Original article| Volume 37, ISSUE 6, P355-363, March 15, 1995

Evidence against changes in corticotroph CRF receptors in depressed patients

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      Previous studies by a number have investigators have documented a decreased adrenocortotropic hormone (ACTH) and β-lipotropin/β-endorphin (β-End) response to ovine corticotropin-releasing factor (oCRF) in depressed patients. Since depressed patients demonstrate higher plasma cortisol concentrations at the time of oCRF challenge, it is difficult to determine if the decreased ACTH response is due to enhanced negative feedback of cortisol on ACTH release or an alteration in CRF receptors in depressed patients. To evaluate the response to oCRF in an “open feedback loop” system, we administered metyrapone 750 mg at 4 pm and 7:30 pm, followed by administration of oCRF 0.3 μg/kg at 8 pm in 10 normal controls and 10 depressed patients. Administration of metyrapone at this time in the circadian rhythm clamped plasma cortisol concentrations to less than 2 μg/dl but did not result in rebound ACTH or β-End secretion in control subjects. In control subjects, metyrapone administration produced a 85% blockade of the cortisol response as well as a 3-fold greater β-End response compared to administration of the same dose of oCRF without metyrapone. The 10 depressed patients and their matched controls demonstrated identical β-End responses (integrated response for controls = 291 ± 61, for patients = 352 ± 86) and cortisol responses (integrated response for controls = 187 ± 38, for patients = 206 ± 52) to oCRF following metyrapone pretreatment. These data confirm that corticotroph CRF receptors are normal in depressed patients, and that cortisol feedback plays an essential role in the abnormal ACTH and β-End response to oCRF in depressed patients.

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        • Amsterdam JC
        • Winokur A
        • Abelman E
        • Lucki I
        • Richels K
        Co-syntropin (ACTH a1–24) stimulation test in depressed patients and healthy subjects.
        Am J Psychiatry. 1983; 140: 907-909
        • Amsterdam JD
        • Maislin G
        • Winokur A
        • Kling M
        • Gold P
        Pituitary and adrenocortical responses to ovine corticotropin releasing hormone in depressed patients and healthy volunteers.
        Arch Gen Psychiatry. 1987; 44: 775-781
        • Amsterdam JD
        • Winokur A
        • Caroff SN
        • Conn J
        The dexamethasone suppression test in outpatients with primary affective disorder and healthy control subjects.
        Am J Psychiatry. 1982; 139: 287-291
        • Cahill CA
        • Matthews JD
        • Akil H
        Human plasma betaendorphin-like peptides: A rapid high recovery extraction technique and validation of radioimmunoassay.
        J Clin Endocrinol Metab. 1983; 56: 992-997
        • Carroll B
        • Feinberg M
        • Greden JF
        • et al.
        A specific laboratory test for the diagnosis of melancholia: Standardization, validation, and clinical utility.
        Arch Gen Psychiatry. 1981; 38: 15-22
        • Carroll BJ
        • Curtis GC
        • Mendels J
        Neuroendocrine regulation in depression I. Limbic system-adrenocortical dysfunction.
        Arch Gen Psychiatry. 1976; 33: 1039-1044
        • Carroll BJ
        • Curtis GC
        • Mendels J
        Neuroendocrine regulation in depression: II. Discrimination of depressed from non-depressed patients.
        Arch Gen Psychiatry. 1976; 33: 1051-1058
        • Gold PW
        • Loriaux DL
        • Roy A
        • et al.
        Response to corticotropin-releasing hormone in the hypercortisolism of depression and Cushing's disease.
        N Engl J Med. 1986; 314: 1329-1335
        • Halbreich U
        • Asnis GM
        • Schindledecker R
        • Zurnoff B
        • Nathan RS
        Cortisol secretion in endogenous depression I. Basal plasma levels.
        Arch Gen Psychiatry. 1985; 42: 909-914
        • Hermes A
        • Pieters G
        • Smals A
        • Benraad T
        • Kloppenberg P
        Plasma adrenocorticotropin, cortisol and aldosterone responses to corticotropin releasing factor: modulating effects of basal cortisol levels.
        J Clin Endocrinol Metabol. 1984; 58: 187-190
        • Heuser I
        • Yassouridis A
        • Holsboer-Trachsler E
        • Gotthardt U
        • Holsboer F
        The combined dexamethasone-CRH test in affective disorders: Methodological issues.
        J Psychiatr Res. 1993; (in press)
        • Holsboer F
        • Bardeleden U
        • Gerken A
        • Stalla G
        • Muller O
        Blunted corticotropin and normal cortisol response to human corticotropin-releasing factor in depression.
        N Engl J Med. 1984; 311: 1127
        • Holsboer F
        • Doerr HG
        • Gerken A
        • Muller OA
        • Sippell WG
        Cortisol, 11-deoxycortisol, and ACTH concentrations after dexamethasone in depressed patients and healthy volunteers.
        Psychiatry Res. 1983; 11: 15-23
        • Jaeckle RS
        • Kathol RG
        • Lopez JF
        • Meller WH
        • Krummel SJ
        Enhanced adrenal sensitivity to exogenous ACTH1–24 stimulation in major depression; relationship to dexamethasone suppression test results.
        Arch Gen Psychiatry. 1987; 44: 233-240
        • Kalin NH
        • Weiler SJ
        • Shelton SE
        Plasma ACTH and cortisol concentrations before and after dexamethasone.
        Psychiatry Res. 1982; 7: 87-92
        • Lisansky J
        • Peake GT
        • Strassman RJ
        • et al.
        Augmented pituitary corticotropin response to a threshold dose of human corticotropin releasing hormone in depressives pretreated with metyrapone.
        Arch Gen Psychiatry. 1989; 46: 641-649
        • Lopez JF
        • Palkovits M
        • Arato M
        • Mansour A
        • Akil H
        • Watson SJ
        Localization and quantitation of pro poiomelancortin mRNA and glucocorticoid receptor mRNA in pituitaries in suicide victims.
        Neuroendocrinology. 1992; 56: 491-501
        • Morris H
        • Carr V
        • Gilliland J
        • Hooper M
        Dexamethasone concentrations and the dexamethasone suppression test in psychiatric disorders.
        Br J Psych. 1986; 148: 66-69
        • Nemeroff CB
        The role of corticotropin-releasing hormone in the pathogenesis of major depression.
        Pharmacopsychiatry. 1988; 21: 76-82
        • Pfohl B
        • Sherman B
        • Schlecter J
        • Stone R
        Pituitary/adrenal axis rhythm disturbances in psychiatric patients.
        Arch Gen Psychiatry. 1985; 42: 897-903
        • Reus VI
        • Joseph MS
        • Dallman MF
        Regulation of ACTH and cortisol in depression.
        Peptides. 1983; 4: 785-788
        • Rubin RT
        • Poland RE
        • Lesser IM
        • Winston RA
        • Blodgett N
        Neuroendocrine aspects of primary endogenous depression I. Cortisol secretory dynamics in patients and matched controls.
        Arch Gen Psychiatry. 1987; 44: 328-336
        • Sachar EJ
        • Hellman L
        • Roffwarg HP
        • Halpern FS
        • Fukush DK
        • Gallagher TF
        Disrupted 24 hour patterns of cortisol secretion in psychotic depressives.
        Arch Gen Psychiatry. 1973; 28: 19-24
        • Stokes PE
        • Stoll PM
        • Koslow SH
        • et al.
        Pretreatment DST and hypothalamic-pituitary-adrenocortical function in depressed patients and comparison groups: A multicenter study.
        Arch Gen Psychiatry. 1984; 41: 257-267
        • Vale W
        • Spiess J
        • Rivier J
        • Rivier C
        Characterizations of a 41-residue ovine hypothalamic peptide that stimulates secretions of corticotropin and beta-endorphin.
        Science. 1981; 213: 1394-1397
        • von Bardeleben U
        • Holsboer F
        Cortisol response to a combined dexamethasone hCRH challenge in patients with depression.
        J Neuroendocrinol. 1989; 1: 485-488
        • von Bardeleben U
        • Stalla GK
        • Mueller OA
        • Holsboer F
        Blunting of ACTH response to CRH in depressed patients is avoided by metyrapone pretreatment.
        Biol Psychiatry. 1988; 24: 782-786
        • Wynn PC
        • Harwood JP
        • Catt KJ
        • Aguilera G
        Regulation of corticotropin-releasing factor receptors in the rat pituitary gland.
        Endocrinology. 1985; 116: 1653-1659
        • Young EA
        • Akil H
        Corticotropin-releasing factor stimulation of adrenocorticotropin and beta-endorphin release: Effects of acute and chronic stress.
        Endocrinology. 1985; 117: 23-30
        • Young EA
        • Watson SJ
        • Kotun J
        • et al.
        β-lipotropin-β-endorphin response to low dose ovine corticotropin releasing factor in endogenous depression.
        Arch Gen Psychiatry. 1990; 47: 449-457
        • Young EA
        • Haskett RF
        • Watson SJ
        • Akil H
        Loss of glucocorticoid fast feedback in depression.
        Arch Gen Psychiatry. 1991; 48: 693-699
        • Young EA
        • Akil H
        Paradoxical effect of corticosteroids on pituitary ACTH/β-endorphin release in stressed animals.
        Psychoneuroendocrinology. 1988; 13: 317-320