The effect of stress on the dexamethasone suppression test

189

Psychiatry Research. 14, 189-195 Elsevier

The Effect Test

of Stress

Dominique L.S. Ceulemans, Herman M. van Praag

on the Dexamethasone

Herman G.M. Westenberg,

Suppression

and

Received July 19, 1983; revised version received April 9, 1984: accepted

May 15, 1984.

Abstract. The dexamethasone suppression test (DST) was studied in 40 presurgical subjects and 20 controls. Cortisol plasma concentrations were measured before and after a nocturnal dose of I mg dexamethasone. Nineteen of the 40 patients (47.5%) failed to show a suppression of plasma cortisol after dexamethasone. Nonsuppression on the DST was associated with a significantly higher baseline plasma cortisol concentration. Another putative indicator of emotional stress, the level of acute anxiety, was also studied. There was a significant difference in the level of acute anxiety among suppressors, nonsuppressors, and controlsPthe level of anxiety in nonsuppressors being significantly higher than in controls. It is concluded that stress associated with a physical danger can be a cause of nonsuppression on the DST. Key Words.

Stress, dexamethasone

suppression

test, anxiety,

cortisol.

There has been considerable interest in the utility of the dexamethasone suppression test (DST) as a possible laboratory test in the diagnosis of affective disorders. An abnormal DST, i.e., inadequate suppression of plasma cortisol after an overnight dose of dexamethasone, has been reported to be a selective and sensitive indicator for major depressive illness (Carroll et al., 1976, 1980, 1981). A number of studies have shown that approximately 50% of patients with endogenous depression fail to suppress plasma cortisol adequately after an oral intake of I or 2 mg dexamethasone (Schlesser et al., 1980; Brown and Shuey, 1980; Brown and Qualls, 1981; Kahn et al., 1532). Moreover, the DST seems to have predictive value with respect to the response to antidepressant medication. Thus, Brown and Qualls (1981) have found that nonsuppressors and suppressors respond preferentially to different antidepressants. Similar results were reported by Greden et al. (198 I). The mechanism underlying the failure to suppress plasma cortisol levels after dexamethasone in depression is still controversial (Fang et al., 198 1; Kalin et al., 1982; Reus et al., 1982). Generally, a positive DST in depression is attributed to enhanced activity of the hypothalamic-pituitary-adrenal (HPA) axis. It is well established, however, that the HPA system is also sensitive to psychological stimuli (Bunney et al.,

Dominique L.S. Ceulemans. M.D., is at Janssen Pharmaceutics. Beerse, Belgium. Herman G.M. Westenberg, Ph.D.. is in the Department of Biological Psychiatry, Academic Hospital Utrecht. Catharijnesingel 101. 351 I GV Utrecht. The Netherlands. Herman M. van Praag. M.D.. Ph.D.. is Professor and Chairman. Department of Psychiatry. Albert Einstein College of Medicine, Bronx. NY, USA. (Reprint requests to Dr. H.G.M. Westenberg.) 0165-1781/84/$03.30

@ 1985 Elsevier Science

Publishers

B.V.

190 1965; Bourne et al., 1968; Jones et al., 1970; Sachar, 1970). The main psychological correlate of HPA activity is thought to be an undifferentiated state of emotional arousal (Mason and Fibiger, 1979). In animals, stress can cause increased secretion of adrenocorticotropic hormone (ACTH) (Allen et al., 1973). In rhesus monkeys, the postdexamethasone percent of baseline cortisol has been found to correlate significantly with the individual mean arousal ratings (Kalin et al., 1981). Information about the effect of stress and anxiety on the DST is limited and controversial. Langer et al. ( 1979) failed to observe abnormal DST results in depressed patients treated with high doses of diazepam. They concluded that hypersecretion of cortisol in some depressive patients is secondary to stress rather than to a specific HPA dysfunction. On the other hand, Holsboer et al. (1982) have reported DST nonsuppression in depressive patients despite high doses of anxiolytic and sedative drugs. Finally, Blumenfield et al. ( 1970) have found an impaired suppression of 17-hydroxycorticosteroids in the urine of military trainees under emotional stress. The present study evaluates an effect on the DST.

whether

stress,

associated

with imminent

surgery,

has

Methods Subjects were 40 inpatients (23 males, 17 females; mean age 44 years) at the Department

of Neurosurgery. All patients suffered from hernia nuclei pulposi. Patients were free of physical illness known to affect pituitary-adrenal activity and were not taking drugs known to affect the DST. Fourteen patients were taking psychotropic drugs (benzodiarepines) at the time of the test. Patients with a psychiatric history were excluded from the study. Ten patients underwent a myelographic examination the day before the test. Two days before surgery (day I), a 9 a.m. baseline blood sample was drawn, and at I I p.m. I mg of dexamethasone was administered orally. The following day (day 2) blood samples were taken at 9 a.m.. 4 p.m., and I I p.m. Subjects fasted from I I p.m. on day I until 9 a.m. on day 2 of the DST. Anxiety was assessed on day 2 of the DST with the State--Trait Anxiety Inventory (STAI) (Spielberger, 1980; Dutch version, van der Ploeg et al.. 1981). In addition, patients were evaluated on the Hamilton Rating Scale for Depression (HRSD) (Hamilton, 1967) by a psychiatrist. and completed the mood or contentment (Befindlichkeits) self-rating scale (BS) (von Zerssen et al.. 1974). Twenty healthy volunteers (I I males, 9 females; mean age 41 years) served as controls. None had medical/psychiatric disorders or were taking medication at the time of the study. DST results and STAI, HRSD, and BS scores were obtained for all control subjects. Blood samples for the DST were collected by venipuncture into heparinized glass tubes. Plasma was immediately separated and frozen at -20” C until analyzed in duplicate. Plasma cortisol concentrations were determined by radioimmunoassay (RIA) as described by Thyssen et al. (1980). A subject was considered a nonsuppressor if any of the postdexamethasone plasma cortisol concentrations (8 a.m., 4 p.m., or I I p.m.) exceeded 0. I4 nmole:‘ml (5 pg:‘dl). For statistical analysis, patients were dichotomized into suppressor and nonsuppressor groups on the basis of the DST results. Group means were compared using one-way analysis of variance (ANOVA) by ranks (Kruskal-Wallis) and the aberrant groups were subsequently identified using the Mann-Whitney I/ test. Differences in distribution of the other variables (sex, myelographic examination, and drugs) were analyzed using Fisher’s exact probability test. Values are reported as means + standard deviations.

191 Results Of the 40 presurgical patients, 19 (47.596) failed to suppress plasma cortisol in the 9 1I p.m. postdexamethasone sample. The pattern of plasma a.m., 4 p.m., andjor cortisol response to dexamethasone in nonsuppressors is also noteworthy. Eight (42%) of the nonsuppressors showed resistance to suppression at 9 a.m., I7 (89%) at 4 p.m., and I I (58%) at I I p.m. One nonsuppressor had an elevated plasma cortisol concentration at 9 a.m. only, and one at I I p.m. only. None of the 20 control subjects were nonsuppressors. The results of the psychometric evaluations are summarized in Table I. Anxiety was assessed with the STAI, which consists of two separate rating scales measuring state anxiety (A-state scale) and trait anxiety (A-trait scale). Statistical analysis showed a significant difference among the mean scores of suppressors, nonsuppressors, and controls on the A-state scale (Kruskal-Wallis H = 7.75, n 60, cI~ = 2, y < 0.05). Subsequent multiple comparison analysis revealed that this difference could be attributed to the higher level of state anxiety in nonsuppressors as compared to controls. In contrast, mean scores on the A-trait scale did not differ significantly among the groups. q

Table 1. Age, baseline plasma cortisol and mean psychiatric rating scale scores in presurgical patients (suppressors and nonsuppressors) and controls Imean t SD) Suppressors (n = 21)

Variables

Nonsuppressors (n = 19)

Controls (n = 20)

Age

44

Baseline plasma cortisol t nmole/ml I

0.47 i 0.12

0.55 t 0.121

0.42 t 0.13

40.4 IL 12.1

46.4 i 12.82

35.9 i 7.5

36.6 f

37.3 +

35.3 t 9.3

STAI State scale Trait scale BS [mood

self-rating

HRSD (total

I

Anxiety/somatlzation factor

I

43

*13

9.3

14.2 2 10.52

41

212

8.5

+12

8.8 ? 6.7

15.8 + 10.22

5.7 -t

5.6

6.7 ?

4.7

4.1 ? 4.4

2.8 2

2.6

3.2 t

2.5

1.8?

2.1

STAI = State-Trait Anxiety Inventory; BS = Beflndllchkelts ivon Zerssen mood or contentment self-rating scab. HRSD = Hamilton Rating Scale for Depression. Stat/st~~ One-way analysis of variance by ranks ( Kruskal-Wallis' and subsequently Mann-Whitney IJ test.

Abbrewationst

1. Different 2. Different

from controls and suppressors, from controls, p < 0.05.

p < 0.01

Evaluation of mood, or contentment, self-ratings (von Zerssen et al., 1974) also revealed a significant difference among the groups (H = 6.26, n 60, L&‘=2, y < 0.05). Post hoc analysis showed that this difference could be attributed to the higher score in patients (suppressors and nonsuppressors) as compared to controls. Mean scores on the HRSD did not differ significantly among the groups. The higher mean score on the HRSD in patients is probably due to the anxirt,~ andsonmizution factor. q

192 Examination of the baseline plasma cortisol concentrations revealed a significant difference among the groups (H 9.50, n = 60, elf’= 2,p < 0.01). Subsequent multiple comparison analysis showed that this difference is due to the higher baseline plasma cortisol concentration in nonsuppressors as compared to controls and suppressors. Comparison of other characteristics and variables revealed no differences between the suppressor and nonsuppressor groups in distribution of sex, myelographic examination, and drug administration (Table 2). q

Table 2. Distribution of sex, myelographic drug administration among suppressors sors: Number (O/O) of patients Variable

Suppressors

Nonsuppressors

examination, and and nonsuppresSignificance1

Male/female

ll/lO

7/l 2

0.25

Myelography

4 119)

6 (32)

0.26

Anxiolytics

6 (29)

8 142)

0.29

1. Significance level by Fisher exact probability

test up value,

Discussion The purpose of this study was to determine the effect of stress associated with imminent surgery on the DST in a nonpsychiatric population, and to explore the relationship between emotional and physiological reactions. The present findings reveal that a substantial percentage of subjects exposed to a stressful situation failed to suppress plasma cortisol adequately after an overnight dose of I mg dexamethasone. In fact, the failure of dexamethasone to inhibit cortisol secretion in our population is comparable to that reported by Carroll et al. (1981) for endogenous depressed patients. Surgery may be considered a powerful psychological stimulus that is capable of provoking central nervous system (CNS) arousal in normal subjects---an arousal which may result in both physiological and emotional reactions (Sachar, 1970). To assess the emotional reactions to imminent surgery, we used the STAI as a measure of both state and trait anxiety. The trait score refers to the anxiety proneness of an individual subject and is therefore impervious to situational stress (Spielberger, 1980). In the present study the mean scores for trait anxiety were approximately the same in all three groups, suggesting that the vulnerability to stress among our groups (suppressors, nonsuppressors, and controls) was not different. In contrast, the mean score for state anxiety, which measures the level of transitory anxiety, was found to be elevated in presurgical patients as compared to control subjects, indicating that the threat of imminent surgery produces a significant amount of arousal in normal subjects. The individual emotional response to surgery. as assessed with the state anxiety scale, however, varied considerably among our subjects. This variability probably reflects individual differences in coping with a stressful situation. An important physiological indicator of CNS arousal is thought to be the activity of the HPA system. In animals, stress can cause increased cortisol secretion (Allen et al.,

193

1973). However, the findings in human subjects have been less convincingandsubject 1970). Dexamethasone. a synthetic glucoto great individual variability (Sachar, corticoid, is known to suppress endogenous cortisol secretion in humans for up to 24 hours. Hence. a resistance to or an early escape from plasma cortisol suppression by dexamethasone is thought to be indicative of HPA overactivity (Brown and Qualls, 198 I; Kalin et al.. 1982). The DST was first used to detect patients suspected of having Cushing’s syndrome. Resistance to dexamethasone suppression of plasma cortisol has also been demonstrated in endogenous depression (Carroll et al., 19X1), schizoaffective depression (Meltrer et al., 1982) obsessive-compulsivedisorders (Insel et al., 1982) and borderline personality disorders (Carroll et al.. I98 I). Although the mechanism underlying the resistance to dexamethasone suppression in psychiatric patients has not yet been elucidated. nonsuppression in depressives has been linked to a specific disturbance in the limbic system functioning. The present findings indicate that lack of cortisol suppression by dexamethasone also occurs in normal subjects under emotional stress. This finding is in keeping with the results reported by Blumenfield et al. (1970), who found an impaired urinary 17-hydroxycorticosteroid suppression after dexamethasone administration in some military trainees under emotional stress. In addition, in rhesus monkeys, postdexamethasone cortisol concentrations have been found to correlate significantly with behavioral arousal to a specific experimental stress (Kahn et al., 1981). In contrast, Curtis et al. (1982) did not find nonsuppression in phobic patients with panic attacks. Another finding of the present study was a significantly higher mean basal cortisol concentration in nonsuppressors as compared to suppressors. This suggests that escape from dexamethasone suppression stems from an HPA overactivity rather than from a failure of dexamethasone to stimulate the negative feedback system. Similar results have been reported by Kahn et al. (1982) for depressive patients. The relationship between the level of acute anxiety and the HPA activity was less impressive. In comparisons of the suppressors, nonsuppressors, and controls, asignificant difference was found in the mean acute anxiety level-anxiety being highest in nonsuppressors and lowest in controls. Posteriori analysis, however, just failed to detect a difference between suppressors and nonsuppressors due to the large variances. Nevertheless, there was a strong trend for high levels of acute anxiety to be associated with both predexamethasone and postdexamethasone plasma cortisol levels in presurgical patients. This tendency might reflect a failure to adapt adequately to a stressful situation. i.e., a physical danger, in a subgroup of presurgical patients. Conceivably, the two variables are closely related but independent expressions of the same phenomenon. Finally, two other psychometric instruments were used to explore the effect of mood or depressive state on the DST. Although mood, or contentment, as assessed with the self-rating scale of von Zerssen et al. (1974). was significantly diminished in presurgical patients as compared to controls, no significant relationship was found between mood score and nonsuppression on the DST. Moreover, nonsuppression could not be attributed to a depressive state either, since no difference was seen among the groups on the HRSD. Two other variables might have interfered with the DST results in our patientspain and medication. The role of pain is difficult to evaluate. All patients participating

194 in this study suffered from a hernia nuclei pulposi and were consequently not devoid of inconvenience. None of the patients, however, reported spontaneous pain during the test. Some patients complained of a transient pain due to the myelography before the DST, but statistical analysis determined that patients who underwent myelography were distributed evenly between both groups. The second variable is the effect of medication and, especially, anxiolytic and sedative drugs. The reports on the effect of anxiolytic drugs on the DST are contradictory. Thus, Langer et al. (1979) failed to observe abnormal DST results in depressed patients treated with 20-40 mg diazepam and concluded that hypersecretion of cortisol in some depressives is secondary to stress rather than to a specific limbic system dysfunction. At variance with this finding, Holsboer et al. (1982) reported DST nonsuppression in depressive patients who were receiving high doses of anxiolytic and sedative drugs. Fourteen patients included in this study were treated with either 5 mg nitrazepam as sleeping medication, or 20 mg diazepam as premeditation to myelography. The present findingshowever, do not support circumstantial evidence for an effect of benzodiazepines in low doses on the DST. In conclusion, this study demonstrates that stress, associated with the threat of a primarily physical danger, can definitely be a cause of DST nonsuppression. Furthermore, the emotional reactions, expressed as the level of anxiety on the STAI, and the endocrine reactions, expressed as both the baseline plasma cortisol concentration and the response to the DST, seem to occur synchronously in presurgical patients. Future studies are warranted to evaluate whether stress, anxiety, or a combination thereof are implicated in the failure of dexamethasone to inhibit cortisol secretion in other patients. Acknowledgments. The authors thank Prof. Dr. C.A.F. Tulleken, Head of the Department of Neurosurgery. and P. Fagginger-Auer, M.D., for their assistance in recruiting and evaluating the subjects. They also thank R. de Kloet. Ph.D., for his advice. Theexpert technicalassistance of Mrs. A. Mathijs-Rijsenbult, Mr. L.A. Meyer, and Mr. L. Nijo is gratefully acknowledged. Mrs. M. van Kempen and Mrs. J.B. van de Meent provided valuable secretarial assistance. The research reported was supported in part by grant 13-3 l-50 from the Durch Foundation for Medical Research (FUNGO-ZWO).

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