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Dexamethasone suppression test using saliva cortisol measurement in bulimia nervosa
Physiology & Behavior 72 (2001) 93 ± 98
Dexamethasone suppression test using saliva cortisol measurement in bulimia nervosa$ Peter Neudecka,*, Georg E. Jacobyb, Irmela Florinc,1 a
Christoph-Dornier Foundation for Clinical Psychology, Marienstraûe 18, D-10117, Berlin, Germany b Klinik am Korso, Ostkorso 4, 32545 Bad Oeynhausen, Germany c Department of Psychology, Philipps University Marburg, Gutenbergstrasse 5, 35032 Marburg, Germany Received 11 April 2000; received in revised form 9 June 2000; accepted 25 August 2000
Abstract The assessment of cortisol in saliva has been proven a valid and reliable reflection of the respective unbound hormone in blood. In the present study, a standard dexamethasone suppression test (DST) with measures of salivary cortisol levels was performed in bulimic women without depression (DSM-IV; N = 48) and healthy controls (N = 24) matched for age. Feedback sensitivity was assessed using the standard DST with pre- and post-measures of salivary cortisol. Subjects were divided into suppressors and nonsuppressors according to their post-DST levels. Bulimic suppressors and nonsuppressors were compared for their basal cortisol levels, body weight (body mass index, BMI), previous episodes of anorexia nervosa, and their results in psychometric tests. A total of 16 (33.3%) out of 48 women with bulimia nervosa (BN) failed to suppress in the DST. Basal salivary cortisol levels were elevated in bulimic nonsuppressors. Significant differences between suppressors and nonsuppressors were found for body weight and previous episodes of anorexia nervosa. The results are in accordance with recent findings. They support the hypothesized association between low body weight and DST nonsuppression. Using saliva cortisol in the standard DST could be advantageous for studying bulimic patients. Furthermore, the results show the importance of determining HPA reagibility when measuring cortisol in bulimic patients. D 2001 Elsevier Science Inc. All rights reserved. Keywords: Dexamethasone suppression test; Bulimia; Salivary cortisol
1. Introduction Several studies have examined the dexamethasone suppression test (DST) in bulimia nervosa (BN) [1 ±4]. These studies reported rates of nonsuppression of about 35 ± 67%. This rate of nonsuppression is higher than the incidence of 7 ±10% found in a normal population [5,6], but similar to rates found in depressed patients [7]. Most of the variables considered in recent research (duration of illness, Eating Attitudes Test scores [8], age, binge frequency) were unre$ Statement of informed consent: We ensure that all subjects were informed aboutthe aim of the study, especially about the use of dexamethasone. The experiment was authorized by the ``Ethik Kommision'' of the German Society of Psychology. * Corresponding author. Christoph-Dornier Foundation for Clinical Psychology, Marienstrabe 18, D-10117 Berlin. Tel.: +49 30 25298473; Fax: +49 (0) 30 25298470. E-mail address: [email protected] (P. Neudeck). 1 Deceased in December 1998.
lated to DST nonsuppression in BN. However, some studies reported a relation between low body weight and nonsuppression [9± 12]. All studies mentioned above used measures of plasma cortisol to detect suppressors and nonsuppressors. Since the results of several studies suggest that the diagnostic value of salivary cortisol DSTs equals that of blood borne tests [7,13 ± 15], the present study used measures of salivary cortisol in the DST with bulimic patients for the first time. The previously reported literature on DST in BN held some methodical problems including small sample sizes, the use of outpatients (particularly, the poor control over compliance and actual eating behavior, which may differ between subjects), the lack of information about basal cortisol patterns during the day, and the dosage of DEX used. With the exception of one study [4], the amount of dexamethasone used was 1.0 mg. However, the results of a few studies [16 ± 19] revealed that the quantity of 1.0-mg DEX might not be sufficient for detecting hyperreagibility
0031-9384/01/$ ± see front matter D 2001 Elsevier Science Inc. All rights reserved. PII: S 0 0 3 1 - 9 3 8 4 ( 0 0 ) 0 0 3 8 7 - 5
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of the HPA. Therefore, the standard DST (1.5 mg) was chosen for the present study. 2. Materials and methods Forty-eight female inpatients with a diagnosis of BN meeting DSM-IV [20] criteria participated in the study. Patients with comorbidity (Axes I and II, according to DSM-IV) or past physical disorders, as described by DressendoÈrfer et al. [22], had been excluded using a standardized interview for psychiatric diseases [21]. Participants' mean age was 26.3 (S.D. = 12.2) years. Their average body mass index (BMI) was 20.18 (S.D. = 3.95), mean duration of illness was 7.8 (S.D. = 4.6) years, and the average number of past treatments for BN was 1.3 (S.D. = 1.06). All participants of the BN group were patients of an inpatient unit for eating disorders. At the point of data collection, the mean duration of current treatment in the hospital had been 5.91 (S.D. = 3.3) weeks. All patients were free of medication and were treated with an integrative concept of psychotherapy (cognitive ± behavioral/psychodynamic; single and group). Thirty-three percent of the patients had a history of anorexia nervosa. Prior to admission to the inpatient unit, patients had experienced an average of 2.5 (S.D. = 1.6) binge episodes per day. On average, the last binge episode had occurred 11.2 (S.D. = 14.5) days before the experiment was performed. Data showed that 27.8% of the patients had an amenorrhea, 43.7% were in the follicle phase, and 29.1% were in the luteal phase. Fifty-one percent of the patients were smokers. There was no significant difference between patients and controls regarding the use of oral contraceptives [c2(2) = 1.41, n.s.] or the BMI [ F(1,70) = 1.64, n.s.]. Selection criteria and methods for controls were the same as in patients. The control group consisted of 24 women of normal weight who had no present or past signs of mental illness or significant physical disorders [22]. Controls' mean age was 27.1 (S.D. = 5.3) years and their average BMI was 22.14 (S.D. = 3.07). Twenty-five percent of the controls were smokers. The control group was recruited by announcements in local newspapers and they were paid an equivalent of US$15.00 for their participation. 2.1. Experimental protocol To assess the HPA activity during the day, samples of saliva cortisol were taken at 8 a.m., 3 p.m., 4 p.m., and 8 p.m. Inferences with daily life activities were kept at a minimum. The patients were instructed to maintain their daily routines in the inpatient unit, as well as the controls with respect to their daily routine at work or at home. Furthermore, they were instructed to describe their activities during the experimental session, because there is a suggestion that some activities interfere with the HPA system activity (i.e., excessive physical activity, psychosocial stress [23,24]). Saliva samples were used to assess cortisol, as they
are easily collected and stored in the subjects' natural environment. Subjects collected saliva by placing a sterile cotton wad in their mouth for a few minutes and then sealing the cotton in a salivette, a test tube-like container (Sarstedt, Rommelsdorf, Germany). The participants were told to store the salivettes in a freezer until returning them to the experimenters. Salivettes were kept frozen in the laboratory until they were analyzed. All subjects received a list in which the time of their awakening and information on any stress experienced during the day was recorded. For the assessment of feedback sensitivity of the HPA, the DST with 1.5-mg DEX was performed. The participants took the capsule at 11 p.m. On the following day, subjects again collected saliva at 8 a.m., 3 p.m., 4 p.m., and 8 p.m. 2.2. Assays For the assessment of salivary cortisol, a time-resolved fluorescence immunoassay with a biotin ± cortisol conjugate as tracer and a streptavidin ± europium label was used. The lower detection limit of this assay was 0.43 nmol for a 50-ml saliva sample. Thawed saliva samples were centrifuged at 3000 rpm for 5 min resulting in clear saliva with low viscosity. By using a 100-ml sample duplicate, analyses were conducted and all samples from an individual were analyzed in a single assay run. The intra- and inter-assay coefficients of variation were less than 7% and 9%, respectively [22]. 2.3. Data analysis After testing the variables for normal distribution, comparisons of pre- and post-DEX cortisol profiles were assessed by analysis of variance (ANOVA) for repeated measures. Greenhouse Geisser correction of degrees of freedom was applied where appropriate. Post-hoc analyses were computed using Student's t tests. The Nadir Point assessed the maximal suppression of cortisol in the DST. The cortisol response curve (area under the curve, AUC) was computed for the 2 days according to the trapezoid formula. The AUC were compared by a one-way ANOVA. The cut-off point for the detection of DST nonsuppression was a concentration of cortisol more than 4.8 nmol/l at one measurement point of the day following the DST [7,14]. We compared the suppressors and nonsuppressors for their BMI, locus of control, self-efficacy, self-concept (FKK) [23], subjective ratings of depressiveness [24 ± 26], binge attacks per day, and a history of anorexia nervosa by one-way ANOVA. 3. Results 3.1. Baseline data The ANOVA for repeated measures revealed a significant group effect, as well as a significant time effect. No
P. Neudeck et al. / Physiology & Behavior 72 (2001) 93±98
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Table 1 Cortisol levels in saliva (nmol/l) under basal conditions (means and S.D.) Time
BN suppressors (N = 32)
BN nonsuppressors (N = 16)
Controls (N = 24)
8 3 4 8
15.27 7.73 7.67 3.55
22.04 (3.06) 11.86 (1.56) 12.81 (2.83) 7.89 (0.79)
16.42 5.95 5.93 2.89
a.m. p.m. p.m. p.m.
(1.20) (0.63) (0.71) (0.32)
significant interaction was found. Under unstimulated conditions, bulimic nonsuppressors had higher cortisol levels in saliva. The diurnal profile was reflected by the significant effect of the time. For a comparison between bulimic patients (N = 48) and the control group (N = 24), an ANOVA for the AUC0 was computed. A significant difference between the groups [ F(1,70) = 4.47, P < .05] was found. The AUC0 of the BN group (20.39, S.D. = 1.40) was higher than the AUC0 of the control group (15.61, S.D. = 1.32). 3.2. DST data The ANOVA for repeated measures showed a significant group effect. No time effect or interaction effect was revealed. After 1.5-mg DEX, bulimic nonsuppressors showed higher saliva cortisol levels. The diurnal pattern of cortisol had disappeared, as reflected by the missing effect of time. The one-way ANOVA for the AUC0 showed a significant difference between bulimic patients (N = 48) and the control group (N = 24) [ F(1,70) = 6.13, P < .05]. The AUC0 of the BN group (12.83, S.D. = 2.18) was higher than the AUC0 of the control group (4.81, S.D. = 0.71). Nadir Cort was defined as the lowest value of saliva cortisol at any time point after the administration of 1.5-mg DST. One-way ANOVA revealed a significant difference between the groups [ F(1,70) = 5.9, P < .05]. The average maximum cortisol suppression (Table 1) of the controls (1.46, S.D. = 0.64) was significantly lower than that of the BN group (3.82, S.D. = 0.91). 3.3. DST nonsuppression As accentuated above, a cut-off point of 4.8 nmol/l was chosen to distinguish suppressors from nonsuppressors. A total of 16 (33.3%) out of 48 patients with BN had abnormal DST results compared with two (8.3%) of the controls [c2(1) = 8.97, P < .0001].
(1.57) (0.62) (1.02) (0.30)
ANOVA group: F(1,69) = 4.73, P < .05; time: F(2.04,207) = 62.37, P < .0001; interaction: F(2.04,207) = 0.53, n.s.
Since only two nonsuppressors were detected in the control group, the statistics below were performed only for the BN group. Significant differences were found between suppressors and nonsuppressors for the BMI [ F(1,46) = 5.69, P < .05] and for the three categories (underweight, normal weight, overweight) of the BMI (K ±S z = 1.93, P < .0001). The BMI of the suppressors was higher than the BMI of the nonsuppressors. Furthermore, we found significant differences between subjects with and without a history of anorexia nervosa [c2(1) = 5.67, P < .001]. After controlling for current weight, significantly more subjects with a history of anorexia nervosa were in the nonsuppressor group [ F(1,46) = 7,82, P > .001]. The average number of binge attacks per day, self-concept, internal locus of control, selfefficacy, cognitive control over food consumption, and subjective ratings of depressiveness did not differ between suppressors and nonsuppressors. There was no association between depression ratings and current body weight status in the patient group (see Table 2). A linear regression model showed no significant impact on the DST reaction after administration of 1.5-mg DEX for ``age'' (b = .11, n.s.), ``nicotine consumption'' (b = .03, n.s.), ``use of oral contraceptives'' (b = .02, n.s.), and ``phase of menstrual cycle'' (b = .07, n.s.). 4. Discussion Female bulimic inpatients and age-matched control subjects underwent a standard DST with measures of saliva cortisol before and after suppression with 1.5-mg DEX. A total of 16 (33.3%) out of 48 inpatients with BN had abnormal DST results (i.e., a level of saliva cortisol higher than 4.8 nmol/l, for at least one measurement point following the administration of the DEX). The rate of nonsuppressors in the control group (8.3%) was comparable to other studies [6,7]. The rate of BN nonsuppressors in our
Table 2 Cortisol levels in saliva (nmol/l) after 1.5-mg DEX (means and S.D.) Time
BN suppressors (N = 32)
BN nonsuppressors (N = 16)
Controls (N = 24)
8 3 4 8
1.77 1.54 1.47 1.28
5.42 4.68 4.41 3.15
1.50 1.23 1.04 1.18
a.m. p.m. p.m. p.m.
(0.40) (0.43) (0.31) (0.28)
(1.08) (0.97) (1.71) (0.71)
(0.41) (0.23) (0.17) (0.21)
ANOVA group: F(1,69) = 7.51, P < .01; time: F(1.35,207) = 0.88, n.s.; interaction: F(1.35,207) = 0.34, n.s.
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study corresponds with the rate (35%) found in a former report [27], but is somewhat lower than the rates found in other studies [9,11,12,28]. The subjects' characteristics (age, frequency of binge attacks, duration of illness, and BMI) in the present study are comparable to those in studies where cortisol was measured in plasma (Table 3). It has been shown that binge attacks influence the HPA function [29]. The patients in this study were binge-free for more than 1 week before the investigation, which may account for the lower nonsuppression rate. This should be considered, even if the patients in our study were not recovered. Moreover, in the studies cited above, a dosage of only 1-mg DEX was used; whereas in the present study, the dose was 1.5 mg. Although there is some evidence that the dexamethasone dosage has no effect on the post-DEX levels of cortisol [30,31], one should take in account that 1.5-mg DEX is a dosage that leads to a higher specificity and lowers the sensitivity of the test. No significant interaction effects between time and group could be found for the pre- or for the post-DEX day. Since the course of diurnal cortisol patterns of depressive patients is different from healthy controls, this might be due to the exclusion of bulimic patients with depression (DSM-IV) in our study. BN suppressors and nonsuppressors showed differences regarding their actual BMI and their history of anorexia nervosa. The BMI was significantly higher in the suppressor group than in the nonsuppressor group. Although 53% of the suppressors had a normal body weight (BMI: 20 ±24), none of the nonsuppressors had. In the nonsuppressor group, 94% were underweight (BMI < 20). These results are in concordance with recent findings [9,11,12] and support other findings suggesting that low body weight is associated with an abnormal post-DST reaction [32 ± 34] for women with eating disorders. In the nonsuppressor group, we found significantly more subjects who had a history of anorexia than in the suppressor group. One study [12] found 70% of
nonsuppressors among BN patients had a history of anorexia nervosa. In our study, 56% of the nonsuppressors and only 21% of the suppressors had a history of anorexia nervosa. This result supports the hypothesis that DST nonsuppression is typical for a special group of patients with BN, namely those with a history of anorexia nervosa [12]. Since 33% of the bulimic patients had a history of anorexia nervosa, and roughly 28% had amenorrhea, one might expect the patients experiencing amenorrhea to be identical with DST nonsuppressors. In fact, we found 28% of patients with amenorrhea in the nonsuppression group. Since recent findings suggest leptin to be involved in eating behavior, reproduction system, and HPA regulation [35 ± 38], future studies should investigate the relationship between intermitted diet, HPA regulation, and leptin in patients with BN, binge eating disorder, and anorexia nervosa. The diurnal cortisol patterns of the bulimic nonsuppressors were significantly higher than those of the bulimic suppressors and the controls. However, we did not find significant differences between the diurnal cortisol profiles of the bulimic suppressors and the control group. Since 53% of the suppressors in our study were of normal weight, and only 21% had a history of anorexia nervosa, we suggest that differences in diurnal or nocturnal cortisol patterns between women with BN and healthy controls appear only if the BN patients are currently underweight or have a history of anorexia nervosa. This should be considered in future research of BN measuring cortisol levels during an experiment (i.e., stress experiments). As DEX levels were not measured in the blood, there is no indication whether all subjects ingested the DEX [33] or vomited the DEX after the intake. Since clinical staff observed the procedure of the experiment, we suggest that the compliance was relatively high. Considering our findings, we conclude that low body weight or a history of anorexia nervosa is a common
Table 3 Differences between bulimic suppressors and nonsuppressors for chosen variables Variables
Suppression (N = 32)
Nonsuppression (N = 16)
Significance
BMI BMI categories Underweight (15 ± 20) Normal weight (20 ± 25) Overweight (>25) Anorexia nervosa in past history Yes No Duration of illness (years) Binge attacks per day Self-concept (FKK-SK) Self-efficacy (FKK-SKI) Internal locus of control (FKK-I) Cognitive control (FEV) Self-rated depression (BDI)
21.21 (0.91)
18.11 (1.00)
F(1,46) = 5.69, P < .05
34.4% 53.1% 12.5%
93.8% / 6.3%
K ± S z = 1.93, P < .0001
21.9% 78.1% 2.47 (1.3) 2.37 (0.315) 24.40 (1.25) 30.46 (0.72) 54.81 (1.17) 14.29 (0.71) 20.34 (1.95)
56.3% 43.8% 2.58 (1.2) 2.59 (0.33) 24.93 (0.61) 30.6 (0.88) 55.00 (0.81) 15.00 (0.51) 20.81 (2.49)
a
Fisher's exact test, one-tailed.
c2(1) = 5.67, P < .001a F(1,46) = 1.31, F(1,46) = 1.39, K ± S z = 1.15, K ± S z = 1.08, K ± S z = 0.95, K ± S z = 1.15, K ± S z = 0.74,
n.s. n.s. n.s. n.s. n.s. n.s. n.s.
P. Neudeck et al. / Physiology & Behavior 72 (2001) 93±98
characteristic of women with BN showing DST nonsuppression. There is some evidence that 3 months after a normalization of body weight, the abnormal DST results disappeared [39]. It should be mentioned that the present study did not obtain information on the length of time BN patients had normal weight. The present study proposes the use of salivary cortisol instead of total blood cortisol assessment because of the independence of estrogen medication (i.e., use of oral contraceptives). The results lead to the assumption that the assessment of saliva cortisol in the DST in BN is a useful tool. For clinical use, there are some advantages of salivary samples for the DST in BN, such as a better compliance, stress-free sampling, independence from estrogen levels [40], and only minor influence on daily routines. Acknowledgments We would like to thank Dr. D.H. Hellhammer and Dr. C. Kirschbaum (Department of Psychology of the University of Trier) for their help. We would also like to thank the Klinik am Korso, Bad Oeynhausen, Germany, for support of this study. Parts of the article were presented at the XXIXth annual meeting of the International Society of Psychoneuroendocrinology in Trier (Germany) last August 6, 1998. References [1] Hudson JI, Laffer PS, Pope HG. Bulimia related to affective disorder by family history and response to the dexamethasone-suppression-test. Am J Psychiatry 1982;135:685 ± 7. [2] Mitchell JE, Bantle JP. Metabolic and endocrine investigations in women with the bulimia syndrome. Biol Psychiatry 1983;18:355 ± 65. [3] Perez EL, Blouin J, Blouin A. The dexamethasone suppression test in bulimia: nonsuppression associated with depression and sub-optimal weight. J Clin Psychiatry 1988;49:94 ± 7. [4] Fichter MM, Pirke KM, PoÈllinger J, Wolfram G, Brunner E. Disturbances in the hypothalamo-pituitary-adrenal and other neuroendocrine axes in bulimia. Biol Psychiatry 1990;27:1021 ± 37. [5] Rosenbaum AH, Schatzberg AF, MacLaughlin RA, Snyder K, Jiang NS, Ilstrup D, et al. The dexamethasone suppression test in normal control subjects: comparison of two assays and effect of age. Am J Psychiatry 1984;141:1550 ± 5. [6] Zimmerman M, Coryell W. The dexamethasone suppression test in healthy controls. Psychoneuroendocrinology 1986;12:245 ± 51. [7] Cook N, Harris B, Walker R, Hailwood R, Jones E, Johns S, et al. Clinical utility of the dexamethasone suppression test assessed by plasma and salivary cortisol determinations. Psychiatry Res 1986;18: 143 ± 50. [8] Garner DM, Garfinkel PE. The Eating Attitudes Test: an index of the symptoms of anorexia nervosa. Psychol Med 1979;9:273 ± 9. [9] Edelstein CK, Roy-Byrne P, Fawzy FI, Dornfeld L. Effects of weight loss on the dexamethasone suppression test. Am J Psychiatry 1983;140:338 ± 41. [10] Walsh BT, Roose SP, Katz JL, Dryenfurth I, Wright L, Vande Wiele R, et al. Hypothalamic-pituitary-adrenal-cortical activity in anorexia nervosa and bulimia. Psychoneuroendocrinology 1987;12: 131 ± 40.
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Dexamethasone suppression test using saliva cortisol measurement in bulimia nervosa$ Peter Neudecka,*, Georg E. Jacobyb, Irmela Florinc,1 a
Christoph-Dornier Foundation for Clinical Psychology, Marienstraûe 18, D-10117, Berlin, Germany b Klinik am Korso, Ostkorso 4, 32545 Bad Oeynhausen, Germany c Department of Psychology, Philipps University Marburg, Gutenbergstrasse 5, 35032 Marburg, Germany Received 11 April 2000; received in revised form 9 June 2000; accepted 25 August 2000
Abstract The assessment of cortisol in saliva has been proven a valid and reliable reflection of the respective unbound hormone in blood. In the present study, a standard dexamethasone suppression test (DST) with measures of salivary cortisol levels was performed in bulimic women without depression (DSM-IV; N = 48) and healthy controls (N = 24) matched for age. Feedback sensitivity was assessed using the standard DST with pre- and post-measures of salivary cortisol. Subjects were divided into suppressors and nonsuppressors according to their post-DST levels. Bulimic suppressors and nonsuppressors were compared for their basal cortisol levels, body weight (body mass index, BMI), previous episodes of anorexia nervosa, and their results in psychometric tests. A total of 16 (33.3%) out of 48 women with bulimia nervosa (BN) failed to suppress in the DST. Basal salivary cortisol levels were elevated in bulimic nonsuppressors. Significant differences between suppressors and nonsuppressors were found for body weight and previous episodes of anorexia nervosa. The results are in accordance with recent findings. They support the hypothesized association between low body weight and DST nonsuppression. Using saliva cortisol in the standard DST could be advantageous for studying bulimic patients. Furthermore, the results show the importance of determining HPA reagibility when measuring cortisol in bulimic patients. D 2001 Elsevier Science Inc. All rights reserved. Keywords: Dexamethasone suppression test; Bulimia; Salivary cortisol
1. Introduction Several studies have examined the dexamethasone suppression test (DST) in bulimia nervosa (BN) [1 ±4]. These studies reported rates of nonsuppression of about 35 ± 67%. This rate of nonsuppression is higher than the incidence of 7 ±10% found in a normal population [5,6], but similar to rates found in depressed patients [7]. Most of the variables considered in recent research (duration of illness, Eating Attitudes Test scores [8], age, binge frequency) were unre$ Statement of informed consent: We ensure that all subjects were informed aboutthe aim of the study, especially about the use of dexamethasone. The experiment was authorized by the ``Ethik Kommision'' of the German Society of Psychology. * Corresponding author. Christoph-Dornier Foundation for Clinical Psychology, Marienstrabe 18, D-10117 Berlin. Tel.: +49 30 25298473; Fax: +49 (0) 30 25298470. E-mail address: [email protected] (P. Neudeck). 1 Deceased in December 1998.
lated to DST nonsuppression in BN. However, some studies reported a relation between low body weight and nonsuppression [9± 12]. All studies mentioned above used measures of plasma cortisol to detect suppressors and nonsuppressors. Since the results of several studies suggest that the diagnostic value of salivary cortisol DSTs equals that of blood borne tests [7,13 ± 15], the present study used measures of salivary cortisol in the DST with bulimic patients for the first time. The previously reported literature on DST in BN held some methodical problems including small sample sizes, the use of outpatients (particularly, the poor control over compliance and actual eating behavior, which may differ between subjects), the lack of information about basal cortisol patterns during the day, and the dosage of DEX used. With the exception of one study [4], the amount of dexamethasone used was 1.0 mg. However, the results of a few studies [16 ± 19] revealed that the quantity of 1.0-mg DEX might not be sufficient for detecting hyperreagibility
0031-9384/01/$ ± see front matter D 2001 Elsevier Science Inc. All rights reserved. PII: S 0 0 3 1 - 9 3 8 4 ( 0 0 ) 0 0 3 8 7 - 5
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of the HPA. Therefore, the standard DST (1.5 mg) was chosen for the present study. 2. Materials and methods Forty-eight female inpatients with a diagnosis of BN meeting DSM-IV [20] criteria participated in the study. Patients with comorbidity (Axes I and II, according to DSM-IV) or past physical disorders, as described by DressendoÈrfer et al. [22], had been excluded using a standardized interview for psychiatric diseases [21]. Participants' mean age was 26.3 (S.D. = 12.2) years. Their average body mass index (BMI) was 20.18 (S.D. = 3.95), mean duration of illness was 7.8 (S.D. = 4.6) years, and the average number of past treatments for BN was 1.3 (S.D. = 1.06). All participants of the BN group were patients of an inpatient unit for eating disorders. At the point of data collection, the mean duration of current treatment in the hospital had been 5.91 (S.D. = 3.3) weeks. All patients were free of medication and were treated with an integrative concept of psychotherapy (cognitive ± behavioral/psychodynamic; single and group). Thirty-three percent of the patients had a history of anorexia nervosa. Prior to admission to the inpatient unit, patients had experienced an average of 2.5 (S.D. = 1.6) binge episodes per day. On average, the last binge episode had occurred 11.2 (S.D. = 14.5) days before the experiment was performed. Data showed that 27.8% of the patients had an amenorrhea, 43.7% were in the follicle phase, and 29.1% were in the luteal phase. Fifty-one percent of the patients were smokers. There was no significant difference between patients and controls regarding the use of oral contraceptives [c2(2) = 1.41, n.s.] or the BMI [ F(1,70) = 1.64, n.s.]. Selection criteria and methods for controls were the same as in patients. The control group consisted of 24 women of normal weight who had no present or past signs of mental illness or significant physical disorders [22]. Controls' mean age was 27.1 (S.D. = 5.3) years and their average BMI was 22.14 (S.D. = 3.07). Twenty-five percent of the controls were smokers. The control group was recruited by announcements in local newspapers and they were paid an equivalent of US$15.00 for their participation. 2.1. Experimental protocol To assess the HPA activity during the day, samples of saliva cortisol were taken at 8 a.m., 3 p.m., 4 p.m., and 8 p.m. Inferences with daily life activities were kept at a minimum. The patients were instructed to maintain their daily routines in the inpatient unit, as well as the controls with respect to their daily routine at work or at home. Furthermore, they were instructed to describe their activities during the experimental session, because there is a suggestion that some activities interfere with the HPA system activity (i.e., excessive physical activity, psychosocial stress [23,24]). Saliva samples were used to assess cortisol, as they
are easily collected and stored in the subjects' natural environment. Subjects collected saliva by placing a sterile cotton wad in their mouth for a few minutes and then sealing the cotton in a salivette, a test tube-like container (Sarstedt, Rommelsdorf, Germany). The participants were told to store the salivettes in a freezer until returning them to the experimenters. Salivettes were kept frozen in the laboratory until they were analyzed. All subjects received a list in which the time of their awakening and information on any stress experienced during the day was recorded. For the assessment of feedback sensitivity of the HPA, the DST with 1.5-mg DEX was performed. The participants took the capsule at 11 p.m. On the following day, subjects again collected saliva at 8 a.m., 3 p.m., 4 p.m., and 8 p.m. 2.2. Assays For the assessment of salivary cortisol, a time-resolved fluorescence immunoassay with a biotin ± cortisol conjugate as tracer and a streptavidin ± europium label was used. The lower detection limit of this assay was 0.43 nmol for a 50-ml saliva sample. Thawed saliva samples were centrifuged at 3000 rpm for 5 min resulting in clear saliva with low viscosity. By using a 100-ml sample duplicate, analyses were conducted and all samples from an individual were analyzed in a single assay run. The intra- and inter-assay coefficients of variation were less than 7% and 9%, respectively [22]. 2.3. Data analysis After testing the variables for normal distribution, comparisons of pre- and post-DEX cortisol profiles were assessed by analysis of variance (ANOVA) for repeated measures. Greenhouse Geisser correction of degrees of freedom was applied where appropriate. Post-hoc analyses were computed using Student's t tests. The Nadir Point assessed the maximal suppression of cortisol in the DST. The cortisol response curve (area under the curve, AUC) was computed for the 2 days according to the trapezoid formula. The AUC were compared by a one-way ANOVA. The cut-off point for the detection of DST nonsuppression was a concentration of cortisol more than 4.8 nmol/l at one measurement point of the day following the DST [7,14]. We compared the suppressors and nonsuppressors for their BMI, locus of control, self-efficacy, self-concept (FKK) [23], subjective ratings of depressiveness [24 ± 26], binge attacks per day, and a history of anorexia nervosa by one-way ANOVA. 3. Results 3.1. Baseline data The ANOVA for repeated measures revealed a significant group effect, as well as a significant time effect. No
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Table 1 Cortisol levels in saliva (nmol/l) under basal conditions (means and S.D.) Time
BN suppressors (N = 32)
BN nonsuppressors (N = 16)
Controls (N = 24)
8 3 4 8
15.27 7.73 7.67 3.55
22.04 (3.06) 11.86 (1.56) 12.81 (2.83) 7.89 (0.79)
16.42 5.95 5.93 2.89
a.m. p.m. p.m. p.m.
(1.20) (0.63) (0.71) (0.32)
significant interaction was found. Under unstimulated conditions, bulimic nonsuppressors had higher cortisol levels in saliva. The diurnal profile was reflected by the significant effect of the time. For a comparison between bulimic patients (N = 48) and the control group (N = 24), an ANOVA for the AUC0 was computed. A significant difference between the groups [ F(1,70) = 4.47, P < .05] was found. The AUC0 of the BN group (20.39, S.D. = 1.40) was higher than the AUC0 of the control group (15.61, S.D. = 1.32). 3.2. DST data The ANOVA for repeated measures showed a significant group effect. No time effect or interaction effect was revealed. After 1.5-mg DEX, bulimic nonsuppressors showed higher saliva cortisol levels. The diurnal pattern of cortisol had disappeared, as reflected by the missing effect of time. The one-way ANOVA for the AUC0 showed a significant difference between bulimic patients (N = 48) and the control group (N = 24) [ F(1,70) = 6.13, P < .05]. The AUC0 of the BN group (12.83, S.D. = 2.18) was higher than the AUC0 of the control group (4.81, S.D. = 0.71). Nadir Cort was defined as the lowest value of saliva cortisol at any time point after the administration of 1.5-mg DST. One-way ANOVA revealed a significant difference between the groups [ F(1,70) = 5.9, P < .05]. The average maximum cortisol suppression (Table 1) of the controls (1.46, S.D. = 0.64) was significantly lower than that of the BN group (3.82, S.D. = 0.91). 3.3. DST nonsuppression As accentuated above, a cut-off point of 4.8 nmol/l was chosen to distinguish suppressors from nonsuppressors. A total of 16 (33.3%) out of 48 patients with BN had abnormal DST results compared with two (8.3%) of the controls [c2(1) = 8.97, P < .0001].
(1.57) (0.62) (1.02) (0.30)
ANOVA group: F(1,69) = 4.73, P < .05; time: F(2.04,207) = 62.37, P < .0001; interaction: F(2.04,207) = 0.53, n.s.
Since only two nonsuppressors were detected in the control group, the statistics below were performed only for the BN group. Significant differences were found between suppressors and nonsuppressors for the BMI [ F(1,46) = 5.69, P < .05] and for the three categories (underweight, normal weight, overweight) of the BMI (K ±S z = 1.93, P < .0001). The BMI of the suppressors was higher than the BMI of the nonsuppressors. Furthermore, we found significant differences between subjects with and without a history of anorexia nervosa [c2(1) = 5.67, P < .001]. After controlling for current weight, significantly more subjects with a history of anorexia nervosa were in the nonsuppressor group [ F(1,46) = 7,82, P > .001]. The average number of binge attacks per day, self-concept, internal locus of control, selfefficacy, cognitive control over food consumption, and subjective ratings of depressiveness did not differ between suppressors and nonsuppressors. There was no association between depression ratings and current body weight status in the patient group (see Table 2). A linear regression model showed no significant impact on the DST reaction after administration of 1.5-mg DEX for ``age'' (b = .11, n.s.), ``nicotine consumption'' (b = .03, n.s.), ``use of oral contraceptives'' (b = .02, n.s.), and ``phase of menstrual cycle'' (b = .07, n.s.). 4. Discussion Female bulimic inpatients and age-matched control subjects underwent a standard DST with measures of saliva cortisol before and after suppression with 1.5-mg DEX. A total of 16 (33.3%) out of 48 inpatients with BN had abnormal DST results (i.e., a level of saliva cortisol higher than 4.8 nmol/l, for at least one measurement point following the administration of the DEX). The rate of nonsuppressors in the control group (8.3%) was comparable to other studies [6,7]. The rate of BN nonsuppressors in our
Table 2 Cortisol levels in saliva (nmol/l) after 1.5-mg DEX (means and S.D.) Time
BN suppressors (N = 32)
BN nonsuppressors (N = 16)
Controls (N = 24)
8 3 4 8
1.77 1.54 1.47 1.28
5.42 4.68 4.41 3.15
1.50 1.23 1.04 1.18
a.m. p.m. p.m. p.m.
(0.40) (0.43) (0.31) (0.28)
(1.08) (0.97) (1.71) (0.71)
(0.41) (0.23) (0.17) (0.21)
ANOVA group: F(1,69) = 7.51, P < .01; time: F(1.35,207) = 0.88, n.s.; interaction: F(1.35,207) = 0.34, n.s.
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study corresponds with the rate (35%) found in a former report [27], but is somewhat lower than the rates found in other studies [9,11,12,28]. The subjects' characteristics (age, frequency of binge attacks, duration of illness, and BMI) in the present study are comparable to those in studies where cortisol was measured in plasma (Table 3). It has been shown that binge attacks influence the HPA function [29]. The patients in this study were binge-free for more than 1 week before the investigation, which may account for the lower nonsuppression rate. This should be considered, even if the patients in our study were not recovered. Moreover, in the studies cited above, a dosage of only 1-mg DEX was used; whereas in the present study, the dose was 1.5 mg. Although there is some evidence that the dexamethasone dosage has no effect on the post-DEX levels of cortisol [30,31], one should take in account that 1.5-mg DEX is a dosage that leads to a higher specificity and lowers the sensitivity of the test. No significant interaction effects between time and group could be found for the pre- or for the post-DEX day. Since the course of diurnal cortisol patterns of depressive patients is different from healthy controls, this might be due to the exclusion of bulimic patients with depression (DSM-IV) in our study. BN suppressors and nonsuppressors showed differences regarding their actual BMI and their history of anorexia nervosa. The BMI was significantly higher in the suppressor group than in the nonsuppressor group. Although 53% of the suppressors had a normal body weight (BMI: 20 ±24), none of the nonsuppressors had. In the nonsuppressor group, 94% were underweight (BMI < 20). These results are in concordance with recent findings [9,11,12] and support other findings suggesting that low body weight is associated with an abnormal post-DST reaction [32 ± 34] for women with eating disorders. In the nonsuppressor group, we found significantly more subjects who had a history of anorexia than in the suppressor group. One study [12] found 70% of
nonsuppressors among BN patients had a history of anorexia nervosa. In our study, 56% of the nonsuppressors and only 21% of the suppressors had a history of anorexia nervosa. This result supports the hypothesis that DST nonsuppression is typical for a special group of patients with BN, namely those with a history of anorexia nervosa [12]. Since 33% of the bulimic patients had a history of anorexia nervosa, and roughly 28% had amenorrhea, one might expect the patients experiencing amenorrhea to be identical with DST nonsuppressors. In fact, we found 28% of patients with amenorrhea in the nonsuppression group. Since recent findings suggest leptin to be involved in eating behavior, reproduction system, and HPA regulation [35 ± 38], future studies should investigate the relationship between intermitted diet, HPA regulation, and leptin in patients with BN, binge eating disorder, and anorexia nervosa. The diurnal cortisol patterns of the bulimic nonsuppressors were significantly higher than those of the bulimic suppressors and the controls. However, we did not find significant differences between the diurnal cortisol profiles of the bulimic suppressors and the control group. Since 53% of the suppressors in our study were of normal weight, and only 21% had a history of anorexia nervosa, we suggest that differences in diurnal or nocturnal cortisol patterns between women with BN and healthy controls appear only if the BN patients are currently underweight or have a history of anorexia nervosa. This should be considered in future research of BN measuring cortisol levels during an experiment (i.e., stress experiments). As DEX levels were not measured in the blood, there is no indication whether all subjects ingested the DEX [33] or vomited the DEX after the intake. Since clinical staff observed the procedure of the experiment, we suggest that the compliance was relatively high. Considering our findings, we conclude that low body weight or a history of anorexia nervosa is a common
Table 3 Differences between bulimic suppressors and nonsuppressors for chosen variables Variables
Suppression (N = 32)
Nonsuppression (N = 16)
Significance
BMI BMI categories Underweight (15 ± 20) Normal weight (20 ± 25) Overweight (>25) Anorexia nervosa in past history Yes No Duration of illness (years) Binge attacks per day Self-concept (FKK-SK) Self-efficacy (FKK-SKI) Internal locus of control (FKK-I) Cognitive control (FEV) Self-rated depression (BDI)
21.21 (0.91)
18.11 (1.00)
F(1,46) = 5.69, P < .05
34.4% 53.1% 12.5%
93.8% / 6.3%
K ± S z = 1.93, P < .0001
21.9% 78.1% 2.47 (1.3) 2.37 (0.315) 24.40 (1.25) 30.46 (0.72) 54.81 (1.17) 14.29 (0.71) 20.34 (1.95)
56.3% 43.8% 2.58 (1.2) 2.59 (0.33) 24.93 (0.61) 30.6 (0.88) 55.00 (0.81) 15.00 (0.51) 20.81 (2.49)
a
Fisher's exact test, one-tailed.
c2(1) = 5.67, P < .001a F(1,46) = 1.31, F(1,46) = 1.39, K ± S z = 1.15, K ± S z = 1.08, K ± S z = 0.95, K ± S z = 1.15, K ± S z = 0.74,
n.s. n.s. n.s. n.s. n.s. n.s. n.s.
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characteristic of women with BN showing DST nonsuppression. There is some evidence that 3 months after a normalization of body weight, the abnormal DST results disappeared [39]. It should be mentioned that the present study did not obtain information on the length of time BN patients had normal weight. The present study proposes the use of salivary cortisol instead of total blood cortisol assessment because of the independence of estrogen medication (i.e., use of oral contraceptives). The results lead to the assumption that the assessment of saliva cortisol in the DST in BN is a useful tool. For clinical use, there are some advantages of salivary samples for the DST in BN, such as a better compliance, stress-free sampling, independence from estrogen levels [40], and only minor influence on daily routines. Acknowledgments We would like to thank Dr. D.H. Hellhammer and Dr. C. Kirschbaum (Department of Psychology of the University of Trier) for their help. We would also like to thank the Klinik am Korso, Bad Oeynhausen, Germany, for support of this study. Parts of the article were presented at the XXIXth annual meeting of the International Society of Psychoneuroendocrinology in Trier (Germany) last August 6, 1998. References [1] Hudson JI, Laffer PS, Pope HG. Bulimia related to affective disorder by family history and response to the dexamethasone-suppression-test. Am J Psychiatry 1982;135:685 ± 7. [2] Mitchell JE, Bantle JP. Metabolic and endocrine investigations in women with the bulimia syndrome. Biol Psychiatry 1983;18:355 ± 65. [3] Perez EL, Blouin J, Blouin A. The dexamethasone suppression test in bulimia: nonsuppression associated with depression and sub-optimal weight. J Clin Psychiatry 1988;49:94 ± 7. [4] Fichter MM, Pirke KM, PoÈllinger J, Wolfram G, Brunner E. Disturbances in the hypothalamo-pituitary-adrenal and other neuroendocrine axes in bulimia. Biol Psychiatry 1990;27:1021 ± 37. [5] Rosenbaum AH, Schatzberg AF, MacLaughlin RA, Snyder K, Jiang NS, Ilstrup D, et al. The dexamethasone suppression test in normal control subjects: comparison of two assays and effect of age. Am J Psychiatry 1984;141:1550 ± 5. [6] Zimmerman M, Coryell W. The dexamethasone suppression test in healthy controls. Psychoneuroendocrinology 1986;12:245 ± 51. [7] Cook N, Harris B, Walker R, Hailwood R, Jones E, Johns S, et al. Clinical utility of the dexamethasone suppression test assessed by plasma and salivary cortisol determinations. Psychiatry Res 1986;18: 143 ± 50. [8] Garner DM, Garfinkel PE. The Eating Attitudes Test: an index of the symptoms of anorexia nervosa. Psychol Med 1979;9:273 ± 9. [9] Edelstein CK, Roy-Byrne P, Fawzy FI, Dornfeld L. Effects of weight loss on the dexamethasone suppression test. Am J Psychiatry 1983;140:338 ± 41. [10] Walsh BT, Roose SP, Katz JL, Dryenfurth I, Wright L, Vande Wiele R, et al. Hypothalamic-pituitary-adrenal-cortical activity in anorexia nervosa and bulimia. Psychoneuroendocrinology 1987;12: 131 ± 40.
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