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The relationship of the dexamethasone suppression test (1 mg and 2 mg) to basal plasma cortisol levels in endogenous depression
Psychoneuroendocrinology, Vol.
12, No. 4, pp. 295-301, 1987.
0306-4530187 $3.00 + 0.00 Pergamon Jcernals Ltd.
Printed in Great Britain
THE TEST
RELATIONSHIP (1 m g A N D
OF THE
DEXAMETHASONE
2 mg) TO BASAL ENDOGENOUS
PLASMA
SUPPRESSION
CORTISOL
LEVELS
IN
DEPRESSION
GREGORY M. ASNIS*, URIEL HALBREICH*, NEAL D. RYAN~', HARRY RABINOWICZ't, JOAQUIM PUIG-ANTICHI', BEVERLY NELSON~:, HANNA NOVACENKOt and JILL HARKAVY FRIEDMAN* *Department of Psychiatry, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY 10467, U.S.A., t New York State PsychiatricInstitute and Departmentof Psychiatry, ColumbiaUniversityCollegeof Physicians and Surgeons, New York, NY, U.S.A. and * Western Psychiatric Institute and Clinic, Pittsburgh, PA, U.S.A. (Received 11 July 1985; in final form 3 December 1986) SUMMARY The 1 mg and 2 mg dexamethasone suppression tests (DST) were evaluated in two groups of endogenouslydepressed patients (n = 39 and n = 30, respectively)who also had a 1300-1600 hr basal cortisol assessment. Non-suppressors(on both DSTs) had significantlyhigher basal plasma cortisol levels and thus were significantly associated with relative cortisol hypersecretion. However, there was only a partial overlapbetween DST response and basal plasma cortisol, with a large variation of cortisol levels among non-suppressors. The 2 nag DST appears to be more specificfor cortisol hypersecretionthan the 1 nag DST. If cortisol hypersecretion is to be identified, neither the 1 mg or 2 nag DST is an adequate assessment nor a substitute for a basal cortisol assessment. Key words--Dexamethasone suppression test; cortisol hypersecretion; endogenous depression. INTRODUCTION CORTISOL HYPERSECRETION and non-suppression to dexamethasone are neuroendocrine abnormalities found in approximately 50% o f adult endogenously depressed patients. These abnormalities in depressed patients are limited to their ill state, normalizing after recovery (Sachar et al., 1970; Carroll, 1972; Stokes et al., 1975; Carroll et al., 1976; Brown et al., 1979; Sehlesser et al., 1979). The literature suggests that these two abnormalities are related, both being presumed reflections of increased h y p o t h a l a m i c - p i t u i t a r y - a d r e n a l cortical activity. Several investigators have found that single-sample predexamethasone plasma cortisol levels were elevated in depressed patients who were non-suppressors on the 2 mg dexamethasone suppression test (DST) vs those who were suppressors (Stokes et al., 1975; Can'oll et al., 1976; 'Asnis et al., 1981a). Indwelling catheter studies with sampling every 30 min from 4 to 24 hr have yielded similar results (Asnis et al., 1981a, 1982a). Furthermore, non-suppression to 2 mg dexamethasone occurred predominantly in plasma cortisol hypersecretors, although hypercortisolemia was not equivalent to non-suppression on the DST, since only 50% of cortisol hypersecretors were non-suppressors (Asnis et al., 1981a, 1982a). Most investigators have switched from the 2 mg DST to the I mg DST, since the latter increases the sensitivity without supposedly sacrificing the specificity or the diagnostic confidence of this test in diagnosing depression (Carroll et al., 1976, 1981). More recent studies have now questioned the specificity o f the 1 mg DS"I" in depression (Berger et al., 1984). Similar to the
295
296
G.M.AsNIS et al.
studies d e s c r i b e d for t h e 2 m g D S T a n d b a s a l cortisol, a f e w studies h a v e a d d r e s s e d the r e l a t i o n s h i p o f t h e 1 m g D S T to b a s a l cortisol. V a n d e w a l l e e t a l . (1983), K a t h o l e t al. (1984) a n d B r o w n e t a l . ( 1 9 8 5 ) f o u n d that n o n - s u p p r e s s o r s o n t h e 1 m g D S T h a d a 2 4 h r u r i n e free c o r t i s o l t h a t w a s n o t s i g n i f i c a n t l y d i f f e r e n t f r o m t h a t o f s u p p r e s s o r s . In c o n t r a s t , H o l s b o e r e t a l . (1984) f o u n d t h a t n o n - s u p p r e s s o r s h a d a s i g n i f i c a n t l y h i g h e r b a s a l p l a s m a cortisol ( m e a n 1 4 0 0 - 1 7 0 0 h r p l a s m a cortisol, w i t h e v e r y 2 0 m i n s a m p l i n g ) t h a n s u p p r e s s o r s . T h e r e w a s c o n s i d e r a b l e s p r e a d o f m e a n p l a s m a cortisol values a m o n g the n o n - s u p p r e s s o r s , w i t h n o a p p a r e n t a s s o c i a t i o n ; u n f o r t u n a t e l y , c o r t i s o l h y p e r s e c r e t i o n w a s n o t c l e a r l y d e f i n e d . T h u s , in c o n t r a s t to the f i n d i n g s f o r t h e 2 m g D S T a n d b a s a l c o r t i s o l ( n o n - s u p p r e s s o r s h a v e a n a p p a r e n t l y h i g h e r basal cortisol and are significantly associated with cortisol hypersecretion), the relationship b e t w e e n t h e 1 m g D S T a n d b a s a l c o r t i s o l is c o n t r a d i c t o r y a n d u n c l e a r . Is t h e r e l a t i o n s h i p o f t h e D S T a n d b a s a l c o r t i s o l s e c r e t i o n d e p e n d e n t o n t h e d o s e o f d e x a m e t h a s o n e , as this r e v i e w partially s u g g e s t s ? D u e to t h e s e d i s c r e p a n t f i n d i n g s , w e r e - e x a m i n e d the a s s o c i a t i o n o f D S T a n d b a s a l cortisol r e s p o n s e b y s t u d y i n g b o t h t h e 1 m g D S T a n d t h e 2 m g D S T in t w o g r o u p s o f e n d o g e n o u s l y d e p r e s s e d patients w h o also h a d a basal cortisol a s s e s s m e n t p e r f o r m e d as the m e a n 1 3 0 0 - 1 6 0 0 h r b a s a l cortisol v a l u e . METHODS Sixty-nine patients (27 men and 42 women, mean age ± SD: 42.1 ± 14.0 years) were hospitalized on a psychiatric research ward where they were evaluated with the Schedule for Affective Disorders and Schizophrenia (SADS) (Endicott and Spitzer, 1978) and given a diagnosis of major depressive disorder, endogenous subtype, by the Research Diagnostic Criteria (Spitzer et al., 1978). All were moderately depressed (extracted Hamilton depression score > 18) (Endicott et al., 1981). They gave informed consent to be studied after they were found to be in good medical health. None had present or past clinical or laboratory evidence of an endocrine disorder. All subjects were free of psyehotropic medication for a minimum of 10 days prior to the study, were not taking any hormones and did not have alcohol or drug abuse in the last 6 months. The 2 mg DST was administered to the first 30 patients (mean age 44.3 ± 14.6 years; 10 males and 20 females) and the 1 mg DST to the following 39 patients (mean age 40.5 ± 13.6 years; 17 males and 22 females). There were no significant differences between these two groups with respect to age or sex. Dexamethasone was given orally at 2300 hr the same day of the 1300-1600 hr plasma cortisol assessment, with blood samples for plasma cortisol drawn the following day at 1600 and 2300 hr. A plasma post-dexamethasone eortlsol of > 5 ttg/dl at either time was used to define non-suppression. All subjects had a basal plasma cortisol assessment, which involved the insertion of an angiocatheter in an antecubital vein prior to 1130 hr. Some subjects had a 24 hr catheter study (n = 41), with a mean 1300-1600 hr plasma cortisol of 9.2 ± 3.1 t~g/dl while others had a short study terminating at 1600 hr (n = 28), with a mean 1300-1600 hr plasma cortisol of 8.9.4- 2.7/tg/dl. There were no significant differences between the long and short studies. Blood sampling (3 cc) was performed every 30 min for plasma cortisol determination. Subjects remained supine during the test and were given breaiffast at 0730 hr and lunch at 1100 hr; no snacks or naps were permitted. The mean 1300-1600 hr plasma cortisol was evaluated and used as the representative measure of basal plasma cortisol secretion, since it has been shown to he highly correlated with the mean 24 hr plasma cortisol in both normals and depressives (Asnis et al., 1982a; Halbreich eta/., 1982, 1985). In order to define the mean 1300-1600 hr plasma cortisol level that was abnormal, i.e. cortisol hypersecretion, a group of 41 normal controls had been previously studied (Asnis et al., 1983). A mean 1300-1600 hr plasma level greater than two SDs of the mean obtained from these 41 normal controls (18 men, 23 women; mean age 35.8 ± 14.0 years) was used to define cortisol hyperseeretion: their mean value was 6.4 ± 2.0 #g/dl, and thus cortisol hypersecretion was defmed as > 10.5 #g/all. We have replicated these f'mdings in another group of 61 normal subjects, with mean 1300-1600 hr plasma cortisol assessment by the same methodology fflalbreich et al., unpublished data). This second normal group (36 women, 25 men; mean age 45.4 ± 15.2 years) had an age and sex distribution that was not significantly different from the 69 depressives presented in this paper, although they were significantly older than the first normal group (t = 3.26, p < 0.01). The mean 1300-1600 hr plasma cortisol was almost identical (6.6 ± 2.0 t~g/dl vs 6.4 ± 2.0 t~g/dl), further substantiating the criterion of 10.5 tzg/dl used to define cortisol hypersecretion in the present study. All plasma samples were analyzed in duplicate by a modified competitive binding method, using Florisil to separate
DST AND CORTISOL IN ENDOGENOUSDEPRESSION
297
bound from free fractions (Novacenko et al., 1980). Intra- and interassay coefficients of variation of duplicate samples were 2.9 and 4.8%, respectively, for a plasma cortisol pool of 20.2 ~tg/dl, 3.7 and 4.9% for a cortisol pool of 12.4 Fg/dl; and 9.1 and 9.6% for a cortisol pool of 2.5 ~tg/dl. All samples from a given subject were measured in the same assay. An analysis of covariance (ANOVA) controlling for age was performed for comparing the mean 1300-1600 hr plasma cortisol of the suppressors to the non-suppressors, because age and basal plasma cortisol have been reported to be positively correlated in depressive illness (Asnis e t a l . , 1981b; Halbreich et al., 1984). A Fisher exact test, or chi square when appropriate, was used to compare the frequency of cortisol hypersecretors in suppressors vs non-suppressors. A Pearson correlation coefficient was used in evaluating the correlations of post-dexamethasone plasma cortisol with basal plasma cortisoL RESULTS
The mean 1 3 0 0 - 1 6 0 0 hr plasma cortisol values for the 1 rag and the 2 rag DST suppressors and non-suppressors are presented in Fig. 1 and Table I. As indicated, 26.7% (eight of 30 depressives) were non-suppressors on the 2 rag DST, in contrast to 53.3% (21 of 39 depressives) on the 1 rag DST (x2 = 5.14, p < 0.05). An A N O V A revealed a significant effect for age as a covariate (F = 11.09, df = 1, p = 0.0014). Age was significantly though moderately correlated with mean 1 3 0 0 - 1 6 0 0 hr plasma cortisol (r = 0.28, p < 0.02). There was a main effect of non-suppressor/suppressor status on mean plasma cortisol (F = 15.12, df = 1, p = 0.0002). There was no effect of dose (F = 0.21, df = 1, p = 0.63) and no dose x nonsuppressor/suppressor interaction (F = 0.92, df = 1/64, p = 0.34). Although there was no significant difference in mean 1 3 0 0 - 1 6 0 0 hr plasma cortisol in the 1 rag and 2 rag DST nonsuppressors, the variance of the 1 mg DST non-suppressors was significantly larger than that of the 2 mg DST non-suppressors (F = 4.25, df = 7/20, p = 0.05). However, it is possible
otIIPMonly] i I ° Non-suppress~
16
'
!
i,,i....., °
.......
;___. [
4.
2.
(n=21)(ling) (n=18)
(n=8)(2 rag)
FIG. 1. Mean 1 - 4 pm plasma cortisol 4- SEM vs DST (l or 2 rag) in endogenous depressives.
298
G.M.AsNIs et al. TABLE.I. MEANBASAL1300--1600 hr PLASMACORTISOL(± SEM) IN RELATIONTO 1 mg AND2 mg DST*
1 mg
2 mg
Total
Non-suppressors
Suppressors
Total
10.00 (10.44) SEM 0.63/tg/dl (n = 21) 11.16 (11.15) SEM 0.58 ttg/dl (n = 8) 10.32 (10.79) SEM 0.49 ttg/dl (n = 29)
8.32 (8.10) SEM 0.66 t~g/dl (n = 18) 8.11 (7.86) SEM 0.72 ttg/dl (n = 22) 8.20 (7.99) SEM 0.49 #g/dl (n = 40)
9.23 (9.27) SEM 0.47 ttg/dl (n = 39) 8.92 (9.51) SEM 0.47/~g/dl (n = 30)
*Age-adjusted means are in parentheses. that this finding may be related to the number of 2 mg non-suppressors (n = 8) compared to the number of 1 mg non-suppressors (n = 18). Cortisol hypersecretion, as defined earlier, occurred in 33.3% (23 of 69) of the depressives. It was significantly associated with non-suppression on the 2 mg DST (six of eight non-suppressors were cortisol hypersecretors vs five of 22 suppressors; Fisher's exact testp = 0.014, one-tailed) and with non-suppression on the 1 mg DST (10 of 21 non-suppressors were cortisol hypersecretors vs two of 18 suppressors; Fisher's exact test, p = 0.015, one-tailed). Although non-suppression with both doses was significantly associated with cortisol hypersecretion, non-suppression on the 2 mg DST was more strongly associated with cortisol hypersecretion. This difference failed to reach statistical significance when non-suppression included both the 1600 and the 2300 hr post-dexamethasone cortisol values (Fisher's exact test, p = 0.185, one-tailed). When non-suppression was evaluated with only the 1600 hr postdexamethasone assessment, all (five of five) 2 mg non-suppressors were cortisol hypersecretors, in contrast to 50% (nine of 18) of the 1 mg non-suppressors (Fisher's exact test, p = 0.019, one-tailed). The Pearson correlation coefficients (covarying out age) between mean 1 3 0 0 - 1 6 0 0 hr plasma cortisol and log post-dexamethasone cortisol for the 1 mg DST were non-significant (at 1600 hr, r = 0.22; at 2300 hr, r = 0.09). DISCUSSION The major finding of this study is that for both the 1 mg and the 2 mg DST, the non-suppressors had a significantly higher mean 1 3 0 0 - 1 6 0 0 hr plasma cortisol level than the suppressors. Thus, non-suppression is significantly associated with, though not limited to, cortisol hypersecretion. The findings for the 2 mg DST (n = 30) have been partially presented earlier (Asnis et al., 1982a) and are now extended in this report to the 1 mg DST. Although the literature is consistent regarding these findings for the 2 mg DST, it is contradictory for the 1 mg DST. Similar to this rep6rt, and also utilizing a mean 3 hr plasma cortisol assessment (every 20 min sampling), Holsboer et al. (1984) found that non-suppressors (1 mg DST) had a significantly higher mean 1 4 0 0 - 1 7 0 0 hr plasma cortisol level than suppressors. In contrast, Vandewalle et al. (1983), Kathol et al. (1984) and Brown et al. (1985) failed to find a difference in mean 24 hr urine free cortisol among suppressors and non-suppressors.
D S T AND CORTISOL IN ENDOGENOUS DEPRESSION
299
Interestingly, although the mean 1300-1600 hr plasma cortisol was not significantly different in 1 mg and 2 mg DST non-suppressors, the 1 mg non-suppressors did have a significantly larger variance than the 2 mg non-suppressors. Thus, the 1 mg DST identified more non-suppressor patients with lower basal plasma cortisol levels (including "cortisol normosecretors") than the 2 mg DST and is therefore less specific for cortisol hypersecretion. In addition to the significant association of a positive DST with cortisol hypersecretion, it is striking that there was a sizeable variability in basal plasma cortisol levels among the DST non-suppressors, particularly with the 1 mg DST. One possibility is that the pharmacokinetics of dexamethasone may be involved in the dexamethasone response. Although one study found that plasma dexamethasone did not differ significantly between suppressors and non-suppressors (Carroll et al., 1980), another study found that non-suppressors had significantly lower plasma dexamethasone blood levels than suppressors, with marked variability of blood levels within each group (Berger et al., 1984). Thus, some patients' DST status may be affected by inadequate dexamethasone levels as well as inordinately high levels of the steroid, as has been shown for patients with Cushing's syndrome (Meilke, 1982). Thus a DST response may depend substantially on absorption and/or metabolism of dexamethasone, irrespective of basal cortisol secretion. This would further explain the lack of correlation between post-dexamethasone plasma cortisol and mean 1300-1600 hr plasma cortisol found in the present study. Another explanation for the partial overlap between DST and basal plasma cortisol is that various parts of the cortisol regulatory system may be somewhat independent of each other (Asnis et al., 1981a; Halbreich et al., 1985). The basal cortisol level is a global manifestation of the system influenced by multiple inputs from the hypothalmus to the adrenal gland. The DST is an assessment of a specific aspect of this system, the slow feedback involving dexamethasone receptors predominantly in the pituitary (Sakakura et al., 1981). Several studies have evaluated both plasma cortisol and plasma ACTH after 1 mg dexamethasone. Nasr et al. (1983) found no association between ACTH and post-dexamethasone plasma cortisol, in contrast to Reus et al. (1982) and Berger et al. (1985), who demonstrated a significant positive association. Fang et al. (1981) found a positive association at one post-dexamethasone time (1600 hr), but not at another (0800 hr). Amsterdam et al. (1983) reported that the cortisol response to ACTH was not correlated with post-dexamethasone plasma cortisol in six endogenous depressives. As pointed out by Berger et al. (1985), a possible explanation for these discrepant findings may be that the sensitivity and specificity of the ACTH assay are still problematic. Furthermore, as in the present report, blood levels of dexamethasone were not assessed in these earlier studies. It is clear that the DST response and elevated basal plasma cortisol are significantly but not exclusively associated (Asnis e t a l . , 1981a, 1982a, 1983; Holsboer e t a l . , 1984). Future studies must include dexamethasone blood levels to assess whether the latter accounts for the partial overlap. If cortisol hypersecretion is the parent neuroendorine abnormality to be identified, DST is probably not a good screening test, nor is it a substitute for a basal cortisol evaluation. Nonetheless, DST may have specific value in identifying a particular subset of patients with special clinical features, e.g. high relapse rate (Holsboer et al., 1982; Greden et al., 1983), psychosis (Carroll et al., 1976; Asnis et al., 1982b) and bipolarity (Asnis et al., 1982b), although others have questioned all these claims (Amsterdam et al., 1982; Coryell and Zimmerman, 1983; Stokes et al., 1984).
300
G.M.AsNIS et al. REFERENCES
Amsterdam J D, Winokar A, Caroff S N, Corm J (1982) The dexamethasone suppression test in outpatients with primary affective disorder and healthy control subjects. Am J Psychiatry 139: 287-291. Amsterdam J D, Winokur A, Abelman E, Luki I, Rickels K (1983) Cosyntropin (ACTH 1-24) stimulation test in depressed patients and healthy subjects. Am J Psychiatry 140:907 -914. Asnis G M, Saehar E J, Halbreieh U, Nathan R S, Ostrow L, Halpern F S (1981a) Cortisol secretion and dexamethasone response in depression. Am J Psychiatry 138: 1218-1221. Asnis G M, Sacher E J, Halbreich U, Nathan R S, Novacenko H, Ostrow L C (1981b) Cortisol secretion in relation to age in major depression. Psychosom Med 43:235-242. Asnis G M, Halbreich U, Sachar E J, Nathan R S, Davies M, Novacenko H, Ostrow L C, Endicott J, Puig-Antich J (1982a) The relationship of 2 nag DST and plasma cortisol hypersecretion in depressive illness: clinical and neuroendocrine parameters. Psychopharm Bull 18: 122-126. Asnis G M, Halbreich U, Nathan R S, Ostrow L C, Halpern R, Endicott J, Sachar E J (1982b) The dexamethasone suppression test in depressive illness: clinical correlates. Psychoneuroendocrinology 7: 295- 301. Asnis G M, Halbreich U, Quitkin F, Endicott J, Puig-Antich J, Sachar E J (1983) Mean 1 - 4 pm plasma cortisol levels may distinguish various depressive substances. Presented at Annual Meeting of American College of Neuropsychopharmacology. Berger M, Pirke K M, Doerr P, Krieg J C, von Zerssen D (1984) The limited utility of the dexamethasone suppression test for the diagnostic process in psychiatry. Br J Psychiatry 145: 372-383. Berger M, Pirke K M, Krieg C J, von Zerssen D, Muller O A, Stalla G K (1985) ACTH and cortisol levels in healthy probands and psychiatric patients following the dexamethasone suppression test. Am J Psychiatry 142: 268-269. Brown W A, Johnston R, Mayfield D (1979) The 24 hr dexamethasone suppression test in a clinical setting: relationship to diagnosis, symptoms, and response to treatment. Am J Psychiatry 136:543-547. Brown W A, Keitner G, Quails C P, Haler R (1985) The DST and pituitary-adrenocortical function. Arch Gen Psychiatry 42: 121-123. Carroll B J (1972) The hypothalamic-pituitary-adrenal axis in depression. In: Davies B, Carroll B J, Mowbray R M (Eds) Depressive Illness: Some Research Studies. Charles C Thomas, Springfield, pp. 25-68. Carroll B J, Curtis G C, Mendels J (1976) Neuroendocrine regulation in depression, II: discrimination of depressed from non-depressed patients. Arch Gen Psychiatry 33: 1051-1057. Carroll B J, Sehroeder K, Mukhopadhyay S, Greden J F, Feinberg M, Ritchie J, Tarika J (1980) Plasma dexamethasone concentrations and eortisol suppression response in patients with endogenous depression. J Clin Endocrinol Metab 51: 433-437. Carroll B J, Feinberg M, Greden J F (1981) A specific laboratory test for diagnosis of melancholia: standardization, validation, and clinical utility. Arch Gen Psychiatry 38:15 -22. Coryell W, Zimmerman M (1983) The dexamethasone suppression test and ECT outcome: a six-month follow up. Biol Psychiat 18:21-27. Endicott J, Spitzer R L (1978) A diagnostic interview: the schedule for affective disorders and schizophrenia. Arch Gen Psychiatry 35: 837-844. Endicott J, Cohen J, Nee J, Fleiss J, Sarantakos S (1981) Hamilton depression rating scale: extracted form and change versions of the schedule for affective disorders and schizophrenia. Arch C-en Psychiatry 38: 98-108. Fang V S, Tricou B J, Robertson A, Meltzer H (1981) Plasma ACTH and eortisol levels in depressed patients: relation to dexamethasone suppression test. Life Sci 29:931-938. Greden J F, Gardner R, Kong D, Grunhaus L, Carroll B J, Kronfol Z (1983) Dexamethasone suppression tests in antidepressant treatment of melancholia. Arch Gen Psychiatry 40:493-500. Halbreich U, Zumoff B, Kream J, Fukushima D K (1982) The mean 1 - 4 pm plasma cortisol concentrationas a diagnostic test for hypercortisolism. J Clin Endocrinol Metab 54: 1262-1264. Halbreieh U, Asnis G M, Zumoff B, Nathan R S, Shindiedecker R (1984) Effect of age and sex on cortisol secretion in depressives and normals. Psychiatry Res 13:221-229. Halbreich U, Asnis G M, Shindledecker R, Zumoff B, Nathan R S (1985) Cortisol secretion in depression: I. Basal levels. Arch Gen Psychiatry 42: 904-908. Holsboer F, Diebel R, Hofschuster E (1982) Repeated dexarnethasone suppression test during depressive illness. J Affect Disord 4: 93-101. Holsboer F, Gerken A, Steiger A, Fass V (1984) Mean 14.00-17.00 hr plasma cortisol concentration and its relationship to the 1 nag dexamethasone suppression response in depressives and controls. Acta Psychiat Scand 69:383 -390. Kathol R G, Winokur G, Sherman B M, Lewis D, Schlesser M (1984) Provocative endocrine testing in recovered depressives. Psychoneuroendocrinology 9: 57-67. Meilke A W (1982) Dexamethasone suppression test: usefulness of simultaneous measurement of plasma cortisol and dexamethasone. Clin Endocrinol 16:401-408. Nasr S J, Rodgers C, Pandey G, Altman E G, Gaviria F M, Davis J M (1983) ACTH and the dexamethasonesuppression test. Biol Psychiat 18: 1069-1073.
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Novacenko H, Halpern F, Sachar E J (1980) Improved protein-binding radioassay for plasma cortisol. Clin Chem 26: 312-313. Reus V I, Joseph M S, Dallman M F (1982) ACTH levels after the dexamethasone suppression test in depression. N Engl J Med 306: 238-239. Sachar E J, Hellman L, Fukushima D (1970) Cortisol production in depressive illness. Arch Gen Psychiatry 23: 289-298. Sakakura M, Yoshioka M, Kobayashi M, Takeke K (1981) The site of inhibitory action of a natural (corticosterone) and synthetic steroid (dexamethasone) in the hyphothalamic-pituitary-adrenal axis. Neuroendocrinology 32: 174-178. Schlesser M A, Winokur G, Sherman B M (1979) Genetic subtypes of unipolar primary depressive illness distinguished by hypothalamic-pituitary-adrenal axis activity. Lancet i" 739-741. Spitzer R L, Endicott J, Robins E (1978) Research diagnostic criteria; rationale and reliability. Arch Gen Psychiatry 35: 773 -782. Stokes P E, Pick G R, Stoll P M, Nunn W O (1975) Pituitary-adrenal function in depressed patients: resistance to dexamethasone suppression. J Psychiat Res 12:271-281. Stokes P E, Stoll P M, Koslow S H, Maas J W, Davis J M, Swarm A C, Robins E (1984) Pretreatment DST and hypothalamic-pituitary-adrenal cortisol function in depressed patients and comparison groups. Arch Gen Psychiatry 41: 257-267. Vandewalle J, Charles G, Mardens Y, Mendlewicz J (1983) Dexamethasone resistance and cortisol secretion in depressive illness. Biol Psychiat 18: 385-389.
12, No. 4, pp. 295-301, 1987.
0306-4530187 $3.00 + 0.00 Pergamon Jcernals Ltd.
Printed in Great Britain
THE TEST
RELATIONSHIP (1 m g A N D
OF THE
DEXAMETHASONE
2 mg) TO BASAL ENDOGENOUS
PLASMA
SUPPRESSION
CORTISOL
LEVELS
IN
DEPRESSION
GREGORY M. ASNIS*, URIEL HALBREICH*, NEAL D. RYAN~', HARRY RABINOWICZ't, JOAQUIM PUIG-ANTICHI', BEVERLY NELSON~:, HANNA NOVACENKOt and JILL HARKAVY FRIEDMAN* *Department of Psychiatry, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY 10467, U.S.A., t New York State PsychiatricInstitute and Departmentof Psychiatry, ColumbiaUniversityCollegeof Physicians and Surgeons, New York, NY, U.S.A. and * Western Psychiatric Institute and Clinic, Pittsburgh, PA, U.S.A. (Received 11 July 1985; in final form 3 December 1986) SUMMARY The 1 mg and 2 mg dexamethasone suppression tests (DST) were evaluated in two groups of endogenouslydepressed patients (n = 39 and n = 30, respectively)who also had a 1300-1600 hr basal cortisol assessment. Non-suppressors(on both DSTs) had significantlyhigher basal plasma cortisol levels and thus were significantly associated with relative cortisol hypersecretion. However, there was only a partial overlapbetween DST response and basal plasma cortisol, with a large variation of cortisol levels among non-suppressors. The 2 nag DST appears to be more specificfor cortisol hypersecretionthan the 1 nag DST. If cortisol hypersecretion is to be identified, neither the 1 mg or 2 nag DST is an adequate assessment nor a substitute for a basal cortisol assessment. Key words--Dexamethasone suppression test; cortisol hypersecretion; endogenous depression. INTRODUCTION CORTISOL HYPERSECRETION and non-suppression to dexamethasone are neuroendocrine abnormalities found in approximately 50% o f adult endogenously depressed patients. These abnormalities in depressed patients are limited to their ill state, normalizing after recovery (Sachar et al., 1970; Carroll, 1972; Stokes et al., 1975; Carroll et al., 1976; Brown et al., 1979; Sehlesser et al., 1979). The literature suggests that these two abnormalities are related, both being presumed reflections of increased h y p o t h a l a m i c - p i t u i t a r y - a d r e n a l cortical activity. Several investigators have found that single-sample predexamethasone plasma cortisol levels were elevated in depressed patients who were non-suppressors on the 2 mg dexamethasone suppression test (DST) vs those who were suppressors (Stokes et al., 1975; Can'oll et al., 1976; 'Asnis et al., 1981a). Indwelling catheter studies with sampling every 30 min from 4 to 24 hr have yielded similar results (Asnis et al., 1981a, 1982a). Furthermore, non-suppression to 2 mg dexamethasone occurred predominantly in plasma cortisol hypersecretors, although hypercortisolemia was not equivalent to non-suppression on the DST, since only 50% of cortisol hypersecretors were non-suppressors (Asnis et al., 1981a, 1982a). Most investigators have switched from the 2 mg DST to the I mg DST, since the latter increases the sensitivity without supposedly sacrificing the specificity or the diagnostic confidence of this test in diagnosing depression (Carroll et al., 1976, 1981). More recent studies have now questioned the specificity o f the 1 mg DS"I" in depression (Berger et al., 1984). Similar to the
295
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G.M.AsNIS et al.
studies d e s c r i b e d for t h e 2 m g D S T a n d b a s a l cortisol, a f e w studies h a v e a d d r e s s e d the r e l a t i o n s h i p o f t h e 1 m g D S T to b a s a l cortisol. V a n d e w a l l e e t a l . (1983), K a t h o l e t al. (1984) a n d B r o w n e t a l . ( 1 9 8 5 ) f o u n d that n o n - s u p p r e s s o r s o n t h e 1 m g D S T h a d a 2 4 h r u r i n e free c o r t i s o l t h a t w a s n o t s i g n i f i c a n t l y d i f f e r e n t f r o m t h a t o f s u p p r e s s o r s . In c o n t r a s t , H o l s b o e r e t a l . (1984) f o u n d t h a t n o n - s u p p r e s s o r s h a d a s i g n i f i c a n t l y h i g h e r b a s a l p l a s m a cortisol ( m e a n 1 4 0 0 - 1 7 0 0 h r p l a s m a cortisol, w i t h e v e r y 2 0 m i n s a m p l i n g ) t h a n s u p p r e s s o r s . T h e r e w a s c o n s i d e r a b l e s p r e a d o f m e a n p l a s m a cortisol values a m o n g the n o n - s u p p r e s s o r s , w i t h n o a p p a r e n t a s s o c i a t i o n ; u n f o r t u n a t e l y , c o r t i s o l h y p e r s e c r e t i o n w a s n o t c l e a r l y d e f i n e d . T h u s , in c o n t r a s t to the f i n d i n g s f o r t h e 2 m g D S T a n d b a s a l c o r t i s o l ( n o n - s u p p r e s s o r s h a v e a n a p p a r e n t l y h i g h e r basal cortisol and are significantly associated with cortisol hypersecretion), the relationship b e t w e e n t h e 1 m g D S T a n d b a s a l c o r t i s o l is c o n t r a d i c t o r y a n d u n c l e a r . Is t h e r e l a t i o n s h i p o f t h e D S T a n d b a s a l c o r t i s o l s e c r e t i o n d e p e n d e n t o n t h e d o s e o f d e x a m e t h a s o n e , as this r e v i e w partially s u g g e s t s ? D u e to t h e s e d i s c r e p a n t f i n d i n g s , w e r e - e x a m i n e d the a s s o c i a t i o n o f D S T a n d b a s a l cortisol r e s p o n s e b y s t u d y i n g b o t h t h e 1 m g D S T a n d t h e 2 m g D S T in t w o g r o u p s o f e n d o g e n o u s l y d e p r e s s e d patients w h o also h a d a basal cortisol a s s e s s m e n t p e r f o r m e d as the m e a n 1 3 0 0 - 1 6 0 0 h r b a s a l cortisol v a l u e . METHODS Sixty-nine patients (27 men and 42 women, mean age ± SD: 42.1 ± 14.0 years) were hospitalized on a psychiatric research ward where they were evaluated with the Schedule for Affective Disorders and Schizophrenia (SADS) (Endicott and Spitzer, 1978) and given a diagnosis of major depressive disorder, endogenous subtype, by the Research Diagnostic Criteria (Spitzer et al., 1978). All were moderately depressed (extracted Hamilton depression score > 18) (Endicott et al., 1981). They gave informed consent to be studied after they were found to be in good medical health. None had present or past clinical or laboratory evidence of an endocrine disorder. All subjects were free of psyehotropic medication for a minimum of 10 days prior to the study, were not taking any hormones and did not have alcohol or drug abuse in the last 6 months. The 2 mg DST was administered to the first 30 patients (mean age 44.3 ± 14.6 years; 10 males and 20 females) and the 1 mg DST to the following 39 patients (mean age 40.5 ± 13.6 years; 17 males and 22 females). There were no significant differences between these two groups with respect to age or sex. Dexamethasone was given orally at 2300 hr the same day of the 1300-1600 hr plasma cortisol assessment, with blood samples for plasma cortisol drawn the following day at 1600 and 2300 hr. A plasma post-dexamethasone eortlsol of > 5 ttg/dl at either time was used to define non-suppression. All subjects had a basal plasma cortisol assessment, which involved the insertion of an angiocatheter in an antecubital vein prior to 1130 hr. Some subjects had a 24 hr catheter study (n = 41), with a mean 1300-1600 hr plasma cortisol of 9.2 ± 3.1 t~g/dl while others had a short study terminating at 1600 hr (n = 28), with a mean 1300-1600 hr plasma cortisol of 8.9.4- 2.7/tg/dl. There were no significant differences between the long and short studies. Blood sampling (3 cc) was performed every 30 min for plasma cortisol determination. Subjects remained supine during the test and were given breaiffast at 0730 hr and lunch at 1100 hr; no snacks or naps were permitted. The mean 1300-1600 hr plasma cortisol was evaluated and used as the representative measure of basal plasma cortisol secretion, since it has been shown to he highly correlated with the mean 24 hr plasma cortisol in both normals and depressives (Asnis et al., 1982a; Halbreich eta/., 1982, 1985). In order to define the mean 1300-1600 hr plasma cortisol level that was abnormal, i.e. cortisol hypersecretion, a group of 41 normal controls had been previously studied (Asnis et al., 1983). A mean 1300-1600 hr plasma level greater than two SDs of the mean obtained from these 41 normal controls (18 men, 23 women; mean age 35.8 ± 14.0 years) was used to define cortisol hyperseeretion: their mean value was 6.4 ± 2.0 #g/dl, and thus cortisol hypersecretion was defmed as > 10.5 #g/all. We have replicated these f'mdings in another group of 61 normal subjects, with mean 1300-1600 hr plasma cortisol assessment by the same methodology fflalbreich et al., unpublished data). This second normal group (36 women, 25 men; mean age 45.4 ± 15.2 years) had an age and sex distribution that was not significantly different from the 69 depressives presented in this paper, although they were significantly older than the first normal group (t = 3.26, p < 0.01). The mean 1300-1600 hr plasma cortisol was almost identical (6.6 ± 2.0 t~g/dl vs 6.4 ± 2.0 t~g/dl), further substantiating the criterion of 10.5 tzg/dl used to define cortisol hypersecretion in the present study. All plasma samples were analyzed in duplicate by a modified competitive binding method, using Florisil to separate
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bound from free fractions (Novacenko et al., 1980). Intra- and interassay coefficients of variation of duplicate samples were 2.9 and 4.8%, respectively, for a plasma cortisol pool of 20.2 ~tg/dl, 3.7 and 4.9% for a cortisol pool of 12.4 Fg/dl; and 9.1 and 9.6% for a cortisol pool of 2.5 ~tg/dl. All samples from a given subject were measured in the same assay. An analysis of covariance (ANOVA) controlling for age was performed for comparing the mean 1300-1600 hr plasma cortisol of the suppressors to the non-suppressors, because age and basal plasma cortisol have been reported to be positively correlated in depressive illness (Asnis e t a l . , 1981b; Halbreich et al., 1984). A Fisher exact test, or chi square when appropriate, was used to compare the frequency of cortisol hypersecretors in suppressors vs non-suppressors. A Pearson correlation coefficient was used in evaluating the correlations of post-dexamethasone plasma cortisol with basal plasma cortisoL RESULTS
The mean 1 3 0 0 - 1 6 0 0 hr plasma cortisol values for the 1 rag and the 2 rag DST suppressors and non-suppressors are presented in Fig. 1 and Table I. As indicated, 26.7% (eight of 30 depressives) were non-suppressors on the 2 rag DST, in contrast to 53.3% (21 of 39 depressives) on the 1 rag DST (x2 = 5.14, p < 0.05). An A N O V A revealed a significant effect for age as a covariate (F = 11.09, df = 1, p = 0.0014). Age was significantly though moderately correlated with mean 1 3 0 0 - 1 6 0 0 hr plasma cortisol (r = 0.28, p < 0.02). There was a main effect of non-suppressor/suppressor status on mean plasma cortisol (F = 15.12, df = 1, p = 0.0002). There was no effect of dose (F = 0.21, df = 1, p = 0.63) and no dose x nonsuppressor/suppressor interaction (F = 0.92, df = 1/64, p = 0.34). Although there was no significant difference in mean 1 3 0 0 - 1 6 0 0 hr plasma cortisol in the 1 rag and 2 rag DST nonsuppressors, the variance of the 1 mg DST non-suppressors was significantly larger than that of the 2 mg DST non-suppressors (F = 4.25, df = 7/20, p = 0.05). However, it is possible
otIIPMonly] i I ° Non-suppress~
16
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!
i,,i....., °
.......
;___. [
4.
2.
(n=21)(ling) (n=18)
(n=8)(2 rag)
FIG. 1. Mean 1 - 4 pm plasma cortisol 4- SEM vs DST (l or 2 rag) in endogenous depressives.
298
G.M.AsNIs et al. TABLE.I. MEANBASAL1300--1600 hr PLASMACORTISOL(± SEM) IN RELATIONTO 1 mg AND2 mg DST*
1 mg
2 mg
Total
Non-suppressors
Suppressors
Total
10.00 (10.44) SEM 0.63/tg/dl (n = 21) 11.16 (11.15) SEM 0.58 ttg/dl (n = 8) 10.32 (10.79) SEM 0.49 ttg/dl (n = 29)
8.32 (8.10) SEM 0.66 t~g/dl (n = 18) 8.11 (7.86) SEM 0.72 ttg/dl (n = 22) 8.20 (7.99) SEM 0.49 #g/dl (n = 40)
9.23 (9.27) SEM 0.47 ttg/dl (n = 39) 8.92 (9.51) SEM 0.47/~g/dl (n = 30)
*Age-adjusted means are in parentheses. that this finding may be related to the number of 2 mg non-suppressors (n = 8) compared to the number of 1 mg non-suppressors (n = 18). Cortisol hypersecretion, as defined earlier, occurred in 33.3% (23 of 69) of the depressives. It was significantly associated with non-suppression on the 2 mg DST (six of eight non-suppressors were cortisol hypersecretors vs five of 22 suppressors; Fisher's exact testp = 0.014, one-tailed) and with non-suppression on the 1 mg DST (10 of 21 non-suppressors were cortisol hypersecretors vs two of 18 suppressors; Fisher's exact test, p = 0.015, one-tailed). Although non-suppression with both doses was significantly associated with cortisol hypersecretion, non-suppression on the 2 mg DST was more strongly associated with cortisol hypersecretion. This difference failed to reach statistical significance when non-suppression included both the 1600 and the 2300 hr post-dexamethasone cortisol values (Fisher's exact test, p = 0.185, one-tailed). When non-suppression was evaluated with only the 1600 hr postdexamethasone assessment, all (five of five) 2 mg non-suppressors were cortisol hypersecretors, in contrast to 50% (nine of 18) of the 1 mg non-suppressors (Fisher's exact test, p = 0.019, one-tailed). The Pearson correlation coefficients (covarying out age) between mean 1 3 0 0 - 1 6 0 0 hr plasma cortisol and log post-dexamethasone cortisol for the 1 mg DST were non-significant (at 1600 hr, r = 0.22; at 2300 hr, r = 0.09). DISCUSSION The major finding of this study is that for both the 1 mg and the 2 mg DST, the non-suppressors had a significantly higher mean 1 3 0 0 - 1 6 0 0 hr plasma cortisol level than the suppressors. Thus, non-suppression is significantly associated with, though not limited to, cortisol hypersecretion. The findings for the 2 mg DST (n = 30) have been partially presented earlier (Asnis et al., 1982a) and are now extended in this report to the 1 mg DST. Although the literature is consistent regarding these findings for the 2 mg DST, it is contradictory for the 1 mg DST. Similar to this rep6rt, and also utilizing a mean 3 hr plasma cortisol assessment (every 20 min sampling), Holsboer et al. (1984) found that non-suppressors (1 mg DST) had a significantly higher mean 1 4 0 0 - 1 7 0 0 hr plasma cortisol level than suppressors. In contrast, Vandewalle et al. (1983), Kathol et al. (1984) and Brown et al. (1985) failed to find a difference in mean 24 hr urine free cortisol among suppressors and non-suppressors.
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Interestingly, although the mean 1300-1600 hr plasma cortisol was not significantly different in 1 mg and 2 mg DST non-suppressors, the 1 mg non-suppressors did have a significantly larger variance than the 2 mg non-suppressors. Thus, the 1 mg DST identified more non-suppressor patients with lower basal plasma cortisol levels (including "cortisol normosecretors") than the 2 mg DST and is therefore less specific for cortisol hypersecretion. In addition to the significant association of a positive DST with cortisol hypersecretion, it is striking that there was a sizeable variability in basal plasma cortisol levels among the DST non-suppressors, particularly with the 1 mg DST. One possibility is that the pharmacokinetics of dexamethasone may be involved in the dexamethasone response. Although one study found that plasma dexamethasone did not differ significantly between suppressors and non-suppressors (Carroll et al., 1980), another study found that non-suppressors had significantly lower plasma dexamethasone blood levels than suppressors, with marked variability of blood levels within each group (Berger et al., 1984). Thus, some patients' DST status may be affected by inadequate dexamethasone levels as well as inordinately high levels of the steroid, as has been shown for patients with Cushing's syndrome (Meilke, 1982). Thus a DST response may depend substantially on absorption and/or metabolism of dexamethasone, irrespective of basal cortisol secretion. This would further explain the lack of correlation between post-dexamethasone plasma cortisol and mean 1300-1600 hr plasma cortisol found in the present study. Another explanation for the partial overlap between DST and basal plasma cortisol is that various parts of the cortisol regulatory system may be somewhat independent of each other (Asnis et al., 1981a; Halbreich et al., 1985). The basal cortisol level is a global manifestation of the system influenced by multiple inputs from the hypothalmus to the adrenal gland. The DST is an assessment of a specific aspect of this system, the slow feedback involving dexamethasone receptors predominantly in the pituitary (Sakakura et al., 1981). Several studies have evaluated both plasma cortisol and plasma ACTH after 1 mg dexamethasone. Nasr et al. (1983) found no association between ACTH and post-dexamethasone plasma cortisol, in contrast to Reus et al. (1982) and Berger et al. (1985), who demonstrated a significant positive association. Fang et al. (1981) found a positive association at one post-dexamethasone time (1600 hr), but not at another (0800 hr). Amsterdam et al. (1983) reported that the cortisol response to ACTH was not correlated with post-dexamethasone plasma cortisol in six endogenous depressives. As pointed out by Berger et al. (1985), a possible explanation for these discrepant findings may be that the sensitivity and specificity of the ACTH assay are still problematic. Furthermore, as in the present report, blood levels of dexamethasone were not assessed in these earlier studies. It is clear that the DST response and elevated basal plasma cortisol are significantly but not exclusively associated (Asnis e t a l . , 1981a, 1982a, 1983; Holsboer e t a l . , 1984). Future studies must include dexamethasone blood levels to assess whether the latter accounts for the partial overlap. If cortisol hypersecretion is the parent neuroendorine abnormality to be identified, DST is probably not a good screening test, nor is it a substitute for a basal cortisol evaluation. Nonetheless, DST may have specific value in identifying a particular subset of patients with special clinical features, e.g. high relapse rate (Holsboer et al., 1982; Greden et al., 1983), psychosis (Carroll et al., 1976; Asnis et al., 1982b) and bipolarity (Asnis et al., 1982b), although others have questioned all these claims (Amsterdam et al., 1982; Coryell and Zimmerman, 1983; Stokes et al., 1984).
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G.M.AsNIS et al. REFERENCES
Amsterdam J D, Winokar A, Caroff S N, Corm J (1982) The dexamethasone suppression test in outpatients with primary affective disorder and healthy control subjects. Am J Psychiatry 139: 287-291. Amsterdam J D, Winokur A, Abelman E, Luki I, Rickels K (1983) Cosyntropin (ACTH 1-24) stimulation test in depressed patients and healthy subjects. Am J Psychiatry 140:907 -914. Asnis G M, Saehar E J, Halbreieh U, Nathan R S, Ostrow L, Halpern F S (1981a) Cortisol secretion and dexamethasone response in depression. Am J Psychiatry 138: 1218-1221. Asnis G M, Sacher E J, Halbreich U, Nathan R S, Novacenko H, Ostrow L C (1981b) Cortisol secretion in relation to age in major depression. Psychosom Med 43:235-242. Asnis G M, Halbreich U, Sachar E J, Nathan R S, Davies M, Novacenko H, Ostrow L C, Endicott J, Puig-Antich J (1982a) The relationship of 2 nag DST and plasma cortisol hypersecretion in depressive illness: clinical and neuroendocrine parameters. Psychopharm Bull 18: 122-126. Asnis G M, Halbreich U, Nathan R S, Ostrow L C, Halpern R, Endicott J, Sachar E J (1982b) The dexamethasone suppression test in depressive illness: clinical correlates. Psychoneuroendocrinology 7: 295- 301. Asnis G M, Halbreich U, Quitkin F, Endicott J, Puig-Antich J, Sachar E J (1983) Mean 1 - 4 pm plasma cortisol levels may distinguish various depressive substances. Presented at Annual Meeting of American College of Neuropsychopharmacology. Berger M, Pirke K M, Doerr P, Krieg J C, von Zerssen D (1984) The limited utility of the dexamethasone suppression test for the diagnostic process in psychiatry. Br J Psychiatry 145: 372-383. Berger M, Pirke K M, Krieg C J, von Zerssen D, Muller O A, Stalla G K (1985) ACTH and cortisol levels in healthy probands and psychiatric patients following the dexamethasone suppression test. Am J Psychiatry 142: 268-269. Brown W A, Johnston R, Mayfield D (1979) The 24 hr dexamethasone suppression test in a clinical setting: relationship to diagnosis, symptoms, and response to treatment. Am J Psychiatry 136:543-547. Brown W A, Keitner G, Quails C P, Haler R (1985) The DST and pituitary-adrenocortical function. Arch Gen Psychiatry 42: 121-123. Carroll B J (1972) The hypothalamic-pituitary-adrenal axis in depression. In: Davies B, Carroll B J, Mowbray R M (Eds) Depressive Illness: Some Research Studies. Charles C Thomas, Springfield, pp. 25-68. Carroll B J, Curtis G C, Mendels J (1976) Neuroendocrine regulation in depression, II: discrimination of depressed from non-depressed patients. Arch Gen Psychiatry 33: 1051-1057. Carroll B J, Sehroeder K, Mukhopadhyay S, Greden J F, Feinberg M, Ritchie J, Tarika J (1980) Plasma dexamethasone concentrations and eortisol suppression response in patients with endogenous depression. J Clin Endocrinol Metab 51: 433-437. Carroll B J, Feinberg M, Greden J F (1981) A specific laboratory test for diagnosis of melancholia: standardization, validation, and clinical utility. Arch Gen Psychiatry 38:15 -22. Coryell W, Zimmerman M (1983) The dexamethasone suppression test and ECT outcome: a six-month follow up. Biol Psychiat 18:21-27. Endicott J, Spitzer R L (1978) A diagnostic interview: the schedule for affective disorders and schizophrenia. Arch Gen Psychiatry 35: 837-844. Endicott J, Cohen J, Nee J, Fleiss J, Sarantakos S (1981) Hamilton depression rating scale: extracted form and change versions of the schedule for affective disorders and schizophrenia. Arch C-en Psychiatry 38: 98-108. Fang V S, Tricou B J, Robertson A, Meltzer H (1981) Plasma ACTH and eortisol levels in depressed patients: relation to dexamethasone suppression test. Life Sci 29:931-938. Greden J F, Gardner R, Kong D, Grunhaus L, Carroll B J, Kronfol Z (1983) Dexamethasone suppression tests in antidepressant treatment of melancholia. Arch Gen Psychiatry 40:493-500. Halbreich U, Zumoff B, Kream J, Fukushima D K (1982) The mean 1 - 4 pm plasma cortisol concentrationas a diagnostic test for hypercortisolism. J Clin Endocrinol Metab 54: 1262-1264. Halbreieh U, Asnis G M, Zumoff B, Nathan R S, Shindiedecker R (1984) Effect of age and sex on cortisol secretion in depressives and normals. Psychiatry Res 13:221-229. Halbreich U, Asnis G M, Shindledecker R, Zumoff B, Nathan R S (1985) Cortisol secretion in depression: I. Basal levels. Arch Gen Psychiatry 42: 904-908. Holsboer F, Diebel R, Hofschuster E (1982) Repeated dexarnethasone suppression test during depressive illness. J Affect Disord 4: 93-101. Holsboer F, Gerken A, Steiger A, Fass V (1984) Mean 14.00-17.00 hr plasma cortisol concentration and its relationship to the 1 nag dexamethasone suppression response in depressives and controls. Acta Psychiat Scand 69:383 -390. Kathol R G, Winokur G, Sherman B M, Lewis D, Schlesser M (1984) Provocative endocrine testing in recovered depressives. Psychoneuroendocrinology 9: 57-67. Meilke A W (1982) Dexamethasone suppression test: usefulness of simultaneous measurement of plasma cortisol and dexamethasone. Clin Endocrinol 16:401-408. Nasr S J, Rodgers C, Pandey G, Altman E G, Gaviria F M, Davis J M (1983) ACTH and the dexamethasonesuppression test. Biol Psychiat 18: 1069-1073.
DST AND CORTISOLIN ENDOGENOUSDEPRESSIO~q
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Novacenko H, Halpern F, Sachar E J (1980) Improved protein-binding radioassay for plasma cortisol. Clin Chem 26: 312-313. Reus V I, Joseph M S, Dallman M F (1982) ACTH levels after the dexamethasone suppression test in depression. N Engl J Med 306: 238-239. Sachar E J, Hellman L, Fukushima D (1970) Cortisol production in depressive illness. Arch Gen Psychiatry 23: 289-298. Sakakura M, Yoshioka M, Kobayashi M, Takeke K (1981) The site of inhibitory action of a natural (corticosterone) and synthetic steroid (dexamethasone) in the hyphothalamic-pituitary-adrenal axis. Neuroendocrinology 32: 174-178. Schlesser M A, Winokur G, Sherman B M (1979) Genetic subtypes of unipolar primary depressive illness distinguished by hypothalamic-pituitary-adrenal axis activity. Lancet i" 739-741. Spitzer R L, Endicott J, Robins E (1978) Research diagnostic criteria; rationale and reliability. Arch Gen Psychiatry 35: 773 -782. Stokes P E, Pick G R, Stoll P M, Nunn W O (1975) Pituitary-adrenal function in depressed patients: resistance to dexamethasone suppression. J Psychiat Res 12:271-281. Stokes P E, Stoll P M, Koslow S H, Maas J W, Davis J M, Swarm A C, Robins E (1984) Pretreatment DST and hypothalamic-pituitary-adrenal cortisol function in depressed patients and comparison groups. Arch Gen Psychiatry 41: 257-267. Vandewalle J, Charles G, Mardens Y, Mendlewicz J (1983) Dexamethasone resistance and cortisol secretion in depressive illness. Biol Psychiat 18: 385-389.