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Glucocorticoids and the Genesis of Depressive Illness a Psychobiological Model

Published online by Cambridge University Press:  02 January 2018

Timothy G. Dinan
Timothy G. Dinan*
Affiliation:
St Bartholomew's Hospital, London EC1A 7BE
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Abstract

Abnormalities in the hypothalamic–pituitary–adrenal axis (HPA) have been the most consistently demonstrated biological markers in depressive illness. Numerous other neuroendocrine disturbances have also been described, including blunted clonidine-induced growth hormone release and blunted fenfluramine-induced prolactin release. These disturbances are generally interpreted in terms of monoaminergic receptor dysfunction. The theory presented here suggests that chronic stress which activates the HPA will in certain susceptible people produce changes in central monoamines. The high level of glucocorticoid receptors on such central neurons is postulated as mediating the alterations. Thus monoamine abnormalities, rather than being a core aetiological feature of depression, are seen as secondary to HPA overdrive.

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Peer Review
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The British Journal of Psychiatry , Volume 164 , Issue 3 , March 1994 , pp. 365 - 371
Copyright
Copyright © 1994 The Royal College of Psychiatrists 

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References

American Psychiatric Association Task Force (1987) The dexamethasone suppression test: An overview of its current status in psychiatry. American Journal of Psychiatry, 144, 1253–1262.CrossRefGoogle Scholar
Axelrod, J. & Reisine, T. D. (1984) Stress hormones: their interaction and regulation. Science, 224, 452–459.CrossRefGoogle ScholarPubMed
Beaumont, K. & Fanestil, D. D. (1983) Characterization of rat brain aldosterone receptors reveals high affinity for corticosterone. Endocrinology, 113, 2043–2051.CrossRefGoogle ScholarPubMed
Bondy, P. K. (1985) Disorders of the adrenal cortex. In Williams Textbook of Endocrinology (eds J. D. Wilson & D. W. Foster), pp. 816–890. London: Saunders.Google Scholar
Borrell, J. De Kloet, E. R. & Bohus, B. (1984) Corticosterone decreases the efficacy of adrenaline to affect passive avoidance retention of adrenalectomized rats. Life Sciences, 34, 99–104.CrossRefGoogle ScholarPubMed
Brady, L. S., Whitfield, H. J., Fox, R., et al (1991) Long term antidepressant administration alters corticotropin-releasing hormone, tyrosine hydroxylase and mineralocorticoid receptor gene expression in the rat. Journal of Clinical Investigation, 87, 831–837.CrossRefGoogle Scholar
Brown, G. W., Bhrolchain, M. N. & Harris, T. (1975) Social class and psychiatric disturbance among women in an urban population. Sociology, 9, 225–241.CrossRefGoogle Scholar
Brown, M. R., Fisher, L. A. & Spiess, J. (1982) Corticotropin-releasing factor: actions on the sympathetic nervous system and metabolism. Endocrinology, 111, 928–931.CrossRefGoogle ScholarPubMed
Carlsson, A. (1977). The influence of antidepressants on central monoamine systems. In Neurotransmission and Disturbed Behaviour (eds H. van Praag and J. Bruinvels), pp. 95–108. Utrecht: Bohn Scheltema and Holkena.Google Scholar
Carroll, B. J. (1982) The dexamethasone suppression test for melancholia. British Journal of Psychiatry, 140, 292–304.CrossRefGoogle ScholarPubMed
Carroll, B. J. & Haskett, R. F. (1985) The DST in newly hospitalized patients. American Journal of Psychiatry, 143, 999–1000.CrossRefGoogle Scholar
Checkley, S. A. (1992) Neuroendocrine mechanisms and the precipitation of depression by life events. British Journal of Psychiatry, 160 (Suppl. 15), 7–17.CrossRefGoogle Scholar
Cohen, S. I. (1980) Cushing's syndrome: a psychiatric study of 29 patients. British Journal of Psychiatry, 136, 120–124.CrossRefGoogle ScholarPubMed
Coppen, A., Abou-Saleh, M., Milln, P., et al (1983) Dexamethasone suppression test in depression and other psychiatric illness. British Journal of Psychiatry, 142, 498–504.CrossRefGoogle ScholarPubMed
Cowen, P. J. & Charig, E. M. (1987) Neuroendocrine responses to intravenous tryptophan in major depression. Archives of General Psychiatry, 44, 958–966.CrossRefGoogle ScholarPubMed
Cushing, H. (1913) Psychic disturbances associated with disorders of the ductless glands. American Journal of Insanity, 69, 965–990.Google Scholar
Cushing, H. (1932) The basophil adenomas of the pituitary body and their clinical manifestations (pituitary basophilism). Bulletin of the Johns Hopkins Hospital, 50, 137–195.Google Scholar
Deakin, J. F. W., Pennell, I., Upadhyaya, A. J. & Lofthouse, R. (1990) A neuroendocrine study of 5HT function in depression: evidence for psychosocial causation. Psychopharmacology, 101, 85–92.CrossRefGoogle ScholarPubMed
De Kloet, E. R. & Reul, J. M. H. (1987) Feedback action and tonic influence of corticosteroids on brain function: a concept arising from the heterogeneity of brain receptor systems. Psychoneuroendocrinology, 12, 83–105.CrossRefGoogle ScholarPubMed
De Kloet, E. R., Kovacs, G. L., Szabo, G., et al (1982) Decreased serotonin turnover in the dorsal hippocampus of rat brain shortly after adrenalectomy: Selective normalization after corticosterone substitution. Brain Research, 239, 659–663.CrossRefGoogle ScholarPubMed
De Kloet, E. R., Sybesma, H. & Reul, J. M. H. M. (1986) Selective control by corticosterone of serotonin-1 receptor capacity in raphehippocampal system. Neuroendocrinology, 42, 513–521.CrossRefGoogle Scholar
Dinan, T. G. & Barry, S. (1990) Responses of growth hormone to desipramine in endogenous and non-endogenous depression. British Journal of Psychiatry, 156, 680–684.CrossRefGoogle ScholarPubMed
Dornhorst, A., Carlson, A. & Seif, S. M. (1981) Control of release of adrenocorticotropin and vasopressin by the supraoptic and paraventricular nuclei. Endocrinology, 108, 1420–1424.CrossRefGoogle ScholarPubMed
Duval, F., Macher, J. P. & Mokrani, M. C. (1990) Difference between evening and morning thyrotropin responses to protirelin in major depressive episode. Archives of General Psychiatry, 47, 443–448.CrossRefGoogle ScholarPubMed
Eipper, B. & Mains, R. (1980) Structure and function of proadrenocorticotropin/endorphin and related peptides. Endocrine Reviews, 1, 247–262.CrossRefGoogle Scholar
Evans, D. L. & Golden, R. N. (1987) The dexamethasone suppression test: A review. In Handbook of Clinical Psychoneuroendocrinology (eds C. B. Nemeroff & P. T. Loosen), pp. 220–235. New York: Guilford Press.Google Scholar
Fuxe, K., Wikstrom, A. C. & Okret, S. (1985) Mapping of glucocorticoid receptor immunoreactive neurons in the rat tel- and diencephalon using a monoclonal antibody against rat liver glucocorticoid receptor. Endocrinology, 117, 1803–1812.CrossRefGoogle ScholarPubMed
Gerner, R. & Gwirtsman, H. (1981) Abnormalities of dexamethasone suppression test and urinary MHPG in anorexia nervosa. American Journal of Psychiatry, 138, 650–655.Google ScholarPubMed
Gershon, E. (1983) The genetics of affective disorders. In Psychiatry Update, Vol. 2 (ed. Grinspoon, L.), pp. 105–125. Washington: APA.Google Scholar
Gillin, J. C., Jacobs, L. S., et al (1972) Acute effect of glucocorticoid on normal human sleep. Nature, 237, 398–399.CrossRefGoogle ScholarPubMed
Giustina, A., Girelli, A., Doga, M., et al (1990) Pyridostigmine blocks the inhibitory effect of glucocorticoids on growth hormone releasing hormone secretion in normal man. Journal of Clinical Endocrinology and Metabolism, 71, 580–584.CrossRefGoogle ScholarPubMed
Gold, P., Kling, M. A., Demitrack, M. A., et al (1988) Clinical studies with corticotropin releasing hormone: implications for hypothalamic pituitary adrenal dysfunction in depression and related disorders. In Current Trends in Neuroendocrinology, Vol. 8 (eds D. Genten & D. Pfaff), pp. 238–256. Berlin: Springer Verlag.Google Scholar
Holsboer, F., Gerken, A., Stalla, G. K., et al (1985) ACTH, cortisol and corticosterone output after ovine corticotropin releasing factor challenging during depression and after recovery. Biological Psychiatry, 20, 276–286.CrossRefGoogle ScholarPubMed
Irwin, M., Hauger, R. L., Brown, M. R., et al (1988) CRF activates autonomic nervous systems and reduces natural killer cytotoxicity. American Journal of Physiology, 255, R744–R747.Google ScholarPubMed
Jeffcoate, W., Silverstone, J. T., Edwards, C. R. W. & Besser, G. M. (1979) Psychiatric manifestations of Cushing's syndrome: response to lowering of plasma cortisol. Quarterly Journal of Medicine, 48, 465–472.Google ScholarPubMed
Jenkins, S. W., Robinson, D. S., Fabre, L. F., et al (1990) Gepirone in the treatment of major depression. Journal of Clinical Psychopharmacology, 10, 77S–85S.CrossRefGoogle ScholarPubMed
Jhanwar-Uniyal, M. & Leibowitz, S. F. (1986) Impact of circulating corticosterone on alpha-1 and alpha-2 noradrenergic receptors in discrete brain areas. Brain Research, 368, 404–408.CrossRefGoogle ScholarPubMed
Jones, M. T., Gillham, B., Greenstein, B. D., et al (1982) Feedback action of adrenal steroids. In Current Topics in Neuroendocrinology: Adrenal Action on Brain (eds D. Canten & D. Pfaff), pp. 58–74. Berlin: Springer-Verlag.Google Scholar
Kalin, N. H., Shelton, S. E., Kraemer, G. W., et al (1983) Corticotropin-releasing factor administered intraventricularly in rhesus monkeys. Peptides, 4, 217–220.CrossRefGoogle ScholarPubMed
Kalinyak, J. E., Griffin, C. A., Hamilton, R. W., et al (1989) Developmental and hormonal regulation of glucocorticoid receptor messenger RNA in the rat. Journal of Clinical Investigations, 84, 1843–1848.CrossRefGoogle ScholarPubMed
Katona, C. L. E., Theodorou, A. E., Davies, S. L., et al (1985) Platelet binding and neuroendocrine responses in depression. In The Biology of Depression (ed. Deakin, J. F. W.), pp. 140–175. London: Gaskell.Google Scholar
Kelly, W. F., Checkley, S. A. & Bender, D. A. (1980) Cushing's syndrome, tryptophan and depression. British Journal of Psychiatry, 136, 125–132.CrossRefGoogle ScholarPubMed
Kelly, W. F., Checkley, S. A. & Bender, D. A. et al (1983) Cushing's syndrome and depression - a prospective study of 26 patients. British Journal of Psychiatry, 142, 16–19.CrossRefGoogle ScholarPubMed
Kitayama, I., Janson, A. M., Cintra, A., et al (1988) Effects of chronic imipramine treatment on glucocorticoid receptor immunoreactivity in various regions of the brain. Journal of Neural Transmission, 73, 191–203.CrossRefGoogle Scholar
Kramlinger, K. G., Peterson, G. C., Watson, P. K. & Leonard, L. L. (1985) Metyrapone for depression and delerium secondary to Cushing's syndrome. Psychosomatics, 26, 67–71.CrossRefGoogle Scholar
Krieger, D. T. (1983) Physiopathology of Cushing's disease. Endocrine Reviews, 4, 22–43.CrossRefGoogle ScholarPubMed
Lenz, H. J. (1989) Regulation of duodenal bicarbonate secretion during stress by corticotropin-releasing factor and β-endorphin. Proceedings of the National Academy of Sciences (USA), 86, 1417–1420.CrossRefGoogle ScholarPubMed
Lesch, K. P., Laux, G., Pfuller, H., et al (1987) Growth hormone response to GH releasing hormone in depression. Journal of Clinical Endocrinology and Metabolism, 65, 1278–1281.CrossRefGoogle ScholarPubMed
Lesch, K. P., Mayer, S., Disselkamp-Tietze, J., et al (1990) 5-HT1A receptor responsivity in unipolar depression evaluation of ipsapirone-induced ACTH and cortisol secretion in patients and controls. Biological Psychiatry, 28, 620–628.CrossRefGoogle ScholarPubMed
Liebowitz, S. & Roland, C. R. (1984) Noradrenergic feeding elicited via the paraventricular nucleus is dependent upon circulating corticosterone. Physiology and Behavior, 32, 857–864.CrossRefGoogle Scholar
Ling, M. H., Perry, P. J. & Tsuang, M. T. (1981) Side effects of corticosteroid therapy. Archives of General Psychiatry, 38, 471–477.CrossRefGoogle ScholarPubMed
Loosen, P. T. & Prange, A. J. (1982) The serum thyrotropin (TSH) response to thyrotropin-releasing hormone (TRH) in depression: A review. American Journal of Psychiatry, 139, 405–416.Google ScholarPubMed
McEwen, B. S. (1987) Glucocorticoid-biogenic amine interactions in relation to mood and behavior. Biochemical Pharmacology, 11, 1755–1763.CrossRefGoogle Scholar
McEwen, B. S., Davis, P. G. & Parsons, B. (1979) The brain as a target for steroid hormone action. Annual Review of Neuroscience, 2, 65–112.CrossRefGoogle ScholarPubMed
Mains, R. E., Eipper, B. A. & Ling, N. (1977) Common precursor to corticotropins and endorphins. Proceedings of the National Academy of Sciences (USA), 74, 3014–3018.CrossRefGoogle ScholarPubMed
Nakagawa, K., Akikawa, K., Matsubara, M., et al (1985) Effect of dexamethasone on growth hormone (GH) response to growth hormone releasing hormone in acromegaly. Journal of Clinical Endocrinology and Metabolism, 60, 306–309.CrossRefGoogle ScholarPubMed
Nakanishi, S., Inoue, A., Kita, T., et al (1979) Nucleotide sequence of cloned cDNA for bovine corticotropin-B-lipotropin precursor. Nature, 274, 423–427.CrossRefGoogle Scholar
Nemeroff, C. B. & Eans, D. L. (1984) Correlation between the dexamethasone suppression test in depressed patients and clinical response. American Journal of Psychiatry, 141, 247–249.Google ScholarPubMed
Nemeroff, C. B., Owens, M. J., Bissette, G., et al (1988) Reduced corticotropin releasing factor binding site in frontal cortex of suicide victims. Archives of General Psychiatry, 45, 577–579.CrossRefGoogle ScholarPubMed
O'Flynn, K. & Dinan, T. G. (1993) Baclofen-induced growth hormone release: relationship to dexamethasone suppressor status. American Journal of Psychiatry, 150, 1728–1729.Google Scholar
O'Keane, V. & Dinan, T. G. (1991) Prolactin and cortisol responses to d-Fenfluramine in major depression: evidence for diminished responsivity of central serotonergic function. American Journal of Psychiatry, 148, 1009–1015.Google ScholarPubMed
O'Keane, V., O'Flynn, K., Lucey, J., et al (1992a) Pyridostigmine-induced growth hormone responses in healthy and depressed subjects: evidence for cholinergic supersensitivity in depression. Psychological Medicine, 22, 55–60.CrossRefGoogle ScholarPubMed
O'Keane, V., O'Loughlin, D. & Dinan, T. G. (1992b) D-Fenfluramine induced prolactin release in major depression: response to treatment. Journal of Affective Disorders, 26, 43–52.CrossRefGoogle ScholarPubMed
Paykel, E. S., Myers, J. K. & Dienelt, M. N. (1969) Life events and depression. Archives of General Psychiatry, 21, 735–741.CrossRefGoogle ScholarPubMed
Pepin, M. C., Beaulieu, S. & Barden, N. (1989) Antidepressants regulate glucocorticoid receptor messenger RNA concentrations in primary neuronal cultures. Molecular Brain Research, 6, 77–83.CrossRefGoogle ScholarPubMed
Rees, L. H. (1978) Human adrenocorticotropin and lipotropin (MSH) in health and disease. In Clinical Neuroendocrinology (eds L. Martin & G. M. Besser), pp. 96–103. New York: Academic Press.Google Scholar
Reul, J. M. H. M. & De Kloet, E. R. (1986) Anatomical resolution of two types of corticosterone receptor sites in rat brain with in vitro autoradiography and computerized image analysis. Journal of Steroid Biochemistry, 24, 269–272.CrossRefGoogle ScholarPubMed
Reul, J. M. H. M., Pearce, P. T., Funder, J. W., et al (1989) Type 1 and type 11 corticosteroid receptor gene expression in the rat: effect of adrenalectomy and dexamethasone administration. Molecular Endocrinology, 3, 1674–1680.CrossRefGoogle Scholar
Roberts, V. J., Singhal, R. L. & Roberts, D. C. (1984) Corticosterone prevents the increase in noradrenaline-stimulated adenyl cyclase activity in rat hippocampus following adrenalectomy or metyrapone. European Journal of Pharmacology, 103, 235–240.CrossRefGoogle ScholarPubMed
Rupprecht, R., Kornhuber, J., Wodarz, N., et al (1991) Disturbed glucocorticoid receptor autoregulation and corticotropin response to dexamethasone in depressives pretreated with metyrapone. Biological Psychiatry, 29, 1099–1109.CrossRefGoogle ScholarPubMed
Sachar, E. J., Hellman, L., Roffwarg, H. P., et al (1973) Disrupted 24-hour cortisol secretion in psychotic depression. Archives of General Psychiatry, 28, 19–24.CrossRefGoogle ScholarPubMed
Sachar, E. J., Hellman, L., Fukushima, D. K., et al (1978) Cortisol production in depressive illness. Archives of General Psychiatry, 23, 289–298.CrossRefGoogle Scholar
Scoggins, R. A., Coghlan, J. P. & Denton, D. A. (1984) Intracerebroventricular infusions of corticotropin releasing factor (CRF) and ACTH (1–24) raise blood pressure in sheep. Clinical and Experimental Pharmacology and Physiology, 11, 365–368.CrossRefGoogle ScholarPubMed
Shimoda, K., Yamada, N., Ohi, K., et al (1988) Chronic administration of tricyclic antidepressants suppress hypothalamo-pituitary-adrenocortical activity in male rats. Psychoneuroendocrinology, 13, 431–440.CrossRefGoogle ScholarPubMed
Siever, L. S., Murphy, D. L., Slater, S., et al (1983) Plasma prolactin changes following fenfluramine in depressed patients compared to controls: an evaluation of central serotonergic responsivity in depression. Life Sciences, 34, 1029–1039.CrossRefGoogle Scholar
Sutanto, W. & De Kloet, E. R. (1987) Species-specificity of corticosteroid receptors in hamster and rat brains. Endocrinology, 121, 1405–1411.CrossRefGoogle ScholarPubMed
Trethowan, W. H. & Cobb, S. (1952) Neuropsychiatric aspects of Cushing's syndrome. Archives of Neurology and Psychiatry, 67, 283–309.CrossRefGoogle ScholarPubMed
Trimble, M. R. (1988) Biological Psychiatry, pp. 241–281. Chichester: Wiley.Google Scholar
Ur, E., Dinan, T. G., O'Keane, V., et al (1992) Effect of metyrapone on the pituitary-adrenal axis in depression: relation to dexamethasone suppressor status. Neuroendocrinology, 56, 533–538.CrossRefGoogle ScholarPubMed
Van Eekelen, J. A. M., Kiss, J. Z., Westphal, H. M. & De Kloet, E. R. (1987) Immunocytochemical study on the intracellular localization of the type 2 glucocorticoid receptor in the rat brain. Brain Research, 436, 120–128.CrossRefGoogle Scholar
Williams, C. L., Peterson, J. M., Villar, P. G., et al (1987) Corticotropin-releasing factor directly mediates colonic responses to stress. American Journal of Physiology, 253, G582–G586.Google ScholarPubMed
Young, E. A., Haskett, R. F., Murphy-Weinberg, V., et al (1991) Loss of glucocorticoid fast feedback in depression. Archives of General Psychiatry, 48, 693–699.CrossRefGoogle ScholarPubMed
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