP);22 eatingrelated psychopathology was assessed by means of the Eating Disorder Inventory-223 and the Bulimia Investigation Test of Edinburgh.24 At the time of the study, the patients were medication-free for at least 4 weeks; none had taken fluoxetine in the past. Healthy participants consisted of 29 women, who were regularly menstruating, drug-free, and in good physical and mental health, as assessed by physical examination, routine medical interview, and SCID-I–Nonpatient Edition.25 The experimental protocol was approved by the local ethics committee, and all participants gave their written consent after being fully informed of the nature and procedures of the study. Menstruating women were tested in the early- to midfollicular phases of their menstrual cycle (within the seventh day after start of menses); this time was chosen to have a plasma estrogen milieu in menstruating women as close as possible to that of women with AN who were not menstruating. Indeed, in the early- to mid-follicular phase, plasma estrogen levels, although progressively increasing, are the lowest over the menstrual cycle. None of the participants had participated in our previous studies that assessed the CAR in ED patients,18,19 and all patients were studied before entering specific psychiatric treatment, including psychotherapy and nutritional rehabilitation. International Journal of Eating Disorders 48:6 615–621 2015
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All the participants were asked to fill out the short form of the Childhood Trauma Questionnaire (CTQ),26 a 28-item questionnaire (25 clinical items and 3 validity items) that assesses five specific forms of childhood trauma: sexual abuse, physical abuse, physical neglect, emotional abuse, and emotional neglect. The questionnaire encompasses a series of statements about childhood experiences, and respondents are asked to choose responses on a five-point Likert-type scale that ranges from “never true” to “very often true.” To determine the presence of each type of childhood trauma, we used previously validated cutoff scores for each CTQ subscale27: sexual abuse 8, physical abuse 8, physical neglect 8, emotional abuse 10, emotional neglect 15. By using these scores in each subject group, we constructed two different subgroups: participants who scored at or above the threshold scores for at least one of the five forms of childhood trauma were classified as “maltreated participants” (Mal); those who scored below the thresholds for all five types of childhood trauma were classified as “non-maltreated participants” (NoMal). The CAR was assessed by instructing participants to collect saliva samples at home on a working day, immediately on awakening and 15, 30, and 60 min after awakening; during that time they had to refrain from eating, drinking (except water), smoking, and brushing their teeth. Participants collected saliva samples by placing a roll of cotton in their mouths, chewing on it until it became saturated, and then returning it to the salivette tubes (Sarstedt, Rommelsdorf, Germany). These were stored in home freezers before being returned to the laboratory, where the saliva was separated by centrifugation and stored at 220 C until assayed for cortisol levels. In addition, participants were asked to record information on the duration of their sleep the night before the sampling procedure and their time of awakening on the morning of sampling. Saliva cortisol concentrations were determined by an enzyme immunoassay method, using a commercially available ELISA kit (Biochem Immunosystem, Milan, Italy); intra- and interassay coefficients of variation were less than 8% and 8.7%, respectively. According to Fekedulegn et al.,28 the CAR was calculated for each subject also as the cortisol area under the curve with respect to the increase (AUCi). The BMDP statistical software package29 was used for data analysis; a two-way analysis of variance (ANOVA) was conducted to test the differences in saliva cortisol responses to awakening among the groups, using group as the between-subject factor, the repeated measure of time (0, 15, 30, and 60 min after awakening) as the within-subject factor, and cortisol levels as the dependent variable. Between-group statistical differences in saliva cortisol levels at the different time points were assessed by the post hoc Tukey test. Because our AN International Journal of Eating Disorders 48:6 615–621 2015
patient group included both binge-purging and restrictive patients, a repeated-measure analysis of covariance with group as between-subject factor, the repeated measure of time as within-subject factor, cortisol values as dependent variable, and AN subtype as covariate was performed to exclude a possible effect of the AN subtype on the CAR results. One-way ANOVA and the v2 test were used to assess differences in hormonal, demographic, clinical, and anthropometric continuous and noncontinuous variables among groups, where appropriate.
Results Clinical and Demographic Data
No significant differences in age emerged among the groups (F2,70 5 0.48, p 5 .6). Mean body mass index (BMI) values were statistically different (F2,70 5 23.79, p < .00001), because, as expected, AN patients had a significantly lower BMI than healthy participants (F1,50 5 42.29, p < .00001) (Table 1). None of the healthy participants reported childhood trauma experiences; according to the CTQ cutoff scores reported above, seven patients with AN and six patients with BN reported emotional abuse; three patients with AN and five patients with BN reported physical abuse; one patient with AN and seven patients with BN reported sexual abuse; 10 patients with AN and 8 patients with BN reported emotional neglect; and seven patients with AN and six patients with BN reported physical neglect. Thirteen AN patients and 12 BN patients were classified as Mal participants. The frequency of the various childhood traumatic experiences did not differ significantly between the two patient groups, except for sexual abuse, which was significantly more frequent in the BN group (v2 5 6.20, df 5 1, p 5 .01). When Mal patients with AN and Mal patients with BN were compared with respective NoMal patients, no statistically significant differences emerged with regard to age, BMI, age at onset of the disease, and eating-related psychopathological scores (Table 1). No significant differences emerged between patients and healthy women in the mean time of awakening nor in the mean duration of sleep the night before saliva sampling. CAR Test
In a first analysis, patients with AN and patients with BN were subdivided into a Mal ED group (n 5 25) and a NoMal ED group (n 5 19), according to their history of childhood trauma exposure, and compared with healthy participants by a threegroup two-way ANOVA with repeated measures. 617
MONTELEONE ET AL. TABLE 1.
Clinical characteristics of the study sample
Age, years BMI, kg/m2 Age at onset, years BITE Symptom Score BITE Severity Score EDI-2 Subitem Scores Drive for thinness Bulimia Body dissatisfaction Ineffectiveness Perfectionism Interpersonal distrust Interoceptive awareness Maturity fear Asceticism Impulse regulation Social insecurity
Healthy Women (n 5 29)
Maltreated Women with AN (n 5 13)
No-Maltreated Women with AN (n 5 10)
Maltreated Women with BN (n 5 12)
No-Maltreated Women with BN (n 5 9)
27.6 6 6.7 21.5 6 2.8
31.6 6 9.2 16.5 6 3.0 18.1 6 4.6 13.4 6 7.7 7.4 6 5.7
27.3 6 10.0 17.0 6 1.3 18.7 6 4.9 14.3 6 5.8 4.7 6 3.2
31.1 6 7.7 23.9 6 5.0 17.7 6 4.3 23.6 6 3.0 11.1 6 4.6
26.6 6 7.9 21.3 6 1.8 19.3 6 3.5 23.4 6 2.1 9.6 6 3.0
14.3 6 6.1 7.5 6 7.0 14.8 6 4.7 12.0 6 5.4 7.0 6 3.5 6.3 6 3.9 10.5 6 4.9 9.9 6 6.0 8.1 6 3.5 6.1 6 6.6 9.6 6 3.0
13.7 6 7.2 7.6 6 5.9 11.8 6 5.1 12.0 6 4.1 6.0 6 2.7 8.1 6 5.0 9.1 6 5.0 7.1 6 3.6 6.0 6 2.5 5.5 6 4.6 8.4 6 4.5
16.1 6 7.0 9.6 6 5.9 16.4 6 5.8 11.3 6 7.4 4.0 6 3.0 6.8 6 5.2 12.4 6 6.2 8.5 6 4.7 7.1 6 3.0 8.0 6 7.8 7.8 6 3.9
17.6 6 3.4 10.7 6 6.3 16.1 6 5.7 11.1 6 7.9 6.2 6 4.0 6.5 6 5.0 15.0 6 5.4 8.2 6 7.3 8.8 6 3.9 8.4 6 4.3 8.1 6 4.3
Notes: AN, anorexia nervosa; BITE, Bulimia Investigation Test of Edinburgh; BMI, body mass index; BN, bulimia nervosa; EDI, Eating Disorder Inventory.
The analysis showed significant main effects for group (F2,70 5 8.52, p < .0005) and time (F3,210 5 30.37, p < .00001), and a significant group 3 time interaction (F6,210 5 3.51, p 5 .002), indicating that the CAR significantly differed among the groups in both the magnitude and the time pattern. Indeed, in NoMal ED patients, saliva cortisol levels significantly increased after awakening, and cortisol values at the various time points were significantly higher than both healthy controls and Mal ED patients (Fig. 1). The cortisol increase, instead, was significantly blunted in Mal ED participants, who exhibited cortisol levels significantly lower than healthy women 15 and 30 min after awakening (Fig. 1). In this three-group comparison, the repeated-measure analysis of covariance controlling for subtype of AN showed that this variable had no significant effects on CAR (F2,69 5 0.39, p 5 .5). One-way ANOVA showed that the CAR, evaluated as cortisol AUCi, significantly differed among the three groups (F2,70 5 12.06, p < .00001), being significantly higher in the NoMal ED patients as compared with both Mal ED women (p < .001) and healthy women (p < .05) (Fig. 1). In a second analysis, patients with AN and patients with BN were subdivided into NoMal and Mal and compared with healthy women by a fivegroup two-way ANOVA with repeated measures. The analysis showed significant main effects for group (F4,68 5 10.73, p < .00001) and time (F3,204 5 26.80, p < .00001) and a significant group 3 time interaction (F12,204 5 2.42, p 5 .006), indicating that the CAR significantly differed among the groups in both the magnitude and the time pattern. In NoMal AN patients, saliva cortisol levels significantly increased after awakening and cortisol 618
values were significantly higher than in healthy women; instead, the cortisol increase was significantly blunted in Mal AN participants, who exhibited cortisol levels comparable with those of healthy women (Fig. 2). In the BN group, NoMal BN patients exhibited a CAR that did not differ from healthy participants, whereas such a response was significantly decreased in Mal BN participants (Fig. 2). In this five-group comparison, the repeatedmeasure analysis of covariance controlling for subtype of AN showed that this variable had no significant effects on CAR (F4,67 5 0.43, p 5 .5). One-way ANOVA showed that the CAR, evaluated as cortisol AUCi, significantly differed among the five groups (F4,68 5 9.42, p < .00001). It was significantly higher in NoMal AN patients as compared with both Mal ones (p < .001) and healthy women (p < .001), and in NoMal BN participants as compared with Mal ones (p < .05) (Fig. 3). All the results did not change when BN patients with a lifetime history of major depression were removed from the analyses.
Discussion In AN patients without childhood trauma exposure, the CAR was characterized by a higher increase of saliva cortisol levels than in healthy controls; in contrast, in BN patients without childhood maltreatment, the CAR did not differ from normal controls. These results confirm our previous findings of a deranged CAR in symptomatic AN but not in symptomatic BN.17,18 Moreover, for the first time, we report here that both patients with AN and patients with BN with a positive history of International Journal of Eating Disorders 48:6 615–621 2015
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FIGURE 1. Salivary cortisol awakening response (CAR) and area under the curve with respect to the increase (AUCi) in drug-free maltreated (Mal) and non-maltreated (NoMal) patients with eating disorders (ED) and healthy controls. Data are expressed as mean 6 SD. *p < .05 and **p < .001 vs. both healthy controls and Mal ED patients; §p < .02 and #p < .01 vs. healthy controls (Tukey post hoc test); ***p < .0001 vs. Mal ED patients; p < .01 vs. healthy controls (Tukey post hoc test).
childhood maltreatment exhibited a lower CAR than NoMal patients. These results were not explained by differences in age, BMI, duration of the illness, or severity of eating-related psychopathology, because no statistically significant differences emerged according to these variables between Mal and NoMal patients. Although disease-induced malnutrition has been proposed as the main cause of HPA-axis dysfunctions in symptomatic patients with AN (see, for review16), our results suggest that childhood trauma exposure also affects HPA-axis activity in adult patients with AN. Indeed, an enhanced CAR was present only in symptomatic women with AN without childhood trauma exposure, which suggests that, in AN, malnutrition and early maltreatment may have opposite effects on HPA function. Because we did not recruit a group of maltreated weight-restored AN patients and/or a group of healthy women with childhood trauma exposure, we cannot disentangle the effect of the disease from that of childhood trauma on HPA-axis activity in AN. Moreover, because a blunted CAR occurred in our Mal BN patients but not in those without childhood trauma, we can propose that, in the absence of malnutrition (at least as documented by the normal BMI of BN participants), the exposure International Journal of Eating Disorders 48:6 615–621 2015
to childhood traumatic experiences would be associated with a dampened CAR. The present findings are in line with a large body of literature showing significant associations between childhood trauma exposure and adult HPA-axis hyporeactiviy in both nonclinical and clinical samples.12,14,30,31 In particular, a lower CAR after exposure to childhood trauma has been detected in healthy adults,30,31 in adults with personality disorders,32 in women with a history of intimate partner violence,33 as well as in abused and nonabused patients with PTSD.12,34 However, HPA-axis hyperresponsiveness has been also reported in adults with psychopathology, especially depression, who were exposed to negative childhood experiences.1,9–11 It has been proposed that such inconsistency may depend on factors such as the subject’s age at trauma exposure, the nature, severity, and duration of the trauma events,35 and the type of co-occurring psychopathology.9,11,14 To the best of our knowledge, the impact of childhood maltreatment on HPA-axis function in patients with EDs has been investigated in only three studies. In the first study, Steiger et al.36 reported that the secretion of cortisol after a serotonergic challenge test was reduced in women with 619
MONTELEONE ET AL. FIGURE 2. Salivary cortisol awakening response (CAR) in drug-free maltreated (Mal) and non-maltreated (NoMal) patients with anorexia nervosa (AN) or bulimia nervosa (BN) and healthy controls. Data are expressed as mean 6 SD. *p < .05 and **p < .001 vs. NoMal BN patients (Tukey post hoc test); §p < .05 vs. healthy controls (Tukey post hoc test); ***p < .0001 vs. both healthy controls and Mal AN patients (Tukey post hoc test).
BN with childhood trauma or abuse. In the second study,37 a hypersensitive HPA axis to DEX was found in binge-purging ED patients who reported childhood trauma or abuse. The third study, exploring sexual function in women with EDs, found no significant correlation between blood levels of cortisol and childhood abuse in a mixed sample of adult women with AN and BN.38 However, the results of the last study were based on a single morning value of blood cortisol, which cannot be representative of the HPA-axis functioning. Therefore, our findings are generally consistent with others in the available literature that support the idea that childhood trauma experiences may impair the activity of HPA axis in adult patients with AN and BN. The limitations of our study concern the procedure of the CAR test and the use of retrospective self-reports of childhood experiences. Indeed, our participants collected saliva samples at home rather than under strict observation in our clinical research unit. Moreover, because the CAR is sensitive to state variations in day-to-day activities, it has been recommended to assess the CAR on more than one working day.39 Finally, the CTQ does not investigate the age of exposure to trauma and is based on retrospective self-report of negative childhood experiences, a procedure that is influenced 620
FIGURE 3. Salivary cortisol area under the curve with respect to the increase (AUCi) in maltreated (Mal) and non-maltreated (NoMal) patients with anorexia nervosa (AN) or bulimia nervosa (BN) and healthy controls. Data are expressed as mean 6 SD. Data are expressed as mean 6 SD. *p < .05 vs. NoMal BN patients (Tukey post hoc test); **p < .001 vs. both healthy controls and Mal AN patients (Tukey post hoc test).
by several factors, such as forgetting, repression, or reporting biases. A strength of our study is that our patients were free from current comorbid psychiatric disorders, especially depression and PTSD, which are known to affect HPA-axis activity and the CAR.1,4,40 In conclusion, the present findings add to evidence supporting the concept that there is a dysregulation of HPA-axis activity in symptomatic patients with EDs and suggest that not only malnutrition but also childhood trauma exposure contribute to such a dysregulation in adult individuals with AN and BN.
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Childhood Trauma and Cortisol Awakening Response in Symptomatic Patients with Anorexia Nervosa and Bulimia Nervosa Alessio Maria Monteleone, MD1 Palmiero Monteleone, MD1,2* Ismene Serino, PhD3 Pasquale Scognamiglio, MD1 Monica Di Genio, MD1 Mario Maj, MD, PhD1
ABSTRACT Objective: Exposure to trauma during childhood is a risk factor for eating disorders (EDs) in adulthood. The biological mechanisms underlying such increased risk seem to involve the endogenous stress response system (i.e., the hypothalamic-pituitary-adrenal [HPA] axis), which undergoes trauma-induced functional changes that may persist later in life. In the present study, we examined the effects of childhood trauma experiences on HPA-axis activity, comparing saliva cortisol awakening response (CAR) in adult patients with anorexia nervosa (AN) or bulimia nervosa (BN) with CAR in adult healthy controls. Method: Twenty-three patients with symptomatic AN, 21 patients with symptomatic BN, and 29 healthy women collected saliva samples at awakening and again after 15, 30, and 60 min. Participants also completed the Childhood Trauma Questionnaire and eating-related psychopathological rating scales.
Introduction Available data suggest that childhood maltreatment, such as abuse, neglect, or loss, increases the risk of developing a wide range of psychological and behavioral problems in adulthood, including depression, anxiety, posttraumatic stress disorder (PTSD), bulimia nervosa (BN), and substance
Accepted 20 November 2014 The authors declare no biomedical financial interests or potential conflicts of interest. *Correspondence to: Palmiero Monteleone, Neuroscience Section, Department of Medicine and Surgery, University of Salerno, via Allende, 84081 Baronissi, Salerno, Italy. E-mail: [email protected] 1 Department of Psychiatry, University of Naples SUN, Naples, Italy 2 Neurosciences Section, Department of Medicine and Surgery, University of Salerno, Salerno, Italy 3 Department of Experimental Medicine, University of Naples SUN, Naples, Italy Published online 23 March 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/eat.22375 C 2014 Wiley Periodicals, Inc. V
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Results: According to the Childhood Trauma Questionnaire, 13 individuals with AN and 12 individuals with BN, but none of the healthy women, reported childhood maltreatment. Compared with the control group, the non-maltreated AN patient group exhibited an enhanced CAR, whereas the group of nonmaltreated BN patients showed a normal CAR. Moreover, both AN and BN patient groups with childhood maltreatment exhibited statistically significant blunting of CAR compared with non-maltreated groups. Discussion: The present findings add to the evidence supporting the concept that there is a dysregulation of HPA-axis activity in symptomatic patients with EDs and suggest that childhood trauma exposure may contribute to such dysreC 2014 Wiley Periodicals, Inc. gulation. V
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abuse,1–3 as well as the risk of cardiovascular diseases,4 HIV, and herpes virus type 2 infection5 and several other major causes of death.6 Therefore, childhood trauma exposure is a documented risk factor for adult psychopathology in general, although the biological mechanisms that mediate such increased risk are not fully understood. Both animal and human studies support the idea that the endogenous stress response system, including the hypothalamic-pituitary-adrenal (HPA) axis, is probably involved, and that early traumatic events can induce persistent changes in HPA-axis activity.7,8 HPA-axis dysregulation has been documented in both normal adults and adult psychiatric patients9–14 exposed to early traumatic experiences, although the direction of such dysregulation is not consistent across the studies. In particular, hyperresponsiveness of the HPA axis to the combined dexamethasone/corticotrophin-releasing factor (DEX/CRF) test has been detected in depressed adult patients with 615
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early trauma exposure, as compared with those without childhood trauma exposure; this effect was not explained by concomitant PTSD.10 Oppositely, in the same study, participants without depression but with PTSD exposed to early traumatic events had a decreased HPA-axis response to the combined DEX/CRF test. Results that were similar were also reported by Rinne et al.11 Moreover, women with PTSD who had been abused during childhood had lower afternoon cortisol levels than abused women without PTSD,12 and a hypoactivity of the HPA axis has been repeatedly reported in patients with PTSD.13 These data suggest the need to control for the presence of PTSD in studies assessing HPAaxis activity in subjects exposed to trauma. Moreover, regardless of the presence of PTSD, a hypoactivity of the corticosteroid axis has also been reported in adult subjects exposed to childhood trauma.14 An association has been reported between stressful life events and the onset or the course of anorexia nervosa (AN) and BN15; therefore, a role for the endogenous stress response system in the pathophysiology of eating disorders (EDs) seems likely. Actually, an increase of plasma and salivary and urinary cortisol levels as well as an increase of plasma and cerebrospinal fluid CRF concentrations and a reduced or absent suppression of cortisol to DEX suppression test have been detected in both patients with AN and patients with BN, although in the latter, such alterations were generally milder (see, for review16). All HPA-axis changes have been ascribed mainly to ED-induced malnutrition, because most of them receded or were not found in recovered patients with AN and BN (see, for review16). In the past several years, the cortisol awakening response (CAR) has received increasing attention as a useful method of assessing HPA-axis functioning.17 We recently reported an increased CAR in adult patients with symptomatic AN but not in patients with BN.18,19 However, to the best of our knowledge, the effects of childhood trauma exposure on the CAR of adult ED patients have not been explored yet. This area seems worthy of investigation, because patients with EDs report childhood trauma experiences more frequently than matched healthy controls.20,21 Therefore, in the present exploratory study, we examined possible associations between childhood traumatic experiences and HPA-axis functioning in adult patients with AN or BN and in healthy adult women. We hypothesized that adult patients with AN and adult patients with BN who were exposed 616
to early traumatic experiences would have a different CAR from adult ED patients without childhood trauma exposure.
Methods Patients consecutively attending the outpatient facilities of the Eating Disorders Center of the Department of Psychiatry of the University of Naples SUN were screened for inclusion in the study. They were required to meet DSM-IV diagnostic criteria for current AN or BN. Exclusion criteria were age less than 18 years, use of hormones or drugs, history of psychosis, diabetes mellitus, psychoactive substance use or head trauma, presence of severe physical diseases, or current comorbid Axis I psychiatric disorders, including depression and PTSD. According to these criteria, 12 patients with AN and 8 patients with BN with current major depression, and 7 patients with AN and 5 patients with BN with concomitant anxiety disorders were excluded. Moreover, five patients with AN and seven patients with BN who were eligible for the study refused to participate. The final patient sample included 23 women with the diagnosis of AN (8 were of the binge-purging subtype and 15 were of the restrictive subtype) and 21 women with the diagnosis of BN. Three patients with BN had a lifetime diagnosis of major depression. Diagnostic assessment was made by a trained interviewer by using the Structured Clinical Interview for Axis I DSM-IV Disorders2Patient Edition (SCID-IP);22 eatingrelated psychopathology was assessed by means of the Eating Disorder Inventory-223 and the Bulimia Investigation Test of Edinburgh.24 At the time of the study, the patients were medication-free for at least 4 weeks; none had taken fluoxetine in the past. Healthy participants consisted of 29 women, who were regularly menstruating, drug-free, and in good physical and mental health, as assessed by physical examination, routine medical interview, and SCID-I–Nonpatient Edition.25 The experimental protocol was approved by the local ethics committee, and all participants gave their written consent after being fully informed of the nature and procedures of the study. Menstruating women were tested in the early- to midfollicular phases of their menstrual cycle (within the seventh day after start of menses); this time was chosen to have a plasma estrogen milieu in menstruating women as close as possible to that of women with AN who were not menstruating. Indeed, in the early- to mid-follicular phase, plasma estrogen levels, although progressively increasing, are the lowest over the menstrual cycle. None of the participants had participated in our previous studies that assessed the CAR in ED patients,18,19 and all patients were studied before entering specific psychiatric treatment, including psychotherapy and nutritional rehabilitation. International Journal of Eating Disorders 48:6 615–621 2015
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All the participants were asked to fill out the short form of the Childhood Trauma Questionnaire (CTQ),26 a 28-item questionnaire (25 clinical items and 3 validity items) that assesses five specific forms of childhood trauma: sexual abuse, physical abuse, physical neglect, emotional abuse, and emotional neglect. The questionnaire encompasses a series of statements about childhood experiences, and respondents are asked to choose responses on a five-point Likert-type scale that ranges from “never true” to “very often true.” To determine the presence of each type of childhood trauma, we used previously validated cutoff scores for each CTQ subscale27: sexual abuse 8, physical abuse 8, physical neglect 8, emotional abuse 10, emotional neglect 15. By using these scores in each subject group, we constructed two different subgroups: participants who scored at or above the threshold scores for at least one of the five forms of childhood trauma were classified as “maltreated participants” (Mal); those who scored below the thresholds for all five types of childhood trauma were classified as “non-maltreated participants” (NoMal). The CAR was assessed by instructing participants to collect saliva samples at home on a working day, immediately on awakening and 15, 30, and 60 min after awakening; during that time they had to refrain from eating, drinking (except water), smoking, and brushing their teeth. Participants collected saliva samples by placing a roll of cotton in their mouths, chewing on it until it became saturated, and then returning it to the salivette tubes (Sarstedt, Rommelsdorf, Germany). These were stored in home freezers before being returned to the laboratory, where the saliva was separated by centrifugation and stored at 220 C until assayed for cortisol levels. In addition, participants were asked to record information on the duration of their sleep the night before the sampling procedure and their time of awakening on the morning of sampling. Saliva cortisol concentrations were determined by an enzyme immunoassay method, using a commercially available ELISA kit (Biochem Immunosystem, Milan, Italy); intra- and interassay coefficients of variation were less than 8% and 8.7%, respectively. According to Fekedulegn et al.,28 the CAR was calculated for each subject also as the cortisol area under the curve with respect to the increase (AUCi). The BMDP statistical software package29 was used for data analysis; a two-way analysis of variance (ANOVA) was conducted to test the differences in saliva cortisol responses to awakening among the groups, using group as the between-subject factor, the repeated measure of time (0, 15, 30, and 60 min after awakening) as the within-subject factor, and cortisol levels as the dependent variable. Between-group statistical differences in saliva cortisol levels at the different time points were assessed by the post hoc Tukey test. Because our AN International Journal of Eating Disorders 48:6 615–621 2015
patient group included both binge-purging and restrictive patients, a repeated-measure analysis of covariance with group as between-subject factor, the repeated measure of time as within-subject factor, cortisol values as dependent variable, and AN subtype as covariate was performed to exclude a possible effect of the AN subtype on the CAR results. One-way ANOVA and the v2 test were used to assess differences in hormonal, demographic, clinical, and anthropometric continuous and noncontinuous variables among groups, where appropriate.
Results Clinical and Demographic Data
No significant differences in age emerged among the groups (F2,70 5 0.48, p 5 .6). Mean body mass index (BMI) values were statistically different (F2,70 5 23.79, p < .00001), because, as expected, AN patients had a significantly lower BMI than healthy participants (F1,50 5 42.29, p < .00001) (Table 1). None of the healthy participants reported childhood trauma experiences; according to the CTQ cutoff scores reported above, seven patients with AN and six patients with BN reported emotional abuse; three patients with AN and five patients with BN reported physical abuse; one patient with AN and seven patients with BN reported sexual abuse; 10 patients with AN and 8 patients with BN reported emotional neglect; and seven patients with AN and six patients with BN reported physical neglect. Thirteen AN patients and 12 BN patients were classified as Mal participants. The frequency of the various childhood traumatic experiences did not differ significantly between the two patient groups, except for sexual abuse, which was significantly more frequent in the BN group (v2 5 6.20, df 5 1, p 5 .01). When Mal patients with AN and Mal patients with BN were compared with respective NoMal patients, no statistically significant differences emerged with regard to age, BMI, age at onset of the disease, and eating-related psychopathological scores (Table 1). No significant differences emerged between patients and healthy women in the mean time of awakening nor in the mean duration of sleep the night before saliva sampling. CAR Test
In a first analysis, patients with AN and patients with BN were subdivided into a Mal ED group (n 5 25) and a NoMal ED group (n 5 19), according to their history of childhood trauma exposure, and compared with healthy participants by a threegroup two-way ANOVA with repeated measures. 617
MONTELEONE ET AL. TABLE 1.
Clinical characteristics of the study sample
Age, years BMI, kg/m2 Age at onset, years BITE Symptom Score BITE Severity Score EDI-2 Subitem Scores Drive for thinness Bulimia Body dissatisfaction Ineffectiveness Perfectionism Interpersonal distrust Interoceptive awareness Maturity fear Asceticism Impulse regulation Social insecurity
Healthy Women (n 5 29)
Maltreated Women with AN (n 5 13)
No-Maltreated Women with AN (n 5 10)
Maltreated Women with BN (n 5 12)
No-Maltreated Women with BN (n 5 9)
27.6 6 6.7 21.5 6 2.8
31.6 6 9.2 16.5 6 3.0 18.1 6 4.6 13.4 6 7.7 7.4 6 5.7
27.3 6 10.0 17.0 6 1.3 18.7 6 4.9 14.3 6 5.8 4.7 6 3.2
31.1 6 7.7 23.9 6 5.0 17.7 6 4.3 23.6 6 3.0 11.1 6 4.6
26.6 6 7.9 21.3 6 1.8 19.3 6 3.5 23.4 6 2.1 9.6 6 3.0
14.3 6 6.1 7.5 6 7.0 14.8 6 4.7 12.0 6 5.4 7.0 6 3.5 6.3 6 3.9 10.5 6 4.9 9.9 6 6.0 8.1 6 3.5 6.1 6 6.6 9.6 6 3.0
13.7 6 7.2 7.6 6 5.9 11.8 6 5.1 12.0 6 4.1 6.0 6 2.7 8.1 6 5.0 9.1 6 5.0 7.1 6 3.6 6.0 6 2.5 5.5 6 4.6 8.4 6 4.5
16.1 6 7.0 9.6 6 5.9 16.4 6 5.8 11.3 6 7.4 4.0 6 3.0 6.8 6 5.2 12.4 6 6.2 8.5 6 4.7 7.1 6 3.0 8.0 6 7.8 7.8 6 3.9
17.6 6 3.4 10.7 6 6.3 16.1 6 5.7 11.1 6 7.9 6.2 6 4.0 6.5 6 5.0 15.0 6 5.4 8.2 6 7.3 8.8 6 3.9 8.4 6 4.3 8.1 6 4.3
Notes: AN, anorexia nervosa; BITE, Bulimia Investigation Test of Edinburgh; BMI, body mass index; BN, bulimia nervosa; EDI, Eating Disorder Inventory.
The analysis showed significant main effects for group (F2,70 5 8.52, p < .0005) and time (F3,210 5 30.37, p < .00001), and a significant group 3 time interaction (F6,210 5 3.51, p 5 .002), indicating that the CAR significantly differed among the groups in both the magnitude and the time pattern. Indeed, in NoMal ED patients, saliva cortisol levels significantly increased after awakening, and cortisol values at the various time points were significantly higher than both healthy controls and Mal ED patients (Fig. 1). The cortisol increase, instead, was significantly blunted in Mal ED participants, who exhibited cortisol levels significantly lower than healthy women 15 and 30 min after awakening (Fig. 1). In this three-group comparison, the repeated-measure analysis of covariance controlling for subtype of AN showed that this variable had no significant effects on CAR (F2,69 5 0.39, p 5 .5). One-way ANOVA showed that the CAR, evaluated as cortisol AUCi, significantly differed among the three groups (F2,70 5 12.06, p < .00001), being significantly higher in the NoMal ED patients as compared with both Mal ED women (p < .001) and healthy women (p < .05) (Fig. 1). In a second analysis, patients with AN and patients with BN were subdivided into NoMal and Mal and compared with healthy women by a fivegroup two-way ANOVA with repeated measures. The analysis showed significant main effects for group (F4,68 5 10.73, p < .00001) and time (F3,204 5 26.80, p < .00001) and a significant group 3 time interaction (F12,204 5 2.42, p 5 .006), indicating that the CAR significantly differed among the groups in both the magnitude and the time pattern. In NoMal AN patients, saliva cortisol levels significantly increased after awakening and cortisol 618
values were significantly higher than in healthy women; instead, the cortisol increase was significantly blunted in Mal AN participants, who exhibited cortisol levels comparable with those of healthy women (Fig. 2). In the BN group, NoMal BN patients exhibited a CAR that did not differ from healthy participants, whereas such a response was significantly decreased in Mal BN participants (Fig. 2). In this five-group comparison, the repeatedmeasure analysis of covariance controlling for subtype of AN showed that this variable had no significant effects on CAR (F4,67 5 0.43, p 5 .5). One-way ANOVA showed that the CAR, evaluated as cortisol AUCi, significantly differed among the five groups (F4,68 5 9.42, p < .00001). It was significantly higher in NoMal AN patients as compared with both Mal ones (p < .001) and healthy women (p < .001), and in NoMal BN participants as compared with Mal ones (p < .05) (Fig. 3). All the results did not change when BN patients with a lifetime history of major depression were removed from the analyses.
Discussion In AN patients without childhood trauma exposure, the CAR was characterized by a higher increase of saliva cortisol levels than in healthy controls; in contrast, in BN patients without childhood maltreatment, the CAR did not differ from normal controls. These results confirm our previous findings of a deranged CAR in symptomatic AN but not in symptomatic BN.17,18 Moreover, for the first time, we report here that both patients with AN and patients with BN with a positive history of International Journal of Eating Disorders 48:6 615–621 2015
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FIGURE 1. Salivary cortisol awakening response (CAR) and area under the curve with respect to the increase (AUCi) in drug-free maltreated (Mal) and non-maltreated (NoMal) patients with eating disorders (ED) and healthy controls. Data are expressed as mean 6 SD. *p < .05 and **p < .001 vs. both healthy controls and Mal ED patients; §p < .02 and #p < .01 vs. healthy controls (Tukey post hoc test); ***p < .0001 vs. Mal ED patients; p < .01 vs. healthy controls (Tukey post hoc test).
childhood maltreatment exhibited a lower CAR than NoMal patients. These results were not explained by differences in age, BMI, duration of the illness, or severity of eating-related psychopathology, because no statistically significant differences emerged according to these variables between Mal and NoMal patients. Although disease-induced malnutrition has been proposed as the main cause of HPA-axis dysfunctions in symptomatic patients with AN (see, for review16), our results suggest that childhood trauma exposure also affects HPA-axis activity in adult patients with AN. Indeed, an enhanced CAR was present only in symptomatic women with AN without childhood trauma exposure, which suggests that, in AN, malnutrition and early maltreatment may have opposite effects on HPA function. Because we did not recruit a group of maltreated weight-restored AN patients and/or a group of healthy women with childhood trauma exposure, we cannot disentangle the effect of the disease from that of childhood trauma on HPA-axis activity in AN. Moreover, because a blunted CAR occurred in our Mal BN patients but not in those without childhood trauma, we can propose that, in the absence of malnutrition (at least as documented by the normal BMI of BN participants), the exposure International Journal of Eating Disorders 48:6 615–621 2015
to childhood traumatic experiences would be associated with a dampened CAR. The present findings are in line with a large body of literature showing significant associations between childhood trauma exposure and adult HPA-axis hyporeactiviy in both nonclinical and clinical samples.12,14,30,31 In particular, a lower CAR after exposure to childhood trauma has been detected in healthy adults,30,31 in adults with personality disorders,32 in women with a history of intimate partner violence,33 as well as in abused and nonabused patients with PTSD.12,34 However, HPA-axis hyperresponsiveness has been also reported in adults with psychopathology, especially depression, who were exposed to negative childhood experiences.1,9–11 It has been proposed that such inconsistency may depend on factors such as the subject’s age at trauma exposure, the nature, severity, and duration of the trauma events,35 and the type of co-occurring psychopathology.9,11,14 To the best of our knowledge, the impact of childhood maltreatment on HPA-axis function in patients with EDs has been investigated in only three studies. In the first study, Steiger et al.36 reported that the secretion of cortisol after a serotonergic challenge test was reduced in women with 619
MONTELEONE ET AL. FIGURE 2. Salivary cortisol awakening response (CAR) in drug-free maltreated (Mal) and non-maltreated (NoMal) patients with anorexia nervosa (AN) or bulimia nervosa (BN) and healthy controls. Data are expressed as mean 6 SD. *p < .05 and **p < .001 vs. NoMal BN patients (Tukey post hoc test); §p < .05 vs. healthy controls (Tukey post hoc test); ***p < .0001 vs. both healthy controls and Mal AN patients (Tukey post hoc test).
BN with childhood trauma or abuse. In the second study,37 a hypersensitive HPA axis to DEX was found in binge-purging ED patients who reported childhood trauma or abuse. The third study, exploring sexual function in women with EDs, found no significant correlation between blood levels of cortisol and childhood abuse in a mixed sample of adult women with AN and BN.38 However, the results of the last study were based on a single morning value of blood cortisol, which cannot be representative of the HPA-axis functioning. Therefore, our findings are generally consistent with others in the available literature that support the idea that childhood trauma experiences may impair the activity of HPA axis in adult patients with AN and BN. The limitations of our study concern the procedure of the CAR test and the use of retrospective self-reports of childhood experiences. Indeed, our participants collected saliva samples at home rather than under strict observation in our clinical research unit. Moreover, because the CAR is sensitive to state variations in day-to-day activities, it has been recommended to assess the CAR on more than one working day.39 Finally, the CTQ does not investigate the age of exposure to trauma and is based on retrospective self-report of negative childhood experiences, a procedure that is influenced 620
FIGURE 3. Salivary cortisol area under the curve with respect to the increase (AUCi) in maltreated (Mal) and non-maltreated (NoMal) patients with anorexia nervosa (AN) or bulimia nervosa (BN) and healthy controls. Data are expressed as mean 6 SD. Data are expressed as mean 6 SD. *p < .05 vs. NoMal BN patients (Tukey post hoc test); **p < .001 vs. both healthy controls and Mal AN patients (Tukey post hoc test).
by several factors, such as forgetting, repression, or reporting biases. A strength of our study is that our patients were free from current comorbid psychiatric disorders, especially depression and PTSD, which are known to affect HPA-axis activity and the CAR.1,4,40 In conclusion, the present findings add to evidence supporting the concept that there is a dysregulation of HPA-axis activity in symptomatic patients with EDs and suggest that not only malnutrition but also childhood trauma exposure contribute to such a dysregulation in adult individuals with AN and BN.
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