Psychological Medicine, 1992, 22, 317-329 Printed in Great Britain

Adrenocorticotropin hormone, /?-endorphin and cortisol responses to oCRF in melancholic patients M. MAES,1 M. CLAES, M. VANDEWOUDE, C. SCHOTTE, M. MARTIN, P. BLOCKX AND P. COSYNS From the Department of Psychiatry, Department of Internal Medicine, and Department of Nuclear Medicine, University Hospital of Antwerp, Belgium

Several authors have reported attenuated adrenocorticotropin hormone (ACTH) responses to corticotropin releasing factor (CRF) administration in melancholic patients as compared with healthy controls. In order to explore the integrity of the hypothalamicpituitary-adrenal (HPA)-axis in melancholies, we examined the following parameters in 98 subjects: the ACTH; /?-endorphin; and cortisol responses to ovine CRF (oCRF) (100/ 3-5 fig/d\: sensitivity = F= 7-4, df = 1/76, P = 0.008, ANOVA). 57%, specificity = 8 3 % , PV+ = 77%, kappa The post-dexamethasone cortisol values were = 0-39, / = 1-95, P = 005, Y = 0-43). significantly related to the following SCIDWe found no significant relationships between items: anorexia-weight loss {r = 0-37, P = the DST results and the oCRF-induced hormone 0-001), sleep disorders (r = 0-32, P = 0-004), a responses as shown by: (1) an absence of distinct quality of depressed mood (r = 0-30, significant correlations between the post- p = 0-008), early morning wakening (r = 0-35, dexamethasone cortisol values and the oCRF- P = 0-002) and non-reactivity (r = 0-37, P = induced hormone responses; (2) no significant 0001) (all point-biserial correlation coefficients). differences in post-dexamethasone cortisol Up to 22% of the variance in the postvalues between depressed patients with and dexamethasone cortisol values could be exwithout disordered ACTH response (cut-off plained by the multiple regression on anorexiavalue ^ 15 pg/ml); and (3) no dependency be- weight loss and non-reactivity (F = 10, df = tween subjects with a disturbed DST (i.e. post- 2/75, P = 00002). The post-dexamethasone dexamethasone ^ 3-5/tg/dl; Maes et al. 1989) cortisol values and the HDRS-score were sigand abnormal oCRF-test (results of contingency nificantly and positively correlated (r = 0-30, analysis: / = 0-38, P = 0-54). P = 0007). We found that a combination of the DST and the oCRF-test (i.e. delta ACTH values) in a DISCUSSION LDA-score performed better in discriminating melancholic from minor depressives than any CRF-induced hormone responses and DSM-III one of these variables alone (area under the classification Our melancholic patients showed a significantly ROC curve = 88 %).

plasma cortisol (F = 59, df = 2/86, P < 0-0001), while 17% of the variance in the ACTH responsivity was explained by the diagnostic classification and baseline cortisol (F = 4-4, df = 4/84, P = 0-003).

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blunted ACTH response to oCRF administration, as opposed to healthy controls and minor depressives, while simple major depressives occupied an intermediate position. These data are in agreement with the findings of Gold et al. (1986, 1987), Holsboer et al. (19846, 1988) and Lesch et al. (1988) who found significantly attenuated CRF-induced ACTH responses in severely depressed patients as compared with normal controls. Like Gold et al. (1986, 1987), Holsboer et al. (19846, 1988) and Lesch et al. (1988) we found no differences in the oCRF-stimulated cortisol responses between the study samples. We noted that, despite the blunted ACTH responses to oCRF administration, melancholic patients exhibited a robust /?-endorphin response comparable to normal controls, minor and simple major depressives. Thisfindingconcurs with the study of Rupprecht et al. (1989). We established that the delta ACTH responses were of some use in confirming the clinical diagnosis of melancholia and distinguishing that illness from the healthy and minor depressed states. A delta ACTH value of ^ 15 pg/ml performed best for this purpose. This indicates that within the depressed population an attenuated ACTH response to oCRF tends to be specific for melancholia. We established that feelings of guilt and worthlessness are the psychopathological correlates of the blunted ACTH responses. This finding is rather surprising since other biological markers of depression (e.g. DST, thyreotropin releasing hormone test, availability of L-tryptophan) were not related to these symptoms, but rather to psychomotor disorders, non-reactivity, anhedonia and vegetative symptoms (Maes et al. 1991a). We found no change with age in the ACTH, /?-endorphin, and cortisol responses to oCRF. Thesefindingscorroborate those of Ohashi et al. (1986), and Pavlov et al. (1986), who concluded that presumably pituitary sensitivity to hypothalamic CRF does not change with increasing age. Relationships between ACTH and cortisol responses

An important part of the variability in the oCRF-induced cortisol responses was determined by the ACTH responses and by the baseline plasma cortisol secretion. A close

association between the integrated ACTH and cortisol responses was also reported to occur in depression by Lesch et al. (1988) but not by Amsterdam et al. (1988). Also, in patients with Cushing's syndrome the pattern of cortisol secretion after CRF corresponded to that of ACTH secretion (Muller et al. 1986). Like Gold et al. (1986), we noted that melancholies show a proportionally higher cortisol response in relation to the attenuated ACTH responses. However, the statements of Gold et al. (1988 a) and Holsboer et al. (1988) that normal cortisol but decreased ACTH responses to CRF in depression indicate an enhanced adrenocortical cell sensitivity to ACTH are, in our opinion, limited. The above mentioned observation may be attributed to several other mechanisms despite its compatibility with the development of adrenal cortex hyperresponsivity caused by a prolonged ACTH secretion during depression (Amsterdam et al. 1983, 1986). Other peptides secreted by CRF are known to affect the adrenal function, e.g. the potentially ACTH synergistic a-MSH (Calogero et al. 1988; Coates et al. 1988; Henville et al. 1989). It is possible that small increments in ACTH levels induced by CRF were sufficient to induce nearly maximal adrenocortical activation. In this respect, Oelkers et al. (1988) found that low plasma ACTH levels stimulated cortisol to almost 80 % of the maximal increment obtained with 6-fold higher ACTH levels. Moreover, CRF may be able to stimulate directly cortisol release even in the absence of pituitary ACTH (Fehm et al. 1988). Finally, CRF may increase the adrenocortical responsiveness to ACTH (De-Souza & Van Loon, 1984). Relationships between ACTH responses and baseline cortisol

Only a smaller part (approximately 22 %) of the variance in the ACTH responses to oCRF could be attributed to the cumulative effects of the depressive state (i.e. feelings of guilt) and basal plasma cortisol. Like Gold et al. (1986, 1987), we found a significant negative correlation between the baseline plasma cortisol levels prior to oCRF-testing and the ACTH responses. Lesch et al. (1988), on the other hand, found no significant relationship between the two factors. In addition, in normal controls, but not in patients with Cushing's disease, inverse correlations between basal cortisol levels and

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ACTH responses were observed (Hermus et al. 1986 a). Gold et al. (1986) and Holsboer et al. (1988) have suggested that the pituitary corticotropic cell function of depressed patients responds appropriately to the negative feedback by glucocorticoids, whereas Cushing's disease patients exhibit a gross impairment in the negative feedback. They concluded that the 'normal' functioning of the ACTH-secreting cells, the presumed integrity of the glucocorticoid negative feedback, and the disordered CRF tests indicate a suprapituitary abnormality. The following arguments underline some of the inaccuracies in those statements. First, melancholia is characterized by an augmented ACTH//?-endorphin escape from dexamethansone suppression, which reflects abnormalities in corticotropic cell feedback inhibition (Maes et al. 1990 a, b). Secondly, Familari & Funder (1989) observed that the rapid inhibitory effects of glucocorticoids on ACTH release in response to CRF do not occur at the level of the pituitary, but rather on the hypothalamus or higher centres. Thirdly, our pathway analysis has shown that the depressive state and basal cortisol act cumulatively and independently from each other, predisposing towards a blunted oCRF test. This may suggest that the physiological, inhibitory effects of the circulating plasma cortisol levels on oCRF-induced ACTH responses take place independently from the suppressive effects of the depressive state. Furthermore, it should be noted that the melancholic patients in our study do not reveal increased plasma cortisol values. Fourthly, when dexamethasone and CRF are administered to depressed subjects they still show a sizeable ACTH response to CRF, whereas normal controls do not (Holsboer et al. 1988). These findings may thus suggest that the HPA-axis responds adequately to the rapid (within minutes) negative feedback actions of glucocorticoids, but that another mechanism linked to the depressive state - determines the reduction in the readily releasable ACTH pool to oCRF administration. Underlying pathophysiology of blunted ACTH responses

The phenomenon of a reduced, readily releasable ACTH pool in melancholic patients may be explained by the various effects of glucocorticoids on the corticotropic cells. Beside a

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fast blockade of POMC-peptides within minutes, glucocorticoids also exert intermediate and delayed (one to several hours) negative feedback effects on the amount of POMC-peptides available for release (Eberwine et al. 1987; Schurmeyer et al. 1987; Calogero et al. 1988). Consequently, the increased 24 h cortisol secretion - recurrent in melancholia (Carroll et al. 1976; Stokes et al. 1984; Maes et al. 1990 c ) may result in enhanced intermediate/delayed inhibitory effects upon the pituitary corticotropic cell secretion. Glucocorticoids inhibit POMC gene transcription and post-translational processing of peptides; they desensitize the CRF receptors and inhibit peptide release (cAMP production) from the corticotropic cell (Jingami et al. 1985; Eberwine et al. 1987; Drouin et al. 1987; Liposits et al. 1987). An endogenous central CRF hypersecretion occurs during melancholia (Nemeroff et al. 1984; Banki et al. 1987; Lowy et al. 1987; Roy et al. 1987). This supports the notion that a primary CRF hypersecretion may underlie depressive hypercortisolism (Sapolsky & McEwen, 1988). Initially, CRF hypersecretion may enhance the stimulation of the POMC gene transcription, resulting in an increased POMC peptide secretion (Vale et al. 1983; Schopohl et al. 1986; Sato & Mains, 1986; Stalla et al. 1986 a, b; Reisine & Affotter, 1987). The induced increments in ACTH (ultra-short feedback) and, consequently, in cortisol secretion could, in turn, restrain the corticotropic cells through a progressive decrease in CRF receptors, mRNA coding for POMC, and peptide release (cAMP production). These alterations in the stimulatory (CRF hypersecretion) and inhibitory (negative feedback) mechanisms may upset the corticotropic cells which partly mediate the physiological balance between those forces. This disruption could lead to a decreased, readily releasable ACTH pituitary pool. This, in turn, may induce a down-regulation of the circulating peripheral ACTH and cortisol levels to quasi-normal or slightly elevated levels. Thus the disordered CRF test in melancholies may reflect an alteration in the setpoint of the corticotropic cells which modulate between these stimulatory and inhibitory forces. In other terms, the corticotropic cell is presumably caught in a balance between the hypothalamic CRF overdrive and

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the intermediate/delayed negative feedback effects of glucocorticoids. Relationships between ACTH and /?-endorphin responses

In the present study we have reported on a close relationship between the ACTH and /?-endorphin responses to oCRF. These findings corroborate those of Jackson et al. (1984), McLoughlin et al. (1984) and Young et al. (1986) who found that the molar concentrations of these peptides were in close parallel to one another after CRF administration. However, our /?-endorphin assay displays a considerable cross-reactivity with /?-lipotropin (16%) and the sensitivity is not great. Therefore the apparent association between ACTH and /?-endorphin secretion may be an artefact of the assay used. Like Rupprecht et al. (1989) we observed that melancholic patients exhibit a proportionally lowered ACTH secretion in relation to the CRF-induced /?-endorphin responses. These findings may, at first sight, contradict our hypothesis as to the existence of a lowered, releasable POMC-peptide pool in the pituitary of depressive patients. Indeed, these different ACTH//?-endorphin responses could point to a defect at the level of the post-translational cleavage, e.g. in the prohormone-cleaving enzymes. However, after stress or longstanding CRF-stimulation, a different pattern of CRFinduced secreted peptides was observed, whereby a selective enhanced secretion of /?-endorphin emerged (Ham & Smyth, 1986; Young et al. 1986). Subsequently, CRF hypersecretion could induce: (1) a primary ACTH/cortisol overdrive, which, in turn, could restrain the corticotropic cell function; and (2) a change in the pattern of secreted peptides with a selective enhancement of /?-endorphin. This could explain the dissociation of/?-endorphin with ACTH secretion.

FIG. 5. Percentages of disordered oCRF and DST tescs in the melancholic patients.

to constitute related phenomena (Hermus et al. 1986 a). We have established that the diagnostic power of each test is enhanced when both the DST and oCRF test results are combined. Up to 56-4 % of the melancholies exhibited a disordered DST; this is in accordance with the established sensitivity of the DST (Carroll et al. 1981; Maes et al. 1986, 1989). Up to 60-8% of our melancholic patients showed a disordered oCRF test, whereas a disorder in both tests occurred in 304% of the patients; in total, 90% of our melancholies had a disorder in one of these probes (Fig. 5). A comparable phenomenon was seen in Cushing's syndrome: the highest discriminant score in the differential diagnosis of this illness was obtained by combining both tests (Hermus et al. 19866; Nieman et al. 1986; Grossman et al. 1988). We found that distinct pathophysiological and pathopsychological factors underlie both DST and CRF tests. The post-dexamethasone cortisol values were shown to be significantly and positively related to age (Stangl et al. 1986; Maes et al. 1990 c), to the severity of illness (this Relationship with the DST study, Feinberg & Carroll, 1984; Maes et al. Like Lesch et al. (1988) we found no significant 1986) and to 8 a.m. basal plasma cortisol (Maes relationships between the results of the DST and et al. \990d). The CRF-induced ACTH reCRF test. Holsboer et al. (19846), on the other sponses, on the other hand, were not related to hand, found a moderate trend towards a positive age (see first paragraph of this discussion), or to correlation between CRF-induced ACTH re- the overall severity of illness (this study; Lesch sponses and the 4 p.m. post-dexamethasone et al. 1988), whereas negative correlations were cortisol values. In Cushing's disease the lack of established with basal plasma cortisol (see third cortisol suppressibility by dexamethasone, com- paragraph of this discussion). Moreover, vital bined with ACTH responsivity to CRF, appear symptoms such as anorexia, sleep disorders, a

HPA-axis activity in melancholic patients

distinct quality of mood and non-reactivity were the psychopathological correlates of a disordered DST (this study; Maes et al. 1990a), whereas feelings of guilt correlated with the blunted ACTH responses (see first paragraph of this discussion). The pathological cortisol escape from suppression by dexamethasone is thought to reflect an augmented escape of POMC-peptides secretion, and this, in turn, may reflect various pathophysiological mechanisms, i.e. (1) increased 24 h cortisol secretion, inducing a down regulation in pituitary glucocorticoid receptors and, subsequently, escape from dexamethasone suppression (Owens & Nemeroff, 1988; Sapolsky & McEwen, 1988); and (2) a POMC-peptide related breakthrough secretion driven by an increased (serotonin/noradrenaline-linked) CRF-secretion (Maes et al. 1990e). Although these mechanisms differ from the hypothesized disorders underlying the blunted ACTH responses to oCRF (see third paragraph of this discussion), both tests may have a common denominator, i.e. the increased endogenous CRF secretion. This hypersecretion could thus induce via an increased peripheral cortisol production rate, divergent disorders in the corticotropic cell. These distinct abnormalities which reside in the corticotropic cells may be detected by DST and CRF testing, while the measurements of the peripheral HPA-axis hormones may be normalized at the time of blood sampling through an ACTH downregulation in the corticotropic cells. Like Gold et al. (1988 a, b), we may conclude that the corticotropic cell is caught in balance between hypothalamic CRF overdrive on the one hand, and inhibitory effects by ultra-short ACTH and intermediate/delayed glucocorticoid feedback actions on the other. Conclusion

Melancholia appears to be characterized by two distinct corticotropic cell disorders: (1) there is a decreased, releasable pituitary ACTH pool after administration of oCRF; this phenomenon may be explained by dynamic shifts in the balance between stimulatory (increased CRF) and inhibitory (increased adrenocortical secretion) influences; (2) there is an increased corticotropic cell peptide escape from suppression by dexamethasone (this phenomenon may be the result of a breakthrough peptide secretion driven by

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CRF hyperactivity and by a glucocorticoid receptor desensitization caused by an enhanced cortisol secretion). The authors would like to thank UCB (Belgium) for financial support, UCB-Bioproducts (Belgium) for providing ovine-CRF and Mrs M. Maes for secretarial support.

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Adrenocorticotropin hormone, beta-endorphin and cortisol responses to oCRF in melancholic patients.

Several authors have reported attenuated adrenocorticotropin hormone (ACTH) responses to corticotropin releasing factor (CRF) administration in melanc...
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