Plasma Dexamethasone Concentrations and Cortisol Suppression ...

0021-972X/80/5103-0433$02.00/0 Journal of Clinical Endocrinology and Metabolism Copyright © 1980 by The Endocrine Society

Vol. 51, No. 3 Printed in U.S.A.

Plasma Dexamethasone Concentrations and Cortisol Suppression Response in Patients with Endogenous Depression* BERNARD J. CARROLL, KATHLEEN SCHROEDER, SUNIL MUKHOPADHYAY, JOHN F. GREDEN, MICHAEL FEINBERG, JAMES RITCHIE, AND JANET TARIKA Clinical Studies Unit and Mental Health Research Institute, Department of Psychiatry, University of Michigan, Ann Arbor, Michigan 48109

ED in association with normal plasma concentrations of dexamethasone. After treatment, these patients maintained normal suppression of plasma cortisol for 24 h after dexamethasone administration, without any change in their plasma dexamethasone concentrations. Patients with nonendogenous depression and those who had recovered from an episode of endogenous depression maintained normal suppression of plasma cortisol through 1600 and 2300 h after dexamethasone despite having low plasma dexamethasone concentrations at these times. We conclude that the abnormal escape of plasma cortisol concentrations from suppression during the 24-h DST in patients with ED cannot be explained by unusually rapid clearance of dexamethasone from plasma. The results indicate that a central neuroendocrine disturbance is present in patients with ED. («/ Clin Endocrinol Metab 51: 433, 1980)

ABSTRACT. An early escape of plasma cortisol concentrations during a 24-h overnight oral dexamethasone suppression test (DST) has been noted in patients with endogenous depression (ED). Among psychiatric patients this finding is highly specific for ED. Plasma dexamethasone and plasma cortisol concentrations were measured in patients with ED and, for comparison, in patients with nonendogenous depression who maintained normal suppression of plasma cortisol during the DST. There was little variation in plasma dexamethasone concentrations between tests within individual patients. In patients with ED tested both before and after treatment the half-life of dexamethasone in plasma between 9-24 h after its administration was the same as that reported by other investigators in normal subjects between 2-8 h after dexamethasone. Abnormally high plasma cortisol concentrations during the DST were observed in patients with

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of dexamethasone (3, 4). Carroll and associates (7, 8) have shown that patients with ED manifest an abnormal early escape of plasma cortisol concentrations from suppression with the overnight dexamethasone suppression test (DST). When oral dexamethasone is given at 23002400 h, normal subjects maintain suppressed plasma cortisol concentrations for at least the next 24 h (9, 10). Patients with ED may suppress their plasma cortisol concentrations temporarily but fail to maintain plasma cortisol suppression below 6 jug/dl for 24 h. This value is a conservative criterion for the upper limit of plasma cortisol concentrations in normal subjects during the 24h overnight DST (8). The abnormal escape of plasma cortisol concentrations usually occurs by 1600 h and may be observed as early as 0800 h. This abnormality of the DST response is not seen in all patients with ED, but among psychiatric patients it is highly specific for ED. For this reason the DST is now used diagnostically to help discriminate patients with ED from patients with other psychiatric disorders accompanied by nonspecific depressive symptoms (8,11-13). After successful treatment of ED or after a switch from depression into mania, normal DST responses are observed

ATIENTS with endogenous depression frequently have disinhibited activity of the hypothalamic-pituitary-adrenocortical (HPA) system. This neuroendocrine disturbance is similar to that seen in pituitarydependent Cushing's disease, though it is quantitatively less severe, and it does not simply reflect the emotional distress experienced by the depressed patients (1-4). Rather, it is regarded as a functional indication of abnormal limbic system activity associated with endogenous depression (1, 2, 5, 6). In addition to baseline indices of HPA activation (high plasma cortisol concentrations, inappropriate nocturnal cortisol secretion, elevated cortisol secretion rates, high urinary free cortisol excretion, and high free cortisol concentrations in plasma or cerebrospinal fluid), it has also been found that many patients with endogenous depression (ED) do not suppress plasma cortisol concentrations normally after an overnight dose Received January 17, 1980. Address all correspondence and requests for reprints to: Dr. Bernard J. Carroll, Mental Health Research Institute, University of Michigan, Ann Arbor, Michigan 48109. * This work was supported by USPHS Grant MH-28294, research funds from the State of Michigan Department of Mental Health, and the Mental Health Research Institute, University of Michigan. 433

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(1, 4, 7, 8). In this study we have examined whether the abnormal escape of plasma cortisol concentrations from suppression after dexamethasone treatment is related to unusually rapid clearance of the steroid by patients with ED. Should this be the case, then while it would not necessarily affect the practical application of the DST for diagnostic purposes, it would have major importance in interpretations of the pathophysiological significance of the abnormal DST responses. For example, Meikle et al. (14) have shown that after an overnight dose of 1 mg dexamethasone, normal subjects with plasma dexamethasone concentrations above 200 ng/dl at 0800 h will have plasma cortisol concentrations suppressed below 5 jug/dl; nonsuppressing patients with Cushing's disease have comparable plasma dexamethasone concentrations. Thus, in Cushing's disease, resistance to suppression of plasma cortisol by dexamethasone is related to disinhibited neuroendocrine activity rather than to abnormally rapid metabolism of dexamethasone. Another important pharmacokinetic variable which could affect the DST in depressed patients is the bioavailability and absorption of oral dexamethasone. Duggan et al. (15) have shown that dexamethasone tablets (which are used in the routine DST procedure) have the same bioavailability as dexamethasone elixir in normal subjects. Any defect of absorption of dexamethasone in depressed patients should be reflected in the plasma dexamethasone concentrations. For this study, therefore, we obtained blood samples at intervals to permit the determination of the plasma dexamethasone concentrations and the half-time of dexamethasone clearance from plasma during the period when abnormal escape of plasma cortisol concentrations was observed (i.e. between 0800-2300 h after the overnight administration of oral dexamethasone). Subjects and Methods Patients were studied at the Clinical Studies Unit, Department of Psychiatry, University of Michigan, where they received diagnostic evaluations, as described previously (7, 8,13). In particular, for the diagnosis of ED, agreement was required between the clinical assessment and the Research Diagnostic Criteria (16). The DST was performed as described by Carroll et al. (7, 8). An oral dose of 1 mg dexamethasone was given at 2300 h, and blood samples were obtained from in-patients on the following day at 0800, 1600, and 2300 h. Only the 1600 h blood sample was obtained from out-patients (13). Four in-patients with ED were studied before treatment (when abnormal DST results were observed) and again after treatment (when the DST results were normal). Each patient thus served as his own control for relating plasma cortisol and plasma dexamethasone concentrations. Three other in-patients with ED were studied in this way, but there was no change in their DST responses with treatment. Throughout the course of

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the treatment of these seven in-patients, a total of 26 tests was obtained, from which the results will be presented to show the overall relationship between plasma cortisol and dexamethasone concentrations. Repeated DSTs were separated by at least 1 week, and all patients were free of drugs known to interfere with the test (7, 8). Ten out-patients with ED were matched for age, sex, and dose of dexamethasone with 10 out-patients diagnosed as experiencing nonendogenous (neurotic) depression. The patients with ED were selected on the basis of a definitely abnormal DST result (plasma cortisol, >6.5 /ig/dl at 1600 h). The matching patients with nonendogenous depression were selected on the basis of a definitely normal DST result (plasma cortisol, 6 jug/ dl) during illness, while completely normal suppression was observed after recovery. The plasma cortisol concentrations observed after dexamethasone during illness were significantly higher than those observed in the same patients after recovery (paired t — 4.1; n = 12; P < 0.001). Despite the change in plasma cortisol concentrations after treatment, there was no significant difference in the plasma dexamethasone concentrations between the two tests (paired t = 0.34). For the 8 tests in Table 1, the mean 0800 h plasma dexamethasone concentration was 279 ng/dl (SD range, 217-357). For comparison, Meikle et al. (14) recorded 0800 h plasma dexamethasone concentrations after 1 mg at 2400 h of 417 ± 105 ng/dl in normal subjects and 361 ± 128 ng/dl in patients with Cushing's disease. For 26 tests with 7 in-patients, we found a mean plasma dexamethasone concentration of 313 ng/dl (SD range, 195501) at 0800 h. Thus, the morning plasma dexamethasone concentrations of our depressed patients were similar to those reported in other subjects by Meikle et al. (14).

More importantly, there was no difference in plasma dexamethasone concentrations between the two tests (Table 1). We cannot compare our plasma dexamethasone concentrations at 1600 and 2300 h with other investigators, since values have not been reported by others beyond 0800 h. The mean rate of disappearance of dexamethasone from plasma in the 8 tests in Table 1 is shown in Fig. 1. The overall mean plasma dexamethasone half-life was 279 min. The value was 295 min during illness and 265 min after recovery. Thus, there was no indication of rapid clearance of dexamethasone from plasma during illness. Plasma dexamethasone half-times reported by others are 200-300 min (18, 22) and 252 ± 21 min. When dexamethasone metabolism was accelerated by phenytoin treatment, the plasma dexamethasone half-life fell from 252 to 123 min (23). Thus, the kinetic estimate of dexamethasone clearance we observed in depressed patients was completely normal despite the escape of plasma cortisol concentrations from suppression during illness, and there was no change between illness and recovery. The 1600 h plasma cortisol and dexamethasone concentrations of the 10 matched pairs of out-patients are shown in Table 2. As intended, the plasma cortisol concentrations of the patients with ED were significantly higher than those of the patients with nonendogenous depression (paired t = 14.5; P < 0.0001). However, there was no significant difference between the plasma dexamethasone concentrations of these matched pairs (paired t = —1.23; NS). The patients with nonendogenous de-

TABLE 1. Plasma cortisol and plasma dexamethasone concentrations in four patients with ED tested during illness and after recovery

400

295min (Depressed)

300 During depression Patient no.

Time (h)

Plasma cortisol (jug/dl)

o—o265min (Recovered)

After recovery

Plasma dexamethasone (ng/dl)

Plasma cortisol (/xg/dl)

Plasma dexamethasone (ng/dl)

0800 1600 2300

1.9 6.7 5.4

197 24 13

1.2 1.0 1.1

208 26 9

0800 1600 2300

1.9 13.8 10.2

351 75 38

1.2 2.7 1.9

332 95 34

0800 1600 2300

1.0 1.0 13.6

348 74 66

1.1 2.6 2.7

219 77 50

0800 1600 2300

9.3 8.0 8.8

331 81 57

1.0 1.0 1.0

302 71 25

Abnormal plasma cortisol values are in italics. Dexamethasone (1 mg) was given orally at 2300 h the preceding night.

435

Plasma

200

Dexamethasone ng/dl 100

50

20

08:00

16.00

23.00 hrs

FIG. 1. Rate of fall of plasma dexamethasone concentrations in four patients with ED (see Table 1) tested when depressed (#, ) and after recovery (O, ).

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CARROLL ET AL.

436

Patient no.

Age (yr)

Sex

1 2

22 21

F F

Plasma cortisol at 1600 h O*g/dl) 9.5
3 4

67 60

F F

17.9 2.1

70 40

5

25 21

F F

7.2

6

21 77

7 8

70 63

F F

11.6
113 (2 mg) 174 (2 mg)

9 10

23 24

F F

16.1
50 326

11 12

39 39

M M

7.4
41 61

13 14

20 21

M M

10.4
62

70

were recorded in 19 of the 45 tests. The mean plasma dexamethasone concentration in these tests was 75 ng/dl (SE range, 63-88), while the corresponding mean concentration in the 26 normal tests was 72 ng/dl (SE range, 6383; t = 0.14; P = NS). In 14 of the 19 abnormal tests (74%), plasma dexamethasone concentrations were below 100 ng/dl. Similarly, plasma dexamethasone concentrations below 100 ng/dl were reported in 20 of the 26 normal tests (77%; x* = 0.04; P = NS). In summary, we found no evidence that the clearance of dexamethasone differed from normal in the patients with either normal or abnormal DST results. There was no indication of retarded clearance of dexamethasone in the group of patients who suppressed plasma cortisol concentrations completely for 24 h after oral dexamethasone. We observed only one instance of definitely retarded clearance of dexamethasone. This patient with ED had a plasma dexamethasone concentration of 653 ng/dl at 0800 h and a plasma dexamethasone half-life of over 8 h. Despite her high plasma dexamethasone concentrations, she also had elevated plasma cortisol concentrations (19.9 /zg/dl at 0800 h, 13.7 /xg/dl at 1600 h, and7.8]Lig/dlat2300h).

15 16

33 34

M M

6.6 2.4

80 40

Discussion

17 18

32 30

F F

8.1 1.0

51 (2 mg) 58 (2 mg)

19 20

50 53

F F

12.6 1.4

TABLE 2. Plasma cortisol and plasma dexamethasone concentrations at 1600 h in 10 matched pairs of out-patients Plasma dexamethasone at 1600 h (ng/dl) 32 81

63 34

The first member of each pair was diagnosed as having ED, the second was diagnosed as having nonendogenous (neurotic) depression. The dexamethasone dose was 1 mg at 2300 h on the preceding night, except in the two pairs where a dose of 2 mg is indicated.

pression tended to have slightly higher plasma dexamethasone concentrations, as seen in 7 of the 10 pairs. By nonparametric evaluation [Wilcoxon matched pairs signed ranks test (24)] this trend was not significant. Thus, these matched pairs with very different postdexamethasone plasma cortisol concentrations had equivalent plasma dexamethasone concentrations at 1600 h. It should be noted that at this time the patients with nonendogenous depression had plasma dexamethasone concentrations well below the 0800 h criterion of 200 ng/ dl (14), yet all continued to maintain suppression of plasma cortisol. When all of the available tests were considered, we found no significant correlation between plasma cortisol and dexamethasone concentrations. Product-moment correlations obtained were -1-0.25 (n = 26) at 0800 h, +0.11 (n = 45) at 1600 h, and +0.39 (n = 25) at 2300 h. By analysis of the values at 1600 h we found that abnormally high plasma cortisol concentrations (>6 jtig/dl)

The relationship between HPA suppression and the rate of dexamethasone clearance has been established for normal subjects, for patients receiving certain drugs, and for endocrine patients. Our own results in psychiatric patients revealed no abnormality of the rate of clearance of dexamethasone in patients with ED. There was little variation in the plasma dexamethasone concentrations within patients tested on different occasions (see Results and Table 1). The plasma dexamethasone concentrations recorded at 0800 h were quite similar to those reported in normal subjects and in patients with Cushing's disease by Meikle et al. (14). As stated above, there are no other published results with which we can compare the plasma dexamethasone concentrations we observed at 1600 and 2300 h. Between 0800 and 2300 h, the plasma dexamethasone concentrations declined with a half-life of 265-295 min (Fig. 1), which is fully comparable to the values reported by others between 2-8 h after oral dexamethasone (18, 22) or between 2-6 h after iv labeled dexamethasone (23). A constant exponential slope was observed by these authors after 2 h, and our data indicate that this same rate of decline is continued for 24 h after oral dexamethasone. Anticonvulsant drugs, such as phenytoin and phenobarbital, accelerate the metabolism of dexamethasone by the liver, and this drug-drug interaction is associated with impaired suppression of plasma cortisol concentra-

PLASMA DEXAMETHASONE AND CORTISOL SUPPRESSION tions (23, 25-27). In such cases the plasma dexamethasone half-life is greatly reduced, e.g. from 252 to 123 min (23). We observed no such change in dexamethasone clearance among patients with ED. Overall, there was no relationship between plasma cortisol and plasma dexamethasone concentrations between 0800 and 2300 h (see Results and Tables 1 and 2). Thus, in the patients with ED who showed escape of plasma cortisol concentrations from suppression during this time, we conclude that a central neuroendocrine disturbance is present. Whether this is a function of the binding and retention of dexamethasone in the pituitary or hypothalamus or whether it reflects an abnormal drive from limbic system nuclei onto the HPA axis, as in patients with Cushing's disease (28), cannot be determined with certainty from the present data. We can, however, now rule out rapid clearance of dexamethasone as the explanation for the abnormal DST results in patients with ED. Note Added in Proof Another group of investigators recently studied plasma dexamethasone concentrations in depressed patients (Poland, R. E., and R. T. Rubin, personal communication, 1980). Their results were consistent with our own conclusion that there is no abnormality of dexamethasone clearance in patients with endogenous depression. Acknowledgments We thank Dr. A. Wayne Meikle for his advice and for generously providing antiserum to dexamethasone. Drs. A. Albala, R. Haskett, N. Mel. James, M. Steiner, and J. P. DeVigne assisted with the diagnostic evaluations and clinical procedures.

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