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Pre- and postdexamethasone plasma acth and β-endorphin levels in endogenous and nonendogenous depression
Brief Reports
BIOL PSYCHIATRY 1988~23531-535
531
Pre- and Postdexamethasone Plasma ACTH and P-Endorphin Levels in Endogenous and Nonendogenous Depression Rainer Rupprecht, Amd Barocka, Georg Beck, Uwe Schrell, and Josef Pichl
Introduction In connection with the discussions on the utility of the Dexamethasone Suppression Test (DST), adrenocorticotrophic hormone (ACTH) levels in depressive disorder have become an interesting object of research. A number of research groups have reported increased ACTH levels associated with cortisol nonsuppression (Reus et al. 1982; Nasr et al. 1983; Holsboer et al. 1984), whereas others were unable to reproduce these findings (Yerevanian et al. 1983). Though Pfohl et al. ( 1985) and Roy et al. ( 1986) reported elevated concentrations of ACTH in depressive disorder, this was not noted by Fang et al. (1981) and Linkowski et al. (1985). Whether or not ACTH and P-endorphin are sufficiently suppressed by dexamethasone during a DST is still not clear. Fang et al. (1981) and Roy et al. (1986) reported a pronounced reduction in ACTH after dexamethasone administration, whereas Lypka and Szczdulik (1985) found no effect of dexamethasone on ACTH values. A suppressive effect of dexamethasone on P-endorphin was reported by Krantz and Brown (1985), but Lypka and Szczdulik (1985)
were unable to confirm these findings. The present paper attempts to determine whether or not the influence of dexamethasone on ACTH and P-endorphin is differently expressed in endogenous and nonendogenous depression and whether or not it is related to the outcome of the DST.
Methods
Fifty patients with a severe depressive syndrome were examined. To exclude any disease other than depression, clinical chemistry, hematology, and complete physical examination were obtained on all subjects. The patients, comprising 15 men and 35 women, were aged between 18 and 65 (mean 45, SD 11). The Hamilton depression score (21 items) on the day of the DST ranged between 19 and 36 points (mean ? SD 25 + 8). Patients were excluded if they were on any drugs known to exert an influence on the DST. The patients included were being treated with orally administered tricyclic antidepressants. Lithium was being given to seven patients. Diagnoses were established on the basis of the ICD-9 glossary. In 28 patients, endogenous depression was diagnosed. Twenty-six had a monopolar (ICD 296.1) and From the Department of Psychiatry (R.R.), University Wibzburg, and the Departments of Psychiatry (A.B., G.B.), Neurosurgery two a bipolar (ICD 296.3) illness. Twenty pa(U.S.), and Internal Medicine (I.P.), University Erlangen-Niimtients were neurotically depressed (ICD 300.4) berg, west Germany. Address reprint requests to Dr. R. Rupprecht, Department of Psy- and two had an adjustment disorder (ICD 309.0 chiatry, University Wiirzburg, Fiichsleinstr. 15, 8700 Wiirzburg, and 309.1). west Germany. Received May 16, 1987; revised August 6, 1987. Blood samples were taken at 7:00 AM and
0 1988 Society of Biological Psychiatry
ooo6-3223/88/$03.50
BIOL PSYCHIATRY 198823531-535
532
Brief Reports
4:00 PM before and after oral administration of 1 mg dexamethasone. The criterion for cortisol nonsuppression was a failure to suppress both postdexamethasone values to below 5 pg/dl. Plasma cortisol was measured by a direct radioimmunoassay (Coming, Medfield, MA). The minimal detectable level was 0.5 FgidI. The intraassay variability was 8% and the interassay variability 9%. Radioimmunoassay for ACTH was performed in our laboratory with an N-terminalspecific antibody using the extraction method with silica gel (Miiller et al. 1978). The minimal detectable concentration for ACTH ranged between 2 and 4 pg/ml; values below 4 pg/ml were defined as undetectable. In the middle range of the standard curve, the intraassay variability was 6.6% and the interassay variability 14.6%; in the lower range (4-10 pglml), the intraassay variability amounted to 15.1% and the interassay va~ability to 19.3%. ~-Endo~hin was determined by a commercial kit (Immune Nuclear Corporation) using pendorphin antibodies coupled to Sepharose for extraction (Krantz and Brown 1985). The minimal detectable concentration was 9.0 pg/ml. The recovery ranged from 91% at lower concentrations (9-20 pg/ml) to 106%. The intraassay variability was 6.0%; the interassay variability was 8.0%. Statistical comparisons were carried out by the Wilcoxon test (two-tailed, paired) and the Mann-Whitney U-test (two-tailed, unpaired). Correlations were established using the methods of Pearson, Spearman, and Kendall. Chi-square analysis, corrected for continuity, was used for testing of contingency tables.
Results The morning basal and both postdexamethasone levels of cortisol (Table I) in patients with endogenous depression were found to be significantly higher than those of patients with nonendogenous depression (p < 0.02, p < 0.001, p < 0.005). However. there was no significant difference in ACTH and ~-endo~hin values (Tables 2 and 3) between these two groups. Cortisol nonsuppressors did not differ from cortisol suppressors with regard to ACTH levels, although cortisol nonsuppressors showed significantly elevated P-endorphin levels after dexamethasone administration (/> < 0.03) (Table 4). There were strongly positive correlations between basal and postdexamethasone levels of cortisol, ACTH, and P-endorphin values (p < 0.05), but no significant correlation couid be found between cortisol, ACTH, or @-endorphin levels and the Hamilton score. Dexamethasone had a pronounced suppressive effect on ACTH and on P-endorphin levels: morning ACTH and P-endorphin values were significantly decreased by 1 mg dexamethasone (p < 0.01) in endogenous and nonendogenous depression, as well as in cortisol nonsuppressors and in cortisol suppressors (17 < 0.01). A comparison of the highest pre- and postdexamethasane ACTH and P-endorphin mean values revealed an ACTH suppression ratio of 36% in endogenous and 3 1% in nonendog~nous depression. The ~~ndo~hin suppression ratio was 56% in endogenous and 45% in nonendogenous depression. These suppression ratios were influenced neither by age nor by sex.
Table 1, Cortisol Mean Values, Standard Deviations
(SD),
and p-Values of Endogenous (n = 28) versus
Nonendogenous (n = 22) Depressives Postdexamethasone
Predexamethasone 7:@ Mean Endogen~us
26.6”
P<
Nonendogenous “&dl.
4%)
AM SD
Mean
5.0
12.9
0.02
22.5
SD
6.4
Mean 6.9
0.4
6.7
11.4
4%)
7:00 AM
PM
sn 7.7
Mean 7.7
O.Gill
5.5
2.4
PM
S[) 6.2
0.05
1.8
3.2
2.5
Brief Reports
BIOL
533
PSYCHIATRY
1988;23:531-535
Table 2. ACTH Mean Values, Standard Deviations (SD), and p-values of Endogenous (n = 28) versus Nonendogenous (n = 22) Depressives and of Cortisol Nonsuppressors(n = 23) versus Suppressors
(n = 27) Postdexamethasone
Predexamethasone 7:00 Endogenous
4:00
AM
7:00 AM Mean
PM
Mean
SD
Mean
SD
29.9”
18.6
15.0
11.1
SD
4:00 Mean
PM SD
10.1
10.1
10.8
9.1
6.0 10.7
2.5 11.2
8.0 11.5
6.5 10.0
6.4
2.3
7.9
5.7
P NS
Nonendogenous Nonsuppressors
25.2 31.4
9.0 20.1
13.5 16.3
8.4 12.2
Suppressors
24.8
8.9
12.7
7.5
P NS
A sufficient specificity, together with an acceptable sensitivity, was obtained using a cutoff of 45% for ACTH and 70% for P-endorphin to distinguish adequate suppression from nonsuppression. According to this “suppression index,” 32% of the patients with endogenous depression (sensitivity) showed “ACTH nonsuppression,” whereas 77% of the nonendogenous depressives (specificity) were able to suppress ACTH sufficiently. Of the patients with endogenous depression, 39% did not suppress P-endorphin to below 70%, but 73% of the nonendogenous depressives met the criterion for “pendorphin suppression.” However, differences in frequency did not reach statistical significance for either ACTH or the P-endorphin “suppression index. ”
Table 3. P-Endorphin versus Nonendogenous Suppressors (n = 27)
Discussion No significant difference was found between ACTH values of cortisol nonsuppressors and suppressors, which is consistent with the results of Yerevanian et al. (1983), but is at variance with the findings of Nasr et al. (1983). Postdexamethasone P-endorphin levels were higher in depressive patients with cortisol nonsuppression, which supports the results of Rish (1982), who found increased P-endorphin concentrations in patients with depression. There were positive correlations among the basal and postdexamethasone values of cortisol, ACTH, and P-endorphin. Similar results were described by Petraglia et al. (1983) and Govoni et al. (1984), but Fang et al. (198 I) reported no significant
Mean Values, Standard Deviations (SD), and p-values of Endogenous (n = 28) (n = 22) Depressives and of Cortisol Nonsuppressors (n = 23) versus Predexamethasone
7:00 Mean Endogenous
40.6”
4:00 Mean
AM SD
24.9
26.3
Postdexamethasone 7:00 Mean
PM SD
14.5
20.3
4:00
AM SD
9.9
PM
Mean
SD
22.8
14.0
P NS
Nonendogenous Nonsuppressors
39.2 47.1
18.9 26.3
suppressors
33.5
15.4
21.8 27.5
9.6 16.0
21.7
8.5
P NS
%w.
17.8 22.2 p < 0.03 16.6
12.2 9.8 11.3
14.9 23.5 p < 0.03 15.6
6.0 14.4 7.5
BIOL PSYCHIATRY 1988;23:531-535
534
Brief Reports
Table 4. Postdexamethasone Corns01 (p.g/dl), ACTH (pg/ml), and P-Endorphin (pg/ml) Mean Values in Endogenous (n = 28) versus Nonendogenous (n = 22) Depressives and in Cortisol Nonsuppressors (n = 23) versus Suppressors (n = 27) Cortisol 7:00 AM Endogenous
P< Nonendogenous Nonsuppressors
P< Suppressors
ACTH 4:00 PM
790
AM
P-Endorphin 4:00 PM
6.9
7.7
10.1
10.8
0.001
0.005
NS
NS
2.4
3.2
6.0
8.0
8.3
9.9
10.7
Il.5
0.001
0.001
NS
NS
2.1
2.1
6.4
1.9
correlation between ACTH and cortisol levels. Dexamethasone had a pronounced suppressive effect on ACTH and B-endorphin in both cortisol suppressors and nonsuppressors, thus supporting the findings of Fang et al. (1981) and Krantz and Brown (1985). The suppression ratio of ACTH and B-endorphin after dexamethasone administration was more marked in nonendogenous than in endogenous depression. However, higher ACTH values were not always associated with higher cortisol levels. Several mechanisms may be involved in the regulation of the hypothalamo-pituitary-adrenal axis in depression: 1. Elevated baseline cortisol has been shown to be associated with a blunted response of ACTH to corticotropin-releasing hormone (CRH) stimulation (Gold et al. 1986; Holsboer et al. 1987). Moreover, an increase in CRH in the cerebral spinal fluid (CSF) of depressed patients has been described by Nemeroff et al. ( 1984), but not by Roy et al. (1987). 2. Glucocorticoid receptors might be diminished in endogenous depression (Gormley et al. 1985), with resultant reduced responsiveness to dexamethasone of various hormone-producing cells. 3. Recent reports of an enhanced elimination of dexamethasone in spite of an unimpaired resorption in cortisol nonsuppressors (Holsboer et al. 1986) suggest that dexamethasone pharmacokinetics might be disturbed in depression.
7:00 AM 20.3
NS
4:00 PM 22.8
NS
17.8
14.9
22.2
23.5
0.003 16.6
0.003 15.6
References Fang VS. Tricou .I, Robertson A, Meltzer HY ( 198 1): Plasma ACTH and cortisol levels in depressed patients: Relation to the Dexamethasone sion Test. Life Sci 29:931-938.
Suppres-
Gold PW, Loriaux DL, Roy A, Kling MA, Calabrese JR, Kellner CH, Nieman LK, Post RM, Pickar D, Gallucci W, Avgerinos P, Paul S, Oldfield EH, Cutler GB, Chrousos GP (1986): Responses to corticotropin-releasing hormone in the hypercortisolism of depression and Cushing’s disease. N Engl .I Med 314:1329-1335. Gormley GJ, Lowy MT, Reder AT, Hospelhom VG. Ante1 JP, Meltzer HY (1985): Glucocorticoid receptors in depression: Relationship to the Dexamethasone Suppression Test. Am J Psychiaty 142:1278-1284. Govoni S, Pasinetti G, Inzoli MR. Rozzini R, Trabucchi M (1984): Correlation between B-endorphin/B-lipotropin-immunoreactivity and cortisol plasma concentrations. Life Sci 35:2549-2552. Holsboer F, Doerr HG, Gerken A, Miiller OA, Sippell WG (1984): Cortisol, 1I-deoxycortisol, and ACTH concentrations after dexamethasone in depressed patients and healthy volunteers. Psychiutry Res I1:15-23. Holsboer F, Wiedemann K, Boll E ( 1986): Shortened dexamethasone half-life time in depressed nonsuppressors. Arch Gen Psyhiurry 43:8 13-8 15. Holsboer F, Gerken A, Stalla GK, Miiller OA ( 1987): Blunted aldosterone and ACTH release after human CRH administration in depressed patients. Am J Psychiatry 144~229-23 I. Krantz DE, Brown WA ( 1985): Dexamethasone suppresses B-endorphin in humans. Psychoneuroendocrinology IO:21 l-2 14. Linkowski P, Cauter E v., Leclerq R, Desmedt D, Brasseur M, Goldstein J, Copinschi G, Mendlew-
Brief Reports
icz J (1985): ACTH, cortisol and growth hormone 24-hour profiles in major depressive illness. Acfa Psychiatr Belg 85:6 15-623. Lypka A, Szczdulik A (1985): Dexamethasone suppresses cortisol but not ACTH and P-endorphin plasma concentrations in healthy man. Horm Metab Res 17547. Milller OA, Fink R, Baur X, Ehbauer M, Madler M, Scriba PC (1978): ACTH im Plasma: Extraktion und Bestimmung, GR’ Labormedizin 2:117-124. Nasr SJ, Rodgers C, Pandey G, Altmann EG, Gaviria FM, Davies JM (1983): ACTH and the Dexamethasone Suppression Test in depression. Biol Psych&y 18:1069-1073. Nemeroff CB, Wider& E, Bisette G, Walleus H, Karlsson I, Eklund K, Kilts CD, Loosen PT, Vale W (1984): Elevated concentrations of CSF COTticotropin-releasing-factor-like immunoreactivity in depressed patients. Science 226: 1342-I 343. Petraglia F, Facchinetti F, Parrini D, Micieii G, Luca SD, Genazzani AR (1983): Simultaneous circadian variation of plasma ACTH, B-lipotropin, Bendorphin and cortisol. Horm Res 17:147-152.
BIOL PSYCHIATRY 1988;23:531-535
535
Pfohl B , Sherman B , Schlechte J , Winokur G ( 1985): Differences in plasma ACTH and cortisol between depressed patients and normal controls. Biol Psychiatry 20:1055-1072. Reus VI, Joseph MS, Dallman MF (1982): ACTH levels after the Dexamethasone Suppression Test in depression. N Engl J Med 306:238-239. Rish SC (1982): B-Endorphin hypersecretion in depression: Possible choiinergic mechanisms. Bio6 Psychiatry 17:1071-1079. Roy A, Gold P, Pickar D, Wolkowitz OM, Chrousos G, Paul SM (1986): Pre- and postdexamethasone ACTH levels in depressed patients and normal controls. J Affect Dis 10:95-99. Roy A, Pickar D, Paul S, Doran A, Chrousos G, Gold PW (1987): CSF corticotropin-releasing hormone in depressed patients and normal control subjects. Am J Psychiatry 144641-645. Yerevanian BI, Woolf PD, Iker HP (1983): Plasma ACTH Ievels in depression before and after recovery: Relationship to the Dexamethasone Suppression Test. Psychiatry Res 10:175-181.
BIOL PSYCHIATRY 1988~23531-535
531
Pre- and Postdexamethasone Plasma ACTH and P-Endorphin Levels in Endogenous and Nonendogenous Depression Rainer Rupprecht, Amd Barocka, Georg Beck, Uwe Schrell, and Josef Pichl
Introduction In connection with the discussions on the utility of the Dexamethasone Suppression Test (DST), adrenocorticotrophic hormone (ACTH) levels in depressive disorder have become an interesting object of research. A number of research groups have reported increased ACTH levels associated with cortisol nonsuppression (Reus et al. 1982; Nasr et al. 1983; Holsboer et al. 1984), whereas others were unable to reproduce these findings (Yerevanian et al. 1983). Though Pfohl et al. ( 1985) and Roy et al. ( 1986) reported elevated concentrations of ACTH in depressive disorder, this was not noted by Fang et al. (1981) and Linkowski et al. (1985). Whether or not ACTH and P-endorphin are sufficiently suppressed by dexamethasone during a DST is still not clear. Fang et al. (1981) and Roy et al. (1986) reported a pronounced reduction in ACTH after dexamethasone administration, whereas Lypka and Szczdulik (1985) found no effect of dexamethasone on ACTH values. A suppressive effect of dexamethasone on P-endorphin was reported by Krantz and Brown (1985), but Lypka and Szczdulik (1985)
were unable to confirm these findings. The present paper attempts to determine whether or not the influence of dexamethasone on ACTH and P-endorphin is differently expressed in endogenous and nonendogenous depression and whether or not it is related to the outcome of the DST.
Methods
Fifty patients with a severe depressive syndrome were examined. To exclude any disease other than depression, clinical chemistry, hematology, and complete physical examination were obtained on all subjects. The patients, comprising 15 men and 35 women, were aged between 18 and 65 (mean 45, SD 11). The Hamilton depression score (21 items) on the day of the DST ranged between 19 and 36 points (mean ? SD 25 + 8). Patients were excluded if they were on any drugs known to exert an influence on the DST. The patients included were being treated with orally administered tricyclic antidepressants. Lithium was being given to seven patients. Diagnoses were established on the basis of the ICD-9 glossary. In 28 patients, endogenous depression was diagnosed. Twenty-six had a monopolar (ICD 296.1) and From the Department of Psychiatry (R.R.), University Wibzburg, and the Departments of Psychiatry (A.B., G.B.), Neurosurgery two a bipolar (ICD 296.3) illness. Twenty pa(U.S.), and Internal Medicine (I.P.), University Erlangen-Niimtients were neurotically depressed (ICD 300.4) berg, west Germany. Address reprint requests to Dr. R. Rupprecht, Department of Psy- and two had an adjustment disorder (ICD 309.0 chiatry, University Wiirzburg, Fiichsleinstr. 15, 8700 Wiirzburg, and 309.1). west Germany. Received May 16, 1987; revised August 6, 1987. Blood samples were taken at 7:00 AM and
0 1988 Society of Biological Psychiatry
ooo6-3223/88/$03.50
BIOL PSYCHIATRY 198823531-535
532
Brief Reports
4:00 PM before and after oral administration of 1 mg dexamethasone. The criterion for cortisol nonsuppression was a failure to suppress both postdexamethasone values to below 5 pg/dl. Plasma cortisol was measured by a direct radioimmunoassay (Coming, Medfield, MA). The minimal detectable level was 0.5 FgidI. The intraassay variability was 8% and the interassay variability 9%. Radioimmunoassay for ACTH was performed in our laboratory with an N-terminalspecific antibody using the extraction method with silica gel (Miiller et al. 1978). The minimal detectable concentration for ACTH ranged between 2 and 4 pg/ml; values below 4 pg/ml were defined as undetectable. In the middle range of the standard curve, the intraassay variability was 6.6% and the interassay variability 14.6%; in the lower range (4-10 pglml), the intraassay variability amounted to 15.1% and the interassay va~ability to 19.3%. ~-Endo~hin was determined by a commercial kit (Immune Nuclear Corporation) using pendorphin antibodies coupled to Sepharose for extraction (Krantz and Brown 1985). The minimal detectable concentration was 9.0 pg/ml. The recovery ranged from 91% at lower concentrations (9-20 pg/ml) to 106%. The intraassay variability was 6.0%; the interassay variability was 8.0%. Statistical comparisons were carried out by the Wilcoxon test (two-tailed, paired) and the Mann-Whitney U-test (two-tailed, unpaired). Correlations were established using the methods of Pearson, Spearman, and Kendall. Chi-square analysis, corrected for continuity, was used for testing of contingency tables.
Results The morning basal and both postdexamethasone levels of cortisol (Table I) in patients with endogenous depression were found to be significantly higher than those of patients with nonendogenous depression (p < 0.02, p < 0.001, p < 0.005). However. there was no significant difference in ACTH and ~-endo~hin values (Tables 2 and 3) between these two groups. Cortisol nonsuppressors did not differ from cortisol suppressors with regard to ACTH levels, although cortisol nonsuppressors showed significantly elevated P-endorphin levels after dexamethasone administration (/> < 0.03) (Table 4). There were strongly positive correlations between basal and postdexamethasone levels of cortisol, ACTH, and P-endorphin values (p < 0.05), but no significant correlation couid be found between cortisol, ACTH, or @-endorphin levels and the Hamilton score. Dexamethasone had a pronounced suppressive effect on ACTH and on P-endorphin levels: morning ACTH and P-endorphin values were significantly decreased by 1 mg dexamethasone (p < 0.01) in endogenous and nonendogenous depression, as well as in cortisol nonsuppressors and in cortisol suppressors (17 < 0.01). A comparison of the highest pre- and postdexamethasane ACTH and P-endorphin mean values revealed an ACTH suppression ratio of 36% in endogenous and 3 1% in nonendog~nous depression. The ~~ndo~hin suppression ratio was 56% in endogenous and 45% in nonendogenous depression. These suppression ratios were influenced neither by age nor by sex.
Table 1, Cortisol Mean Values, Standard Deviations
(SD),
and p-Values of Endogenous (n = 28) versus
Nonendogenous (n = 22) Depressives Postdexamethasone
Predexamethasone 7:@ Mean Endogen~us
26.6”
P<
Nonendogenous “&dl.
4%)
AM SD
Mean
5.0
12.9
0.02
22.5
SD
6.4
Mean 6.9
0.4
6.7
11.4
4%)
7:00 AM
PM
sn 7.7
Mean 7.7
O.Gill
5.5
2.4
PM
S[) 6.2
0.05
1.8
3.2
2.5
Brief Reports
BIOL
533
PSYCHIATRY
1988;23:531-535
Table 2. ACTH Mean Values, Standard Deviations (SD), and p-values of Endogenous (n = 28) versus Nonendogenous (n = 22) Depressives and of Cortisol Nonsuppressors(n = 23) versus Suppressors
(n = 27) Postdexamethasone
Predexamethasone 7:00 Endogenous
4:00
AM
7:00 AM Mean
PM
Mean
SD
Mean
SD
29.9”
18.6
15.0
11.1
SD
4:00 Mean
PM SD
10.1
10.1
10.8
9.1
6.0 10.7
2.5 11.2
8.0 11.5
6.5 10.0
6.4
2.3
7.9
5.7
P NS
Nonendogenous Nonsuppressors
25.2 31.4
9.0 20.1
13.5 16.3
8.4 12.2
Suppressors
24.8
8.9
12.7
7.5
P NS
A sufficient specificity, together with an acceptable sensitivity, was obtained using a cutoff of 45% for ACTH and 70% for P-endorphin to distinguish adequate suppression from nonsuppression. According to this “suppression index,” 32% of the patients with endogenous depression (sensitivity) showed “ACTH nonsuppression,” whereas 77% of the nonendogenous depressives (specificity) were able to suppress ACTH sufficiently. Of the patients with endogenous depression, 39% did not suppress P-endorphin to below 70%, but 73% of the nonendogenous depressives met the criterion for “pendorphin suppression.” However, differences in frequency did not reach statistical significance for either ACTH or the P-endorphin “suppression index. ”
Table 3. P-Endorphin versus Nonendogenous Suppressors (n = 27)
Discussion No significant difference was found between ACTH values of cortisol nonsuppressors and suppressors, which is consistent with the results of Yerevanian et al. (1983), but is at variance with the findings of Nasr et al. (1983). Postdexamethasone P-endorphin levels were higher in depressive patients with cortisol nonsuppression, which supports the results of Rish (1982), who found increased P-endorphin concentrations in patients with depression. There were positive correlations among the basal and postdexamethasone values of cortisol, ACTH, and P-endorphin. Similar results were described by Petraglia et al. (1983) and Govoni et al. (1984), but Fang et al. (198 I) reported no significant
Mean Values, Standard Deviations (SD), and p-values of Endogenous (n = 28) (n = 22) Depressives and of Cortisol Nonsuppressors (n = 23) versus Predexamethasone
7:00 Mean Endogenous
40.6”
4:00 Mean
AM SD
24.9
26.3
Postdexamethasone 7:00 Mean
PM SD
14.5
20.3
4:00
AM SD
9.9
PM
Mean
SD
22.8
14.0
P NS
Nonendogenous Nonsuppressors
39.2 47.1
18.9 26.3
suppressors
33.5
15.4
21.8 27.5
9.6 16.0
21.7
8.5
P NS
%w.
17.8 22.2 p < 0.03 16.6
12.2 9.8 11.3
14.9 23.5 p < 0.03 15.6
6.0 14.4 7.5
BIOL PSYCHIATRY 1988;23:531-535
534
Brief Reports
Table 4. Postdexamethasone Corns01 (p.g/dl), ACTH (pg/ml), and P-Endorphin (pg/ml) Mean Values in Endogenous (n = 28) versus Nonendogenous (n = 22) Depressives and in Cortisol Nonsuppressors (n = 23) versus Suppressors (n = 27) Cortisol 7:00 AM Endogenous
P< Nonendogenous Nonsuppressors
P< Suppressors
ACTH 4:00 PM
790
AM
P-Endorphin 4:00 PM
6.9
7.7
10.1
10.8
0.001
0.005
NS
NS
2.4
3.2
6.0
8.0
8.3
9.9
10.7
Il.5
0.001
0.001
NS
NS
2.1
2.1
6.4
1.9
correlation between ACTH and cortisol levels. Dexamethasone had a pronounced suppressive effect on ACTH and B-endorphin in both cortisol suppressors and nonsuppressors, thus supporting the findings of Fang et al. (1981) and Krantz and Brown (1985). The suppression ratio of ACTH and B-endorphin after dexamethasone administration was more marked in nonendogenous than in endogenous depression. However, higher ACTH values were not always associated with higher cortisol levels. Several mechanisms may be involved in the regulation of the hypothalamo-pituitary-adrenal axis in depression: 1. Elevated baseline cortisol has been shown to be associated with a blunted response of ACTH to corticotropin-releasing hormone (CRH) stimulation (Gold et al. 1986; Holsboer et al. 1987). Moreover, an increase in CRH in the cerebral spinal fluid (CSF) of depressed patients has been described by Nemeroff et al. ( 1984), but not by Roy et al. (1987). 2. Glucocorticoid receptors might be diminished in endogenous depression (Gormley et al. 1985), with resultant reduced responsiveness to dexamethasone of various hormone-producing cells. 3. Recent reports of an enhanced elimination of dexamethasone in spite of an unimpaired resorption in cortisol nonsuppressors (Holsboer et al. 1986) suggest that dexamethasone pharmacokinetics might be disturbed in depression.
7:00 AM 20.3
NS
4:00 PM 22.8
NS
17.8
14.9
22.2
23.5
0.003 16.6
0.003 15.6
References Fang VS. Tricou .I, Robertson A, Meltzer HY ( 198 1): Plasma ACTH and cortisol levels in depressed patients: Relation to the Dexamethasone sion Test. Life Sci 29:931-938.
Suppres-
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