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Neuroendocrine Mechanisms and the Precipitation of Depression by Life Events

  • Stuart Checkley (a1)

It is now generally accepted that stressful life events and chronic difficulties can trigger the onset of depression in predisposed individuals. However, although much is known of the neurobiology of stress, few attempts have been made to provide a biological explanation for the mechanisms whereby life events might trigger depression. Enough is now known of the central control of hypothalamic pituitary adrenal (HPA) function and its response to stress to permit an examination of its role in the neurobiology of the triggering of depression by stress. This evidence is reviewed, and the proposal explored that stress triggers depression by a genomic action of corticosteroids.

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Al-Damluji, S. (1988) Adrenergic mechanisms in the control of corticotrophin secretion. Journal of Endocrinology, 119, 514.
Al-Damluji, S. & Rees, L. H. (1987) Effects of catecholamines on the secretion of adrenocorticotrophin (ACTH) in man. Journal of Clinical Pathology, 40, 10981107.
Al-Damluji, S., Perry, L., Tomlin, S., et al (1987a) Alpha-adrenergic stimulation of corticotrophin secretion by a specific central mechanism in man. Neuroendocrinology, 45, 6876.
Al-Damluji, S., Cunnah, D., Grossman, A., et al (1987b) Effect of adrenaline on basal and ovine corticotrophin-releasing factor-stimulated ACTH secretion in man. Journal of Endocrinology, 122, 145150.
Al-Damluji, S., Cunnah, D., Perry, L., et al (1987c) The effect of alpha adrenergic manipulation on the 24-hour pattern of Cortisol secretion in man. Clinical Endocrinology, 26, 6166.
Al-Damluji, S., Iveson, T., Thomas, J. M., et al (1987d) Food-induced Cortisol secretion is mediated by central alpha-1 adrenoceptor modulation of pituitary ACTH secretion. Clinical Endocrinology, 26, 629636.
Al-Damluji, S., Bouloux, P., White, A., et al (1990) The role of alpha-2 adrenoceptors in the control of ACTH secretion: interaction with the opioid system. Neuroendocrinology, 51, 7678.
Al-Dujaili, E. A. S., Hope, J., Estivariz, F. E., et al (1981) Circulating human pituitary progamma-melanotropin enhances the adrenal response to ACTH. Nature, 291, 156158.
Amsterdam, J. D., Winokur, A., Abelman, E., et al (1983) Cosynotropin (ACTH 1–24) stimulation test in depressed patients and healthy subjects. American Journal of Psychiatry, 140, 907909.
Amsterdam, J. D., Marinelli, D. L., Arger, P., et al (1987a) Assessment of adrenal gland volume by computed tomography in depressed patients and healthy volunteers: a pilot study. Psychiatry Research, 21, 189197.
Amsterdam, J. D., Maislin, G., Winokur, A., et al (1987b) Pituitary and adrenocortical responses to ovine corticotropin releasing hormone in depressed patients and healthy volunteers. Archives of General Psychiatry, 44, 775781.
Arimura, A., Schally, A. V. & Bowers, C. Y. (1969) Corticotropin-releasing activity of lysine vasopressin analogues. Endocrinology, 84, 579583.
Asnis, G. M. & Leuus, C. Z. (1989) Cortisol secretion in psychiatric disorders. In The Handbook of Clinical Psychoneuroendocrinology (eds Nemeroff, C. B. & Loosen, P. T.). Chichester: Wiley.
Banki, C. M., Bisette, G., Arato, M., et al (1987) CSE corticotropin-releasing factor-like immunoreactivity in depression and schizophrenia. American Journal of Psychiatry, 144, 873877.
Bardeleben, U. Von., Holsboer, F., Stalla, G., et al (1985) Combined administration of human corticotropin-releasing factor and lysine vasopressin induces Cortisol escape from dexamethasone suppression in healthy subjects. Life Sciences, 37, 16131618.
Bearn, J. A., Fairhall, K. M., Robinson, I. C. A. F., et al (1989a) A novel neuroendocrine measure of central oestrogen receptor function in women of potential relevance to puerperal psychosis. Journal of Psychopharmacology, 3, 20P.
Bearn, J. A., Franey, C., Arendt, J., et al (1989b) A study of the effects of desipramine treatment alone and in combination with L-triiodothyronine on 6-sulphatoxymelatonin excretion in depressed patients. British Journal of Psychiatry, 155, 341347.
Beato, M. (1989) Gene regulation by steroid hormones. Cell, 56, 335344.
Bebbington, P. E. & McGuffin, P. (1989) Interactive models of depression: the evidence. In Depression, An Integrative Approach (eds Herbst, K. R. & Paykel, E. S.). Oxford: Heinemann Medical.
Britton, D. R., Koob, G. F. & Rivier, J. (1982) Intraventricular corticotropin-releasing factor enhances behavioral effects of novelty. Life Sciences, 31, 363367.
Britton, K. T., Lee, G., Vale, W., et al (1986) Corticotropin releasing factors (CRF) receptor antagonist blocks activating and ‘anxiogenic’ actions of CRF in the rat. Brain Research, 363, 303306.
Britton, K. T. & Koob, G. F. (1988) Behavioural effects of corticotropin releasing factor. In The Hypothalamic Pituitary Adrenal Axis (eds Schatzberg, A. F. & Nemeroff, C. B.). New York: Raven Press.
Brockington, I. F., Kelly, A., Hall, P., et al (1988) Premenstrual relapse of puerperal psychosis. Journal of Affective Disorders, 14, 287292.
Charlton, B. G., Ferrier, I. N. & Perry, R. H. (1987) Distribution of corticotropin-releasing factor-like immunoreactivity in human brain. Neuropeptides, 10, 329334.
Charlton, B. G., Ferrier, I. N., Leake, A., et al (1988) A multiple time-point study of N-terminal pro-opiomelanocortin in depression using a two-site recognition immunoradiometric assay. Clinical Endocrinology, 28, 165172.
Charlton, B. G., & Ferrier, I. N. (1989) Hypothalamo–pituitary–adrenal axis abnormalities in depression: a review and a model. Psychological Medicine, 19, 331336.
Checkley, S. A. (1979) Corticosteroid and growth hormone responses to methylamphetamine in depressive illness. Psychological Medicine, 9, 107116.
Checkley, S. A., Corn, T., Glass, I. B., et al (1986) Neuroendocrine and other studies of the mechanism of action of antidepressant drugs. In Antidepressant Drugs and Receptor Functions (ed. Murphy, D. L.), pp. 126142. CIBA Foundation Symposium, 123. Chichester: Wiley.
Cohen, S.I. (1980) Cushing's syndrome: a psychiatric study of 29 patients. British Journal of Psychiatry, 136, 120124.
Cookson, J. (1982) Post-partum psychosis, dopamine and oestrogens. Lancet, ii, 672.
Coppen, A., Whybrown, P. C., Noguera, R., et al (1972) The comparative antidepressant value of L-tryptophan and imipramine with and without attempted potentiation of liothyronine. Archives of General Psychiatry, 26, 234241.
Crompton, M. R. & Ferrier, I. N. (1988) Corticotropin-releasing factor immunoreactivity in post-mortem brain from depressed suicides. Journal of Psychopharmacology, 2, 1318.
Cummings, S. & Seybold, V. (1988) Relationship of alpha-1 and alpha-2 adrenergic binding sites to regions of the paraventricular nucleus of the hypothalamus containing corticotropin-releasing factor and vasopressin neurons. Neuroendocrinology, 47, 523532.
Cuneo, R. C., Livesey, J. H., Nicholls, M. G., et al (1987) Effects of alpha-1 adrenergic blockade on the hormonal response to hypoglycaemic stress in normal man. Clinical Endocrinology, 26, 18.
Cushing, H. (1932) The basophil adenomas of the pituitary body and their clinical manifestations (pituitary basophilism). Bulletin of the Johns Hopkins Hospital, 50, 137195.
Dallman, M. F., Engeland, W. C. & McBride, M. H. (1977) The neural regulation of compensatory adrenal growth. In ACTH and Related Peptides: Structure, Regulation and Action (eds Krieger, D. T. & Ganong, W. F.). New York: New York Academy of Sciences.
De Kloet, E. R. & Reul, J. M. H. M. (1987) Feedback action and tonic influence of corticosteroids on brain function. A concept arising from heterogeneity of brain receptor systems. Psychoneuroendocrinology, 12, 83105.
De Kloet, E. R., De Kock, S., Schild, V., et al (1988) Antiglucocorticoid RU 38486 attenuates retention of a behaviour and disinhibits the hypothalamic-pituitary and adrenal axis at different brain sites. Neuroendocrinology, 47, 109115.
De Souza, E. B. (1987) Corticotropin-releasing factor receptors in the rat central nervous system: characterisation and regional distribution. Journal of Neuroscience, 7, 88100.
De Souza, E. B., Perrin, H. M., Insel, T., et al (1984) Corticotropin-releasing factor receptors in rat forebrain: autoradiographic identification. Science, 224, 14491450.
Feighner, J. P., King, L. J., Schuckit, M. A., et al (1972) Hormonal potentiation of imipramine and ECT in primary depression. American Journal of Psychiatry, 128, 12301238.
Ganong, W. F., Chalett, J., Jones, H., et al (1982) Further characterization of alpha-adrenergic receptors in brain that affect blood pressure and the secretion of ACTH, GH and renin in dogs. Endocrinologia Experimentalis, 16, 191205.
Gillies, G. E., Linton, E. A. & Lowry, P. J. (1982) Corticotropin releasing activity of the new CRF is potentiated several times by vasopressin. Nature, 299, 355357.
Gitlin, M. J., Weiner, H., Fairbanks, L., et al (1987) Failure of T3 to potentiate tricyclic antidepressant response. Journal of Affective Disorders, 13, 267272.
Gold, P. W., Crousos, G. P., Kellner, C., et al (1984) Psychiatric implications of basic and clinical studies with corticotropin-releasing factor. American Journal of Psychiatry, 141, 619627.
Gold, P. W., Gwirtsman, H., Avgerinos, P. C., et al (1986) Abnormal hypothalamic–pituitary–adrenal function in anorexia nervosa. New England Journal of Medicine, 314, 13351342.
Gold, P. W., 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 in Current Trends in Neuroendocrinology, Volume 8 (eds Ganten, D. & Pfaff, D.). Berlin: Springer Verlag.
Goodwin, F. K., Prange, A. J., Post, R. M., et al (1982) Potentiation of antidepressant effects by L-triiodothyronine in tricyclic nonresponders. American Journal of Psychiatry, 139, 3438.
Gray, J. A. (1987) The Psychology of Fear & Stress. Cambridge: Cambridge University Press.
Halbreich, U., Asnis, G. M., Shindledecker, R., et al (1985) Cortisol secretion in endogenous depression. I. Basal plasma levels. Archives of General Psychiatry, 42, 904908.
Haleem, D. J., Kennett, G. & Curzon, G. (1988) Adaptation of female rats to stress: shift to male pattern by inhibition of corticosterone synthesis. Brain Research, 458, 339347.
Hamilton, J. A. (1982) The identity of post-partum psychosis. In Motherhood & Mental Illness (eds Brockington, I. F. & Kumar, R.), pp. 117. London: Academic Press.
Harfstrand, A., Fuxe, K., Cintra, A., et al (1986) Glucocorticoid receptors immunoreactivity in monoaminergic neurones of rats brain. Proceedings of the National Academy of Sciences (USA), 83, 97799783.
Holsboer, F., Gerken, A., Stalla, G. K., et al (1985a) ACTH, Cortisol and corticosterone output after ovine corticotropin-releasing factor challenging during depression and after recovery. Biological Psychiatry, 20, 276286.
Holsboer, F., Gerken, A., Stalla, G. K., et al (1985b) Blunted corticotropin and normal Cortisol response to corticotropin-releasing factor in depression. New England Journal of Medicine, 311, 1123.
Hunter, R., Dick, H., Christie, J. E., et al (1988) Lymphocyte glucocorticoid receptor binding in depression: normal values following recovery. Journal of Affective Disorders, 14, 155159.
Hurxthal, L. M. & O'Sullivan, J. D. (1959) Cushing's syndrome: clinical differential diagnosis and complications. Annals of Internal Medicine, 51, 116.
Jeffcoate, W. J., Silverstone, J. T., Edwards, C. W. R., et al (1979) Psychiatric manifestation of Cushing's syndrome: response to lowering of plasma Cortisol. Quarterly Journal of Medicine, 191, 465472.
Jones, M. T. & Hillhouse, E. W. (1977) Neurotransmitters control of corticotrophin-releasing factor in vitro. Annals of the New York Academy of Science, 297, 536558.
Jones, M. T. & Gillham, B. (1988) Factors involved in the regulation of adrenocorticotropic hormone/beta lipotropic hormone. Physiological Reviews, 68, 743818.
Kelly, W. F., Checkley, S. A. & Bender, D. A. (1980) Cushing's syndrome, tryptophan and depression. British Journal of Psychiatry, 136, 125132.
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, 1619.
Kennett, G. A., Dickinson, S. L. & Curzon, G. (1985) Central serotonergic responses and behavioural adaptation to repeated immobilisation: the effect of the corticosterone synthesis inhibitor metyrapone. European Journal of Pharmacology, 119, 143152.
Kennett, G. A., Chaouloff, F., Marcou, M., et al (1986) Female rats are more vulnerable than males in an animal model of depression: the possible role of serotonin. Brain Research, 382, 416421.
Krahn, D. D., Gosnell, B. A., Grace, M., et al (1987) CRF antagonist partially reverses CRF and stress-induced effects on feeding. Brain Research Bulletin, 17, 285289.
Kramlinger, K. G., Peterson, G. C., Watson, P. K., et al (1985) Metyrapone for depression and delirium secondary to Cushing's syndrome. Psychosomatics, 26, 6771.
Leibowitz, S. F., Jhanwar-Uniyal, M., Dvorkin, B., et al (1982) Distribution of alpha-adrenergic, beta-adrenergic and dopaminergic receptors in discrete hypothalamic areas of rat. Brain Research, 233, 97114.
Leranth, Cs., Antoni, F. A. & Palkovits, M. (1983) Ultrastructural demonstration of ovine CRF-like immunoreactivity (oCRF-LI) in the rat hypothalamus: processes of magnocellular neurones establish membrane specialisations with parvocellular neurones containing oCRF-LI. Regulatory Peptides, 6, 179188.
Linkowski, P., Mendlewicz, J., Leclerq, R., et al (1985) The 24-hour profile of adrenocorticotropin and Cortisol on major depressive illness. Journal of Clinical Endocrinology & Metabolism, 61, 429438.
Liposits, Zs., Sherman, D., Phelix, C., et al (1986) A combined light and electron immunocytochemical method for the simultaneous localization of multiple tissue antigens. Histochemistry, 85, 95106.
Lowry, P. J. (1984) Pro-opiocortin: the multiple adrenal hormone precursor. Bioscience Reports, 4, 467482.
Lowry, P. J., Silas, I., McLean, C., et al (1983) Pro-gamma-melanocyte stimulating hormone cleavage in adrenal gland undergoing compensatory growth. Nature, 306, 7073.
Lowy, M. T., Reder, A. T., Antel, J. P., et al (1984) Glucocorticoid resistance in depression: the dexamethasone suppression test and lymphocyte sensitivity to dexamethasone. American Journal of Psychiatry, 141, 13651367.
McEwen, B. S., De Kloet, E. R. & Rostene, W. (1980) Adrenal steroid receptors and actions in the nervous system. Physiological Reviews, 66, 11211188.
Millan, M. A., Jacobowitz, D. M., Hauger, R. L., et al (1986) Proceedings of the National Academy of Sciences (USA), 83, 19211925.
Milsom, S. R., Donald, R. A., Espiner, E. A., et al (1986) The effect of peripheral catecholamine concentrations on the pituitary–adrenal response to corticotropin releasing factor in man. Clinical Endocrinology, 25, 241246.
Nelson, D. H., Meakin, J. W., Denby, J. B., et al (1958) ACTH-producing tumor of the pituitary gland. New England Journal of Medicine, 259, 161164.
Nemeroff, C. B., Widerlow, E., Bisette, G., et al (1984) Elevated concentrations of CSF corticotropin-releasing factor-like immunoreactivity in depressed patients. Science, 226, 13421344.
Nemeroff, C. B., Owens, M. J., Bisette, G., et al (1988) Reduced corticotropin releasing factor binding sites in the frontal cortex of suicide victims. Archives of General Psychiatry, 45, 577579.
Owens, M. J. & Nemeroff, C. B. (1988) The neurobiology of corticotrophic releasing factor: implications for affective disorders. In The Hypothalamic-Pituitary-Adrenal Axis (eds Schatzberg, A. F. & Nemeroff, C. B.), pp. 136. New York: Raven Press.
Pfohl, B., Sherman, B., Schlechte, J., et al (1985) Pituitary/adrenal axis rhythm disturbances in psychiatric depression. Archives of General Psychiatry, 42, 897903.
Plotsky, M. M. (1987) Facilitation of immunoreactive corticotropin-releasing factor secretion into the hypophysial-portal circulation after activation of effect on adrenal corticoid release. American Journal of Physiology, 218, 16321641.
Porsolt, R., Le Pichon, M. & Jalfre, M. (1977) Depression: a new animal model sensitive to antidepressant treatments. Nature, 266, 730732.
Prange, A. J., Wilson, I. C., Rabon, A. M., et al (1969) Enhancement of imipramine antidepressant activity by thyroid hormone. American Journal of Psychiatry, 126, 3950.
Price, L. H., Charney, D. S., Rubin, A. L., et al (1985) Alpha-2 adrenergic receptor function in depression. The Cortisol response to yohimbine. Archives of General Psychiatry, 43, 849858.
Ratka, A., Sutanto, W., Bloemers, M., et al (1989) On the role of brain mineralocorticoid (type I) and glucocorticoid (type II) receptors in neuroendocrine regulation. Neuroendocrinology, 50, 117123.
Rees, L., Butler, P. W. P., Gosling, C., et al (1970) Adrenergic blockade and the corticosteroid and growth hormone responses to methylamphetamine. Nature, 228, 565566.
Reul, J. M. H. M. & De Kloet, E. R. (1985) Two-receptor systems for corticosterone in rat brain: microdistribution and differential occupation. Endocrinology, 117, 25052512.
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, 269272.
Reul, J. M. H. M., Van Der Bosch, F. R. & De Kloet, E. R. (1987) Relative occupancy of type I and type II corticosteroid receptors in rat brain following stress and dexamethazone treatment, functional implications. Journal of Endocrinology, 115, 459467.
Roy, A., Pickar, D., Paul, S., et al (1987) CSF corticotropin releasing hormone in depressed patients and normal control subjects. American Journal of Psychiatry, 144, 641645.
Roy-Byrne, P. P., Uhde, T., Post, R. M., et al (1986) Blunted ACTH responses to ovine CRH in panic-anxiety disorder. American Journal of Psychiatry, 143, 896899.
Rubin, R. T., Polan, R. E., Lesser, I. M., et al (1987) Neuroendocrine aspects of primary endogenous depression. Archives of General Psychiatry, 44, 328336.
Sawchenko, P. E. & Swanson, L. W. (1982) The organization of noradrenergic pathways from the brainstem to the paraventricular and supraoptic nuclei in the rat. Brain Research Reviews, 4, 275325.
Schwartz, G., Halaris, A., Baxter, L., et al (1984) Normal thyroid function in desipramine nonresponders converted to responders by the addition of L-triiodothyronine. American Journal of Psychiatry, 141, 16141616.
Siever, L. J., Uhde, T. W., Jimerson, D. C., et al (1984) Plasma Cortisol responses to clonidine in depressed patients and controls. Evidence for a possible alteration in noradrenergic–neuroendocrine relationships. Archives of General Psychiatry, 41, 6368.
Silverman, A. J., Oldfield, B., Hou-Yu, A., et al (1985) The noradrenergic innervation of vasopressin neurons in the paraventricular nucleus of the hypothalamus: an ultrastructural study using radioautography and immunocytochemistry. Brain Research, 325, 215229.
Sladek, J. R. & Zimmerman, E. A. (1982) Simultaneous monoamine histofluorescence and neuropeptide immunocytochemistry: VI. Catecholamine innervation of vasopressin and oxytocin neurons in the rhesus monkey hypothalamus. Brain Research Bulletin, 9, 431440.
Sirinathsinghji, D. J. S., Rees, L. J., Rivier, J., et al (1983) Corticotropin-releasing factor is a potent inhibitor of sexual receptivity in the female rat. Nature, 305, 232235.
Spillane, J. D. (1951) Nervous and mental disorders in Cushing's syndrome. Brain, 74, 7295.
Sutton, R. E., Koob, G. F., Le Moal, M., et al (1982) Corticotropin-releasing factor produces behavioral activation in rats. Nature, 297, 331333.
Swanson, L. W., Sawchenko, P. E., Rivier, J., et al (1983) The organization of ovine corticotropin releasing factor (CRF)-immunoreactive cells and fibers in the rat brain: an immunohistochemical study. Neuroendocrinology, 36, 165186.
Swanson, L. W., Sawchenko, P. E. & Lind, R. W. (1986) Regulation of multiple peptides in CRF parvocellular neurosecretory neurons: implications for the stress response. Progress in Brain Research, 68, 169190.
Szafarczyk, A., Malaval, F., Laurent, A., et al (1987) Further evidence for a central stimulatory action of catecholamines or adrenocorticotropin release in the rat. Endocrinology, 121, 883892.
Trethowan, W. H. & Cobb, S. (1952) Neuropsychiatric aspects of Cushing's syndrome. Archives of Neurology & Psychiatry, 67, 283309.
Tsutsui, S., Yamazaki, Y., Namba, T., et al (1979) Combined therapy of T3 and antidepressants in depression. Journal of International Medical Research, 7, 138146.
Vale, W., Spiess, J., Rivier, C., et al (1981) Characterization of a 41-residue hypothalamic peptide that stimulates secretion of corticotropin and beta endorphin. Science, 213, 13941397.
Vale, W., Vaughan, J., Smith, M., et al (1983) Effects of synthetic ovine corticotropin releasing factor, glucocorticoids, catecholamines, neurohypophysial peptides and other substances on cultured corticotropic cells. Endocrinology, 113, 11211131.
Van Den Pol, A. N. & Tsujimoto, K. L. (1985) Neurotransmitters of the hypothalamic suprachiasmatic nucleus: immunocytochemical analysis of 25 neuronal antigens. Neuroscience, 15, 10491086.
Veldhuis, H. D., De Korte, C. C. M. M. & De Kloet, E. R. (1985) Glucocorticoids facilitate the retention of acquired immobility during forced swimming. European Journal of Pharmacology, 115, 211217.
Whalley, L. J., Borthwick, N., Copdlov, D., et al (1986) Glucocorticoid receptors and depression. British Medical Journal, 292, 859861.
Wheatley, D. (1972) Potentiation of amitryptyline by thyroid hormone. Archives of General Psychiatry, 26, 229233.
Whybrow, P., Brange, A. & Treadway, C. (1969) Mental changes accompanying thyroid gland dysfunction. Archives of General Psychiatry, 20, 4862.
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Neuroendocrine Mechanisms and the Precipitation of Depression by Life Events

  • Stuart Checkley (a1)
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