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The effect of weight loss and inappropriate plasma dexamethasone levels on the DST
Psychiatry
Research.
351
15, 351-360
Elsevier
The Effect of Weight Loss and inappropriate Dexamethasone Levels on the DST Mathias Berger, Karl-Martin Detlev von Zerssen
Pirke, Jilrgen-Christian
Plasma
Krieg, and
Abstract. Recent studies from different research groups have raised fundamental questions about the postulated specificity of the dexamethasone suppression test (DST) for endogenous depression. Findings in 116 psychiatric inpatients and 24 semi-starved healthy volunteers underline the importance of weight loss as a factor affecting DST results. A study of 160 DSTs in 93 psychiatric inpatients further revealed a significant negative correlation of plasma cortisol and plasma dexamethasone levels 10 hours after oral administration of 1 mg of dexamethasone. These results suggest a decisive effect of the pharmacokinetics of dexamethasone, at least on the I-mg DST. Key Words. Depression, dexamethasone sone pharmacokinetics.
suppression test, weight loss, dexametha-
An abnormal dexamethasone suppression test (DST) has been proposed as a specific biological indicator of the endogenous subtype of depressive disorders (Brown et al., 1980; Carroll et al., 1981~~; Rush et al., 1982). Recent findings, however, raise fundamental doubt about this postulated specificity. Abnormal DST results have been found in, among others, neurotic-depressed patients (Holsboer et al., 1980; Berger et al., 1982a), obsessive-compulsive disorders (Insel et al., 1982), borderline syndromes (Carroll et al., 1981 b), pain syndromes (Blumer et al., 1981), schizophrenia (Carman et al., 1981; Dewan et al., 1982), and dementia (Raskind et al., 1982; Spar and Gerner, 1982). These results have focused attention on the extent to which an abnormal DST may reflect a common biological disturbance of the central nervous system (CNS) in a variety of psychopathological states. Our own studies on the 1.5-mg and I-mg DST in 23 1 psychiatric inpatients and 75 healthy volunteers do not support the idea that the DST reflects a specific CNS disease process, but rather suggest that DST results are strongly influenced by intervening variables (Berger et al., 1984). Although the 1.5-mg DST revealed a nonsignificant trend toward a higher rate of DST nonsuppression among endogenous depressives than among nonendogenous depressives or patients with other psychiatric disorders, abnormal DST results were found to be equally distributed among these diagnostic subgroups when a I-mg DST was administered. An earlier version of this article was presented as part of a symposium at the World Congress of Psychiatry, Vienna, July 1983. The article was first submitted on January 18, 1984. A revised version was received on October 2, 1984. Mathias Berger, M.D., is Deputy Head of the Department of Adult Psychiatry; Karl-Martin Pirke, M.D., is Head of the Division of Psychoneuroendocrinology; Jiirgen-Christian Krieg, M.D., is Psychiatrist; and Detlev von Zerssen, M.D., is Professor of Medicine and Head of the Department of Adult Psychiatry, Max-Planck-Institut ftir Psychiatric, Kraepelinstr. 10, D-8000 Miinchen 40, F.R.G. (Reprint requests to Dr. M. Berger.) 0165-1781:85:
$03.30 0 1985 Elsevier Science
Publishers
B.V
352 Data analyses suggested that hospital admission, withdrawal of psychoactive drugs, and suicidal turmoil may have been implicated in DST nonsuppression. Other investigators have emphasized the influence of sleep disturbances and the withdrawal of alcoholic beverages on DST results (Finklestein et al., 1982; Swartz and Dunner, 1982). In our own data, however, weight loss and the pharmacokinetics of dexamethasone emerged as the most important factors affecting DST results independent of psychiatric diagnosis. Preliminary reports of some of these findings have appeared (Berger et al., 19826, 1984; von Zerssen et al., 1984) but a comprehensive analysis is presented here for the first time.
Weight
Loss
Studies of patients with anorexia nervosa or states of severe malnutrition indicate that an insufficient caloric intake may induce DST nonsuppression (Bethge et al., 1970; Smith et al., 1975; Doerr et al., 1980; Gerner and Gwirtsman, 1981). As a result, Carroll et al. (1981a) recommended that patients at less than 80% of their ideal body weight (IBW) be excluded from studies exploring the DST as a diagnostic indicator of endogenous depression. Studies by Doerr et al. (1980) on the DST in anorectic patients, however, demonstrated that the crucial factor may not be the degree to which the patient is underweight but the process of losing weight. Only a slight weight gain in severely starved patients caused a normalization of the DST, although body weight was still well below 20% of IBW. The same conclusion was reached by Fichter and Pirke (1984) in a study of healthy subjects of normal weight during a starvation experiment of 3 weeks’ duration followed by a subsequent weight gain phase. Whereas a few days of starvation, with a weight loss of only 3%, provoked DST nonsuppression, a few days of normal caloric intake normalized the DST. These observations raise the question to what degree DST nonsuppression in depression may be related to weight loss, since insufficient caloric intake very often accompanies this disease (Hopkinson, 198 1). Study I. In a study of 45 depressed inpatients, primarily focused on the diagnostic utility of the DST (Berger et al., 1982~) we also investigated the relationship between DST nonsuppression and weight loss. All patients (22 males, 23 females; mean age 34.7 years, SD 8.8 years) met Research Diagnostic Criteria (RDC) (Spitzer et al., 1978) for major depressive disorder and had been drug free for at least 1week. Twenty-one patients met criteria for definite endogenous, and four for probable endogenous subtypes. Patients had a body weight within a range of +30% and -20% of IBW. After hospital admission, body weights of 43 patients were accurately measured at weekly intervals. All exclusion criteria recommended by Carroll et al. (1981~) were respected. The DST was performed after at least 1 week of hospitalization. After oral administration of 1.5 mg of dexamethasone at 2300h, plasma cortisol was determined at 0900h, 1200h, 1500h, and 1600h on the following day. Cortisol was measured by radioimmunoassay (RIA), without extraction, using a procedure similar to that described by Donohue and Sgoutas (1975). (See Doerr et al., 1980, for methodological details.) A postdexamethasone plasma cortisol > Spg/dl in at least one of the samples was viewed as a failure of normal suppression (abnormal DST). Thirteen of the 43 patients lost weight (mean 0.91 kg, SD 0.76 kg). Seven of these patients had an abnormal DST, whereas’only two of the 30 patients without weight loss were DST nonsuppressors @ < 0.0005, x* test, one-tailed). Patients with weight loss did not differ significantly from patients without weight loss in severity of depression as measured by the self-rating scale of von Zerssen (1976, 1983) or the Inpatient Multidimensional Psychiatric Scale
353 (IMPS) of Lorr (1974) (Table 1). The relationship between weight loss and abnormal DST results is also documented by the finding that the nine nonsuppressors lost -0.63 (SD 1.40) kg, whereas the suppressors gained 0.62 (SD 0.87) kg during the week preceding the DST @ < 0.005, U test, one-tailed).
Table 1. Degree of depression as measured self-rating and/or a clinical rating scale Bf-SlBf-S’2
Patients1 Study
by IMPS3
I
Patients with weight loss (n = 13) Patients without weight loss in = 30) Study II Patients Patients
with weight without
loss (n = 31)
weight
loss (n = 40)
33.6 ? 32.0
f
8.4 11.9
28.2
?c 16.0
30.5
I? 15.8
43.6 ? 41.6
f
5.9 10.0
1. Study I: 45 depressed patients with or without weight loss. Study II: 71 patients with different psychiatric diagnoses with or without weight loss in the week preceding the DST. No differences between groups are significant. 2. Self-rating scale (van Zerssen, 1976, 1983) measuring the degree of well-being; maximal score = 56. 3. Inpatient Multidimensional Psychiatric Scale (Lorr, 19741; % of maximal score.
Study II. In a second study of 71 consecutively admitted patients with a variety of psychiatric diagnoses, the same question regarding the relationship between weight loss and DST results was investigated. The 30 male and 41 female patients (mean age 36.0 years, SD 12.4 years) included patients who were and were not under treatment with psychoactive drugs, but none of them were receiving a medication known to affect dexamethasone pharmacokinetics. The patients suffered from both depressive (n = 27) and nondepressive (n = 44) psychiatric disorders. A I-mg DST, with blood samples drawn at 0900h, 1600h, and 2300h, was performed 7-10 days after admission. Body weight was measured in the week preceding the DST. Thirty-one of the 71 patients lost 1.3 (SD 1.1) kg; 12 of them had a depressive and 19 a nondepressive disorder. Thirteen of these 3 1 patients had an abnormal DST (3 depressives, 10 nondepressives), whereas only 10 of the 40 patients without weight loss were DST nonsuppressors. Although this difference is not statistically significant (~2 text), the 23 DST nonsuppressors lost significantly more weight (-0.5 + SD 1.7 kg) during the week preceding the test than the 48 DST suppressors, who gained 0.44 (SD 1.5) kg during this time (p < 0.025, U test, one-tailed). As in study I, the self-rating of well-being did not differ between patients with or without weight loss (U test, two-tailed) (Table 1). Study III. To examine to what extent weight loss without a coincident depressive syndrome may cause DST nonsuppression, 24 semi-starved healthy volunteers (15 males, 9 females; age range, 18-44 years) were given a I-mg DST. In two baseline I-mg DSTs, all subjects weresuppressors. At baseline, subjects had a body weight within +20% of IBW. The subjects were then restricted to a diet of 1000 to 1300 calories for 2 weeks, which led to a weight loss of 1.5 (SD 0.6) kg per week. The DST, with blood samples drawn at 1600h and 2300h, was performed at the end of each week. In 9 of the 24 subjects (37.5%), DST results showed nonsuppression within the period of semi-fasting. The subjects’ self-ratings of well-being did not change during the study period. These findings support the conclusion that DST nonsuppression can be caused by weight loss, independent of a coincident mood disturbance.
Pharmacokinetics
of Dexamethasone
Since 1965, the overnight Although
DST has been used for the diagnosis of Cushing’s syndrome. the test has proved a useful diagnostic tool in the majority of studies, there
354
have been reports of false-positive or false-negative test results (Krieger, 1982). These reports stimulated research on dexamethasone pharmacokinetics as a possible cause of unsatisfactory DST results. Meikle et al. (1975) measured the 08OOh plasma dexamethasone and plasma cortisol levels following oral dexamethasone administration at midnight in healthy subjects. The data revealed that a plasma dexamethasone level > 200 ng/ dl was necessary to produce regular plasma cortisol suppression, i.e., a value < 5 pg/dl. Meikle (1982) also described a considerable variation of plasma dexamethasone levels in 26 normal subjects. After 1 mg dexamethasone, the dexamethasone concentration on the following morning ranged from about 150 ng/dl to 800 ng/ dl. This is in agreement with results indicating that the half-life of dexamethasone in healthy subjects ranges from 2 to 6 hours (English et al., 1975; Hare et al., 1975). In addition to physiological variations in healthy subjects, there are other possible causes for disturbed dexamethasone pharmacokinetics. Abnormal dexamethasone plasma concentrations after oral administration may be caused by an insufficient resorption or a delayed or enhanced clearance of the drug. Although little is known about disturbances in the process of resorption, it is well established that dexamethasone metabolism by the liver can either be reduced or enhanced by a number of factors. Heart failure with a decreased hepatic circulation, for example, reduces dexamethasone clearance, thereby increasing the effective plasma concentration and possibly resulting in false-negative DST results. Some drugs, such as phenytoin, barbiturates, or carbamazepine, activate hepatic microsomal dexamethasone-metabolizing enzymes, thereby reducing the effective plasma concentration and resulting in falsepositive DST results (Krieger, 1982; Carroll, 1983). Based on the results from healthy subjects concerning the adequate range of plasma dexamethasone within the overnight DST, Meikle (1982) demonstrated, in 157 patients with suspected Cushing’s syndrome, that the I-mg DST led to unsatisfactory test results in 20% of cases. The dexamethasone levels were either too low to suppress cortisol even in states of eucortisolism or the inappropriately high levels of dexamethasone suppressed cortisol, even in states of hypercortisolism. Meikle therefore recommended a simultaneous measurement of dexamethasone and cortisol to exclude tests with inappropriate plasma dexamethasone levels. Pharmacokinetic Study. We studied the question of whether inadequate dexamethasone plasma levels may also influence the results of the standardized DST (Carroll et al., 1981~) in psychiatric patients. A total of 160 DSTs (1 mg) were performed in 93 psychiatric inpatients (38 males, 55 females; mean age 34.9 years, SD 12.0 years; 41 depressives, 52 nondepressives). All exclusion criteria recommended by Carroll et al. (1981~) were respected. The DST was usually performed immediately after hospital admission and was repeated after 7 to IO days. Twelve patients had more than two serial DSTs. The patients who were receiving medication were not on drugs known to influence dexamethasone metabolism. Following oral administration of 1 mg of dexamethasone at 1 IOOh, plasma dexamethasone was measured at 0900h, and plasma cortisol was measured at 0900h, 1600h, and 2300h. Dexamethasone was measured by RIA according to Haak et al. (1980) with minor modifications. (The antiserum was a gift from Professor Vescei, Heidelberg.) Interassay variability was 8.5% at an average concentration of 220 ng/dl. The limit of detection was 10 ngidl. Fig. 1 illustrates the relationship of plasma dexamethasone and plasma cortisol values at 09OOh for all 160 DSTs. The parabolic distribution of the data shows the influence of dexameth-
355
asone concentration on DST results. As Meikle postulated, a morningdexamethasone concentration <200 ng/dl seems to be inappropriately low. About half of the tests with dexamethasone levels beneath this threshold were abnormal, whereas the ratio of suppressed and nonsuppressed DSTs with a dexamethasone concentration >200 ng/dl was 31:2. For all three plasma cortisol measurements, this ratio was 29:4.
Fig. 1. Plasma dexamethasone and plasma cortisol levels at 0900h in 160 DSTs (1 mg) of 93 psychiatric inpatients 30-
.
25-
20.
1
.
. I
Broken lines mark the postdexamethasone plasma cortisol cutoff value of 2 5 pg/dl, and the threshold of morning plasma dexamethasone required to suppress plasma cortisol in normal subjects CMeikleet al., 1975).
The maximal postdexamethasone plasma cortisol levels and the 0900h dexamethasone levels were negatively correlated (IS q -0.44; p < 0.0005, Spearman rank correlation). When the statistical calculation was restricted to only first DSTs of each of the 70 patients, this correlation was significant at the 5% level (rs = -0.34, Spearman rank correlation). In patients with at least three serial DSTs during their hospitalization, the variation of dexamethasone plasma levels was studied following the same oral dose of 1 mg of dexamethasone (see Table 2). The mean deviation of the dexamethasone values was 41.3 f 32.4% of the first value. These data stress the limited intraindividual stability of dexamethasone pharmacokinetics. With regard to the earlier described significant relationship between weight loss and DST nonsuppression, we investigated the possible influence of absolute body weight or theprocess of losing weight on dexamethasone pharmacokinetics. In 70 patients, body weight was correlated with the 0900h dexamethasone values of the first DST. In 59 patients, body weight was
356 measured between the first and second Changes in body weight were correlated
about 1 week apart. values of the second
DSTs, which were performed with the 0900h dexamethasone
DST. The absolute amount of body weight did not correlate significantly with the dexamethasone plasma values. Also, the change in body weight between the first and second DSTs did not
correlate significantly rank correlation).
with a change in dexamethasone
concentration
Table 2. Dexamethasone plasma concentration 0900h after 1 rng dexamethasone at 2300h Patient
1
2
(ng/dl)
Dexamethasone suppression 3 4 5
(r\
q
0.21, NS, Spearman
at test 6
7
1
230
174
2
82
90
98
139
3
213
59
102
82
4
177
90
208
5
113
158
255
6
126
130
205
7
112
108
105
118
110
105
83
8
104
99
100
148
235
85
80
215
9
87
187
134
10
125
240
267
11
177
116
106
135
12
163
12
136
271
1. Values from serial dexamethasone psychiatric diagnoses.
suppression
test studies
281
of 12 psychiatric
inpatients
with different
Other factors which showed no significant correlation with 0900h dexamethasone concentration were uge (rs q 0.11, NS, Spearman rank correlation) and gender (NS, U test, two-tailed). To assess the possible influence of medication on the pharmacokinetics of dexamethasone,
we compared the plasma dexamethasone concentrations at 0900h of the group of 15 nevermedicated patients with that in 3 1 continuously medicated (mostly neuroleptics and/ or antidepressants) patients. In addition, we examined 24 patients who were withdrawn from psychoactive medication at hospital admission. None of the groups differed in their plasma dexamethasone concentrations (CJtest, two-tailed). There was also no significant difference in 0900h dexamethasone levels between leptics and a group of seven patients tailed).
a group of 14 patients continuously treated with neurocontinuously treated with antidepressants (U test, two-
Discussion The findings presented here may shed light on the major discrepancies found in the various studies investigating the DST in psychiatric patients. Most recent studies have demonstrated that DST nonsuppression is neither a specific marker for the endogenous subtype of depression nor for the depressive syndrome (for overview, see Berger et al., 1984; von Zerssen et al., 1984). The numerous reports of abnormal DSTs in obsessive-compulsive neuroses, borderline syndromes, pain syndromes, anxiety neuroses, schizophrenic psychoses, and manias also seem to contradict the assertion that DST nonsuppression reflects a specific limbic-hypothalamic dysfunction in depression and provides a window to the central neurochemical dysfunction underlying depressive disorders.
357 Some authors interpret the lack of specificity of an abnormal DST for depressive disorders as the expression of a common biological basis for all psychiatric disorders in which DST nonsuppression is found. Psychiatric disorders, usually regarded as distinct diagnostic entities-for example, obsessive-compulsive neuroses, anorexia nervosa, bulimia, and schizoaffective psychoses-are regarded as closely related to 1983; Hudson et al., 1983). This affective disorders (Insel et al., 1982; Carroll, viewpoint decisively alters the traditional classification of psychiatric illnesses. Brambilla et al. (in press) discuss this issue in terms of the relationship between anorexia nervosa and primary affective disorders. They argue that DST nonsuppression in anorexia nervosa is not caused by malnutrition but-as in depressive disorders-by a central transmitter disturbance that may effect both depressive mood and alteration of the hypothalamic-pituitary-adrenal (HPA) axis. In their study, antidepressant medication seems to improve the depressive syndrome and the impairment in HPA function, independent of body weight. Our own studies produced conflicting results. We found that weight loss not only was associated with DST nonsuppression in more than half of psychiatric inpatients, independent of the severity of their depressive symptomatology, but also in about 40% of healthy subjects without a coincident deterioration of their self-ratings of well-being. Fichter and Pirke (1984) demonstrated a strong activation of the HPA axis in five healthy subjects during a 21-day period of complete fasting. Their study supports a relationship between weight loss and activation of the HPA axis, although the design subjected subjects to considerable psychological stress. Edelstein et al. (1983) demonstrated that the process of moderate weight loss in obese patients may also cause DST nonsuppression. These data do not support the hypothesis of a close pathogenetic relationship between psychiatric disorders and abnormal DST results, but rather suggest the important influence of weight loss on the test. As many psychiatric illnesses are linked to a loss of appetite and weight loss, this variable has to be regarded as a possible source of abnormal DST results. Since weight loss is present in about three quarters of all depressed patients, it could explain the high proportion of abnormal DSTs in depressed patients in comparison to nondepressed psychiatric patients (Hopkinson, 1981). Some recently published studies do not support the close relationship between weight loss and DST results in patients with depressive disorders (Coppen et al., 1984; Yerevanian et al., 1984; Keitner et al., 1985). These studies, however, are based on patients’ subjective reports and not on consecutive measurements of body weight. Fichter and Pirke (1984) demonstrated that there is an immediate influence of body weight changes on the DST. Short-interval measurements seem to be necessary to reveal this negative correlation. Yerevanian et al. (1984) also studied the effect of weight loss on the DST in healthy subjects. They asked normals to lose IO-15 pounds over a 4-week period and performed a 1-mg DST before and after dieting. This design only revealed a nonsignificant trend toward higher rates of abnormal DSTs after weight loss. The problem with this design is that if the target weight was reached a few days before the second DST, hypercortisolism would no longer be present. Serial DSTs or measurements of metabolites (e.g., P-hydroxybutyric acid) characterizing the catabolic state (Pirke et al., 1985) would minimize this problem. Weight loss, however, is not the only intervening variable that may cause DST nonsuppression. It is well known from the DST literature concerning the diagnosis of
358 Cushing’s syndrome that the I-mg DST has a limited utility because of the possibility of inappropriate dexamethasone levels. Carroll et al. (1980) studied dexamethasone plasma levels after 1 mg of dexamethasone in depressed patients with a normal and an abnormal DST. Both groups of 10 depressives did not differ in the 1600h dexamethasone plasma levels. In 45 DSTs Carroll et al. did not find a significant correlation between dexamethasone and cortisol plasma concentrations. They furthermore described a minor intraindividual variability of dexamethasone plasma levels. Our results are at odds with these data but are in good agreement with those of Holsboer (1983), who described a significant negative correlation between 1600h plasma cortisol and plasma dexamethasone levels. Our studies and those of Meikle (1982) indicated a high variability of dexamethasone levels after a standard I-mg dose and show an important percentage of 0900h dexamethasone levels below a threshold of 200 ng/ dl. Although we determined plasma dexamethasone levels 10 hours after the dexamethasone dose, as compared to Meikle whose determinations were made 8 hours after the dose, our data likewise seem to identify a morning dexamethasone threshold of about 200 ng/ dl as distinguishing DSTs with appropriate or inappropriate dexamethasone levels. The reason for the high interindividual and intraindividual variability of morning plasma dexamethasone levels is not clear. Our study did not link age, gender, body weight, weight loss, or medication status to this variability. Further, studies have not been carried out of the degree to which morning plasma dexamethasone levels reflect plasma levels during the night, which seem to determine the degree of suppression of the HPA axis. Our results cast doubt upon the extent to which the I-mg DST is a valid tool for measuring hypercortisolism. Further research is needed to determine whether higher dexamethasone doses increase the specificity for hypercortisolism and eliminate false-positive and false-negative results. With dexamethasone doses of 2 mg, for example, this problem may be avoided, but results in reduced sensitivity for the test. Asnis et al. (1981) demonstrated that only 50% of patients with hypercortisolism, determined based on 24-hour cortisol profiles, were identified with the 2-mg DST. As these data illustrate, despite the fact that some hundred articles have been published concerning the DST in psychiatry in recent years, many fundamental questions remain to be answered. In conclusion, although the DST is a widely accepted and frequently employed tool for elucidating HPA axis disturbances linked to psychiatric disorders, there remain considerable doubts about its functional utility for this purpose.
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359
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Holsboer, F. Prediction of clinical course by dexamethasone suppression test (DST) response in depressed patients-Physiological and clinical construct validity of the DST. Pharmacopsychiatria, 16, 186 (1983). Holsboer, F., Bender, W., Benkert, O., Klein, H.E., and Schmauss, M. Diagnostic value of dexamethasone suppression test in depression. Lance& II, 706 (1980). Hopkinson, G. A neurochemical theory of appetite and weight changes in depressive states. Acta Psychiarrica Scandinavica, 64, 217 (198 1). Hudson, J.I., Pope, H.G., Jr., Jonas, J.M., Laffer, P.S., Hudson, M.S., and Melby, J.C. Hypothalamic-pituitary-adrenal axis hyperactivity in bulimia. Psychiatry Research, 8, 111 (1983). Insel, T.R., Kalin, N.H., Guttmacher, L.B., Cohen, R.M., and Murphy, D.L. The dexamethasone suppression test in patients with primary obsessive-compulsive disorder. Psychiatry Research, 6, 153 (1982). Keitner, G.J., Brown, W.A., Quails, C.B., Haier, R.J., and Barnes, K.T. Results of the dexamethasone suppression test in psychiatric patients with and without weight loss. American Journal of Psychiatry, 142, 246 (1985). Krieger, D.T. Gushing’s Syndrome. Monographs of Endocrinology. Vol. 22. SpringerVerlag, Berlin-Heidelberg-New York (1982). Lorr, M. Assessing psychotic behaviour by the IMPS. In: Pichot, P., and Olivier-Martin, R., eds. Psychological Measurements in Psychopharmacology. Vol. 7. Karger, Base1 (1974). Meikle, A.W. Dexamethasone suppression tests: Usefulness of simultaneous measurement of plasma cortisol and dexamethasone. Clinical Endocrinology, 16, 401 (1982). Meikle, A.W., Lagerquist, L.G., and Tyler, F.H. Apparently normal pituitary-adrenal suppressibility in Cushing’s syndrome: Dexamethasone metabolism and plasma levels. Journal of Laboratory and Clinical Medicine, 86, 472 (1975). Pirke, K.-M., Schweiger, U., Lemmel, W., Krieg, J.-C., and Berger, M. The influence of dieting on the menstrual cycle of healthy young women. Journal of Clinical Endocrinology and Metabolism, 60, 1174 (1985). Rush, A.J., Giles, D.E., Roffwarg, H.P., and Parker, CR. Sleep EEG and dexamethasone suppression test findings in outpatients with unipolar major depressive disorder. Biological Psychiutry, 17, 327 (1982). Smith, S.R., Bledsoe, T., and Chhetri, M.K. Cortisol metabolism and the pituitary-adrenal axis in adults with protein-caloric malnutrition. Journal of Clinical Endocrinology and Metabolism, 40,43 (1975). Spar, J.E., and Gerner, R. Does the dexamethasone suppression test distinguish dementia from depression? American Journal of Psychiatry, 139, 238 (1982). Spitzer, R.L., Endicott, J., and Robins, E. Research Diagnostic Criteria: Rationale and reliability. Archives of General Psychiatry, 38, 733 (1978). Stokes, P.E., Stoll, P.M., Mattson, M.R., and Sollod, R.N. Diagnosis and psychopathology in psychiatric patients resistant to dexamethasone. In: Sachar, E.J., ed. Hormones, Behavior, and Psychopathology. Raven Press, New York (1976). Swartz, C.M., and Dunner, F.J. Dexamethasone suppression testing of alcoholics. Archives of General Psychiatry, 39, 1309 (1982). Yerevanian, B.J., Baciewicz, G.J., Iker, H.P., and Privitera, M.R. The influence of weight loss on the dexamethasone suppression test. Psychiatry Research, 12, 155 (1984). Zerssen, D. von. Self-rating scales in the evaluation of psychiatric treatment. In: Helgason, T., ed. Methodology in Evaluation of Psychiatric Treatment. Cambridge University Press, Cambridge (1983). Zerssen, D. von, Berger, M., and Doerr, P. Neuroendocrine dysfunction in subtypes of depression. In: Shah, N.S., and Donald, A.G., eds. Influence of Psychopharmacological Agents. Plenum Press, New York (1984). Zerssen, D. von, with the assistance of Koeller, D.M. Die Befindlichkeits-Skala. BeltzVerlag, Weinheim (1976).
Research.
351
15, 351-360
Elsevier
The Effect of Weight Loss and inappropriate Dexamethasone Levels on the DST Mathias Berger, Karl-Martin Detlev von Zerssen
Pirke, Jilrgen-Christian
Plasma
Krieg, and
Abstract. Recent studies from different research groups have raised fundamental questions about the postulated specificity of the dexamethasone suppression test (DST) for endogenous depression. Findings in 116 psychiatric inpatients and 24 semi-starved healthy volunteers underline the importance of weight loss as a factor affecting DST results. A study of 160 DSTs in 93 psychiatric inpatients further revealed a significant negative correlation of plasma cortisol and plasma dexamethasone levels 10 hours after oral administration of 1 mg of dexamethasone. These results suggest a decisive effect of the pharmacokinetics of dexamethasone, at least on the I-mg DST. Key Words. Depression, dexamethasone sone pharmacokinetics.
suppression test, weight loss, dexametha-
An abnormal dexamethasone suppression test (DST) has been proposed as a specific biological indicator of the endogenous subtype of depressive disorders (Brown et al., 1980; Carroll et al., 1981~~; Rush et al., 1982). Recent findings, however, raise fundamental doubt about this postulated specificity. Abnormal DST results have been found in, among others, neurotic-depressed patients (Holsboer et al., 1980; Berger et al., 1982a), obsessive-compulsive disorders (Insel et al., 1982), borderline syndromes (Carroll et al., 1981 b), pain syndromes (Blumer et al., 1981), schizophrenia (Carman et al., 1981; Dewan et al., 1982), and dementia (Raskind et al., 1982; Spar and Gerner, 1982). These results have focused attention on the extent to which an abnormal DST may reflect a common biological disturbance of the central nervous system (CNS) in a variety of psychopathological states. Our own studies on the 1.5-mg and I-mg DST in 23 1 psychiatric inpatients and 75 healthy volunteers do not support the idea that the DST reflects a specific CNS disease process, but rather suggest that DST results are strongly influenced by intervening variables (Berger et al., 1984). Although the 1.5-mg DST revealed a nonsignificant trend toward a higher rate of DST nonsuppression among endogenous depressives than among nonendogenous depressives or patients with other psychiatric disorders, abnormal DST results were found to be equally distributed among these diagnostic subgroups when a I-mg DST was administered. An earlier version of this article was presented as part of a symposium at the World Congress of Psychiatry, Vienna, July 1983. The article was first submitted on January 18, 1984. A revised version was received on October 2, 1984. Mathias Berger, M.D., is Deputy Head of the Department of Adult Psychiatry; Karl-Martin Pirke, M.D., is Head of the Division of Psychoneuroendocrinology; Jiirgen-Christian Krieg, M.D., is Psychiatrist; and Detlev von Zerssen, M.D., is Professor of Medicine and Head of the Department of Adult Psychiatry, Max-Planck-Institut ftir Psychiatric, Kraepelinstr. 10, D-8000 Miinchen 40, F.R.G. (Reprint requests to Dr. M. Berger.) 0165-1781:85:
$03.30 0 1985 Elsevier Science
Publishers
B.V
352 Data analyses suggested that hospital admission, withdrawal of psychoactive drugs, and suicidal turmoil may have been implicated in DST nonsuppression. Other investigators have emphasized the influence of sleep disturbances and the withdrawal of alcoholic beverages on DST results (Finklestein et al., 1982; Swartz and Dunner, 1982). In our own data, however, weight loss and the pharmacokinetics of dexamethasone emerged as the most important factors affecting DST results independent of psychiatric diagnosis. Preliminary reports of some of these findings have appeared (Berger et al., 19826, 1984; von Zerssen et al., 1984) but a comprehensive analysis is presented here for the first time.
Weight
Loss
Studies of patients with anorexia nervosa or states of severe malnutrition indicate that an insufficient caloric intake may induce DST nonsuppression (Bethge et al., 1970; Smith et al., 1975; Doerr et al., 1980; Gerner and Gwirtsman, 1981). As a result, Carroll et al. (1981a) recommended that patients at less than 80% of their ideal body weight (IBW) be excluded from studies exploring the DST as a diagnostic indicator of endogenous depression. Studies by Doerr et al. (1980) on the DST in anorectic patients, however, demonstrated that the crucial factor may not be the degree to which the patient is underweight but the process of losing weight. Only a slight weight gain in severely starved patients caused a normalization of the DST, although body weight was still well below 20% of IBW. The same conclusion was reached by Fichter and Pirke (1984) in a study of healthy subjects of normal weight during a starvation experiment of 3 weeks’ duration followed by a subsequent weight gain phase. Whereas a few days of starvation, with a weight loss of only 3%, provoked DST nonsuppression, a few days of normal caloric intake normalized the DST. These observations raise the question to what degree DST nonsuppression in depression may be related to weight loss, since insufficient caloric intake very often accompanies this disease (Hopkinson, 198 1). Study I. In a study of 45 depressed inpatients, primarily focused on the diagnostic utility of the DST (Berger et al., 1982~) we also investigated the relationship between DST nonsuppression and weight loss. All patients (22 males, 23 females; mean age 34.7 years, SD 8.8 years) met Research Diagnostic Criteria (RDC) (Spitzer et al., 1978) for major depressive disorder and had been drug free for at least 1week. Twenty-one patients met criteria for definite endogenous, and four for probable endogenous subtypes. Patients had a body weight within a range of +30% and -20% of IBW. After hospital admission, body weights of 43 patients were accurately measured at weekly intervals. All exclusion criteria recommended by Carroll et al. (1981~) were respected. The DST was performed after at least 1 week of hospitalization. After oral administration of 1.5 mg of dexamethasone at 2300h, plasma cortisol was determined at 0900h, 1200h, 1500h, and 1600h on the following day. Cortisol was measured by radioimmunoassay (RIA), without extraction, using a procedure similar to that described by Donohue and Sgoutas (1975). (See Doerr et al., 1980, for methodological details.) A postdexamethasone plasma cortisol > Spg/dl in at least one of the samples was viewed as a failure of normal suppression (abnormal DST). Thirteen of the 43 patients lost weight (mean 0.91 kg, SD 0.76 kg). Seven of these patients had an abnormal DST, whereas’only two of the 30 patients without weight loss were DST nonsuppressors @ < 0.0005, x* test, one-tailed). Patients with weight loss did not differ significantly from patients without weight loss in severity of depression as measured by the self-rating scale of von Zerssen (1976, 1983) or the Inpatient Multidimensional Psychiatric Scale
353 (IMPS) of Lorr (1974) (Table 1). The relationship between weight loss and abnormal DST results is also documented by the finding that the nine nonsuppressors lost -0.63 (SD 1.40) kg, whereas the suppressors gained 0.62 (SD 0.87) kg during the week preceding the DST @ < 0.005, U test, one-tailed).
Table 1. Degree of depression as measured self-rating and/or a clinical rating scale Bf-SlBf-S’2
Patients1 Study
by IMPS3
I
Patients with weight loss (n = 13) Patients without weight loss in = 30) Study II Patients Patients
with weight without
loss (n = 31)
weight
loss (n = 40)
33.6 ? 32.0
f
8.4 11.9
28.2
?c 16.0
30.5
I? 15.8
43.6 ? 41.6
f
5.9 10.0
1. Study I: 45 depressed patients with or without weight loss. Study II: 71 patients with different psychiatric diagnoses with or without weight loss in the week preceding the DST. No differences between groups are significant. 2. Self-rating scale (van Zerssen, 1976, 1983) measuring the degree of well-being; maximal score = 56. 3. Inpatient Multidimensional Psychiatric Scale (Lorr, 19741; % of maximal score.
Study II. In a second study of 71 consecutively admitted patients with a variety of psychiatric diagnoses, the same question regarding the relationship between weight loss and DST results was investigated. The 30 male and 41 female patients (mean age 36.0 years, SD 12.4 years) included patients who were and were not under treatment with psychoactive drugs, but none of them were receiving a medication known to affect dexamethasone pharmacokinetics. The patients suffered from both depressive (n = 27) and nondepressive (n = 44) psychiatric disorders. A I-mg DST, with blood samples drawn at 0900h, 1600h, and 2300h, was performed 7-10 days after admission. Body weight was measured in the week preceding the DST. Thirty-one of the 71 patients lost 1.3 (SD 1.1) kg; 12 of them had a depressive and 19 a nondepressive disorder. Thirteen of these 3 1 patients had an abnormal DST (3 depressives, 10 nondepressives), whereas only 10 of the 40 patients without weight loss were DST nonsuppressors. Although this difference is not statistically significant (~2 text), the 23 DST nonsuppressors lost significantly more weight (-0.5 + SD 1.7 kg) during the week preceding the test than the 48 DST suppressors, who gained 0.44 (SD 1.5) kg during this time (p < 0.025, U test, one-tailed). As in study I, the self-rating of well-being did not differ between patients with or without weight loss (U test, two-tailed) (Table 1). Study III. To examine to what extent weight loss without a coincident depressive syndrome may cause DST nonsuppression, 24 semi-starved healthy volunteers (15 males, 9 females; age range, 18-44 years) were given a I-mg DST. In two baseline I-mg DSTs, all subjects weresuppressors. At baseline, subjects had a body weight within +20% of IBW. The subjects were then restricted to a diet of 1000 to 1300 calories for 2 weeks, which led to a weight loss of 1.5 (SD 0.6) kg per week. The DST, with blood samples drawn at 1600h and 2300h, was performed at the end of each week. In 9 of the 24 subjects (37.5%), DST results showed nonsuppression within the period of semi-fasting. The subjects’ self-ratings of well-being did not change during the study period. These findings support the conclusion that DST nonsuppression can be caused by weight loss, independent of a coincident mood disturbance.
Pharmacokinetics
of Dexamethasone
Since 1965, the overnight Although
DST has been used for the diagnosis of Cushing’s syndrome. the test has proved a useful diagnostic tool in the majority of studies, there
354
have been reports of false-positive or false-negative test results (Krieger, 1982). These reports stimulated research on dexamethasone pharmacokinetics as a possible cause of unsatisfactory DST results. Meikle et al. (1975) measured the 08OOh plasma dexamethasone and plasma cortisol levels following oral dexamethasone administration at midnight in healthy subjects. The data revealed that a plasma dexamethasone level > 200 ng/ dl was necessary to produce regular plasma cortisol suppression, i.e., a value < 5 pg/dl. Meikle (1982) also described a considerable variation of plasma dexamethasone levels in 26 normal subjects. After 1 mg dexamethasone, the dexamethasone concentration on the following morning ranged from about 150 ng/dl to 800 ng/ dl. This is in agreement with results indicating that the half-life of dexamethasone in healthy subjects ranges from 2 to 6 hours (English et al., 1975; Hare et al., 1975). In addition to physiological variations in healthy subjects, there are other possible causes for disturbed dexamethasone pharmacokinetics. Abnormal dexamethasone plasma concentrations after oral administration may be caused by an insufficient resorption or a delayed or enhanced clearance of the drug. Although little is known about disturbances in the process of resorption, it is well established that dexamethasone metabolism by the liver can either be reduced or enhanced by a number of factors. Heart failure with a decreased hepatic circulation, for example, reduces dexamethasone clearance, thereby increasing the effective plasma concentration and possibly resulting in false-negative DST results. Some drugs, such as phenytoin, barbiturates, or carbamazepine, activate hepatic microsomal dexamethasone-metabolizing enzymes, thereby reducing the effective plasma concentration and resulting in falsepositive DST results (Krieger, 1982; Carroll, 1983). Based on the results from healthy subjects concerning the adequate range of plasma dexamethasone within the overnight DST, Meikle (1982) demonstrated, in 157 patients with suspected Cushing’s syndrome, that the I-mg DST led to unsatisfactory test results in 20% of cases. The dexamethasone levels were either too low to suppress cortisol even in states of eucortisolism or the inappropriately high levels of dexamethasone suppressed cortisol, even in states of hypercortisolism. Meikle therefore recommended a simultaneous measurement of dexamethasone and cortisol to exclude tests with inappropriate plasma dexamethasone levels. Pharmacokinetic Study. We studied the question of whether inadequate dexamethasone plasma levels may also influence the results of the standardized DST (Carroll et al., 1981~) in psychiatric patients. A total of 160 DSTs (1 mg) were performed in 93 psychiatric inpatients (38 males, 55 females; mean age 34.9 years, SD 12.0 years; 41 depressives, 52 nondepressives). All exclusion criteria recommended by Carroll et al. (1981~) were respected. The DST was usually performed immediately after hospital admission and was repeated after 7 to IO days. Twelve patients had more than two serial DSTs. The patients who were receiving medication were not on drugs known to influence dexamethasone metabolism. Following oral administration of 1 mg of dexamethasone at 1 IOOh, plasma dexamethasone was measured at 0900h, and plasma cortisol was measured at 0900h, 1600h, and 2300h. Dexamethasone was measured by RIA according to Haak et al. (1980) with minor modifications. (The antiserum was a gift from Professor Vescei, Heidelberg.) Interassay variability was 8.5% at an average concentration of 220 ng/dl. The limit of detection was 10 ngidl. Fig. 1 illustrates the relationship of plasma dexamethasone and plasma cortisol values at 09OOh for all 160 DSTs. The parabolic distribution of the data shows the influence of dexameth-
355
asone concentration on DST results. As Meikle postulated, a morningdexamethasone concentration <200 ng/dl seems to be inappropriately low. About half of the tests with dexamethasone levels beneath this threshold were abnormal, whereas the ratio of suppressed and nonsuppressed DSTs with a dexamethasone concentration >200 ng/dl was 31:2. For all three plasma cortisol measurements, this ratio was 29:4.
Fig. 1. Plasma dexamethasone and plasma cortisol levels at 0900h in 160 DSTs (1 mg) of 93 psychiatric inpatients 30-
.
25-
20.
1
.
. I
Broken lines mark the postdexamethasone plasma cortisol cutoff value of 2 5 pg/dl, and the threshold of morning plasma dexamethasone required to suppress plasma cortisol in normal subjects CMeikleet al., 1975).
The maximal postdexamethasone plasma cortisol levels and the 0900h dexamethasone levels were negatively correlated (IS q -0.44; p < 0.0005, Spearman rank correlation). When the statistical calculation was restricted to only first DSTs of each of the 70 patients, this correlation was significant at the 5% level (rs = -0.34, Spearman rank correlation). In patients with at least three serial DSTs during their hospitalization, the variation of dexamethasone plasma levels was studied following the same oral dose of 1 mg of dexamethasone (see Table 2). The mean deviation of the dexamethasone values was 41.3 f 32.4% of the first value. These data stress the limited intraindividual stability of dexamethasone pharmacokinetics. With regard to the earlier described significant relationship between weight loss and DST nonsuppression, we investigated the possible influence of absolute body weight or theprocess of losing weight on dexamethasone pharmacokinetics. In 70 patients, body weight was correlated with the 0900h dexamethasone values of the first DST. In 59 patients, body weight was
356 measured between the first and second Changes in body weight were correlated
about 1 week apart. values of the second
DSTs, which were performed with the 0900h dexamethasone
DST. The absolute amount of body weight did not correlate significantly with the dexamethasone plasma values. Also, the change in body weight between the first and second DSTs did not
correlate significantly rank correlation).
with a change in dexamethasone
concentration
Table 2. Dexamethasone plasma concentration 0900h after 1 rng dexamethasone at 2300h Patient
1
2
(ng/dl)
Dexamethasone suppression 3 4 5
(r\
q
0.21, NS, Spearman
at test 6
7
1
230
174
2
82
90
98
139
3
213
59
102
82
4
177
90
208
5
113
158
255
6
126
130
205
7
112
108
105
118
110
105
83
8
104
99
100
148
235
85
80
215
9
87
187
134
10
125
240
267
11
177
116
106
135
12
163
12
136
271
1. Values from serial dexamethasone psychiatric diagnoses.
suppression
test studies
281
of 12 psychiatric
inpatients
with different
Other factors which showed no significant correlation with 0900h dexamethasone concentration were uge (rs q 0.11, NS, Spearman rank correlation) and gender (NS, U test, two-tailed). To assess the possible influence of medication on the pharmacokinetics of dexamethasone,
we compared the plasma dexamethasone concentrations at 0900h of the group of 15 nevermedicated patients with that in 3 1 continuously medicated (mostly neuroleptics and/ or antidepressants) patients. In addition, we examined 24 patients who were withdrawn from psychoactive medication at hospital admission. None of the groups differed in their plasma dexamethasone concentrations (CJtest, two-tailed). There was also no significant difference in 0900h dexamethasone levels between leptics and a group of seven patients tailed).
a group of 14 patients continuously treated with neurocontinuously treated with antidepressants (U test, two-
Discussion The findings presented here may shed light on the major discrepancies found in the various studies investigating the DST in psychiatric patients. Most recent studies have demonstrated that DST nonsuppression is neither a specific marker for the endogenous subtype of depression nor for the depressive syndrome (for overview, see Berger et al., 1984; von Zerssen et al., 1984). The numerous reports of abnormal DSTs in obsessive-compulsive neuroses, borderline syndromes, pain syndromes, anxiety neuroses, schizophrenic psychoses, and manias also seem to contradict the assertion that DST nonsuppression reflects a specific limbic-hypothalamic dysfunction in depression and provides a window to the central neurochemical dysfunction underlying depressive disorders.
357 Some authors interpret the lack of specificity of an abnormal DST for depressive disorders as the expression of a common biological basis for all psychiatric disorders in which DST nonsuppression is found. Psychiatric disorders, usually regarded as distinct diagnostic entities-for example, obsessive-compulsive neuroses, anorexia nervosa, bulimia, and schizoaffective psychoses-are regarded as closely related to 1983; Hudson et al., 1983). This affective disorders (Insel et al., 1982; Carroll, viewpoint decisively alters the traditional classification of psychiatric illnesses. Brambilla et al. (in press) discuss this issue in terms of the relationship between anorexia nervosa and primary affective disorders. They argue that DST nonsuppression in anorexia nervosa is not caused by malnutrition but-as in depressive disorders-by a central transmitter disturbance that may effect both depressive mood and alteration of the hypothalamic-pituitary-adrenal (HPA) axis. In their study, antidepressant medication seems to improve the depressive syndrome and the impairment in HPA function, independent of body weight. Our own studies produced conflicting results. We found that weight loss not only was associated with DST nonsuppression in more than half of psychiatric inpatients, independent of the severity of their depressive symptomatology, but also in about 40% of healthy subjects without a coincident deterioration of their self-ratings of well-being. Fichter and Pirke (1984) demonstrated a strong activation of the HPA axis in five healthy subjects during a 21-day period of complete fasting. Their study supports a relationship between weight loss and activation of the HPA axis, although the design subjected subjects to considerable psychological stress. Edelstein et al. (1983) demonstrated that the process of moderate weight loss in obese patients may also cause DST nonsuppression. These data do not support the hypothesis of a close pathogenetic relationship between psychiatric disorders and abnormal DST results, but rather suggest the important influence of weight loss on the test. As many psychiatric illnesses are linked to a loss of appetite and weight loss, this variable has to be regarded as a possible source of abnormal DST results. Since weight loss is present in about three quarters of all depressed patients, it could explain the high proportion of abnormal DSTs in depressed patients in comparison to nondepressed psychiatric patients (Hopkinson, 1981). Some recently published studies do not support the close relationship between weight loss and DST results in patients with depressive disorders (Coppen et al., 1984; Yerevanian et al., 1984; Keitner et al., 1985). These studies, however, are based on patients’ subjective reports and not on consecutive measurements of body weight. Fichter and Pirke (1984) demonstrated that there is an immediate influence of body weight changes on the DST. Short-interval measurements seem to be necessary to reveal this negative correlation. Yerevanian et al. (1984) also studied the effect of weight loss on the DST in healthy subjects. They asked normals to lose IO-15 pounds over a 4-week period and performed a 1-mg DST before and after dieting. This design only revealed a nonsignificant trend toward higher rates of abnormal DSTs after weight loss. The problem with this design is that if the target weight was reached a few days before the second DST, hypercortisolism would no longer be present. Serial DSTs or measurements of metabolites (e.g., P-hydroxybutyric acid) characterizing the catabolic state (Pirke et al., 1985) would minimize this problem. Weight loss, however, is not the only intervening variable that may cause DST nonsuppression. It is well known from the DST literature concerning the diagnosis of
358 Cushing’s syndrome that the I-mg DST has a limited utility because of the possibility of inappropriate dexamethasone levels. Carroll et al. (1980) studied dexamethasone plasma levels after 1 mg of dexamethasone in depressed patients with a normal and an abnormal DST. Both groups of 10 depressives did not differ in the 1600h dexamethasone plasma levels. In 45 DSTs Carroll et al. did not find a significant correlation between dexamethasone and cortisol plasma concentrations. They furthermore described a minor intraindividual variability of dexamethasone plasma levels. Our results are at odds with these data but are in good agreement with those of Holsboer (1983), who described a significant negative correlation between 1600h plasma cortisol and plasma dexamethasone levels. Our studies and those of Meikle (1982) indicated a high variability of dexamethasone levels after a standard I-mg dose and show an important percentage of 0900h dexamethasone levels below a threshold of 200 ng/ dl. Although we determined plasma dexamethasone levels 10 hours after the dexamethasone dose, as compared to Meikle whose determinations were made 8 hours after the dose, our data likewise seem to identify a morning dexamethasone threshold of about 200 ng/ dl as distinguishing DSTs with appropriate or inappropriate dexamethasone levels. The reason for the high interindividual and intraindividual variability of morning plasma dexamethasone levels is not clear. Our study did not link age, gender, body weight, weight loss, or medication status to this variability. Further, studies have not been carried out of the degree to which morning plasma dexamethasone levels reflect plasma levels during the night, which seem to determine the degree of suppression of the HPA axis. Our results cast doubt upon the extent to which the I-mg DST is a valid tool for measuring hypercortisolism. Further research is needed to determine whether higher dexamethasone doses increase the specificity for hypercortisolism and eliminate false-positive and false-negative results. With dexamethasone doses of 2 mg, for example, this problem may be avoided, but results in reduced sensitivity for the test. Asnis et al. (1981) demonstrated that only 50% of patients with hypercortisolism, determined based on 24-hour cortisol profiles, were identified with the 2-mg DST. As these data illustrate, despite the fact that some hundred articles have been published concerning the DST in psychiatry in recent years, many fundamental questions remain to be answered. In conclusion, although the DST is a widely accepted and frequently employed tool for elucidating HPA axis disturbances linked to psychiatric disorders, there remain considerable doubts about its functional utility for this purpose.
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