To focus on hypothalamic-pituitary-adrenal (HPA) axis activity, especially endogenous hypercortisolemia, to study its role in the maintenance of psychiatric illness, and to entertain the probability that the elderly are vulnerable.
Method:
Case presentation, clinical and research literature review, and theoretical discussion.
Results:
Clinical and research evidence overwhelmingly suggest that hypercortisolemia is toxic to the hippocampus. Some research supports the position that it can be a treatable perpetuating factor in a subset of affective disorders and psychoses. Pharmacological treatments to correct hypercortisolemia have been used by endocrinologists. Hypercortisolemic treatment-resistant and nontreatment-resistant psychoses and affective disorders have been successfully treated by a small number of researchers who remain interested in this subject. Data pertaining to geriatric psychoses may be germane but are sparse.
Conclusions:
It behooves us to research diagnostic methods pertaining to psychoses and affective disorders associated with hypercortisolemic states. Very little research is available, but we must be alert to the possibility that the elderly are more susceptible to cortisol endotoxicosis than the younger adult population. Without accurate diagnosis, we cannot take advantage of existing antiglucocorticoid strategies.
BertholdAA. Transplantation der Hoden. Archiv Anatomisch Physiologisch Wissenschaft Medizin1849;16:42–6.
2.
AsherR.Myxoedematous madness. BMJ1949;2:555–62.
3.
CushingH.Psychiatric disturbances associated with disorders of ductless glands. American Journal of Insanity1913;69:965–90.
4.
CushingH.Basophil adenomas of the pituitary body and their clinical manifestations. Bulletin of the Johns Hopkins Hospital1932;50:137–95.
5.
McEwenBSDavisPGParsonsBPfaffWG. The brain as target for steroid hormone action. Annu Rev Neurosci1979;2:65–112.
6.
SvanborgMA. Aging, health and vitality: Results from the Gothenburg longitudinal study [keynote address]. Canadian Association on Gerontology, 19th Annual Meeting; 1990 Oct 26.
7.
GnamWFlintAJ. New onset rapid cycling bipolar disorder in an 87 year old woman. Can J Psychiatry1993;38:324–6.
8.
YoungRCKlermanGL. Mania in late life: Focus on age at onset. Am J Psychiatry1992;149:867–76.
9.
AlexopoulosGSYoungRCMeyersBS. Late onset depression. Psychiatr Clin North Am1988;2:101–15.
10.
StarkmanMNSchteingartDE. Neuropsychiatric manifestations of patients with Cushing's syndrome: Relationship to cortisol and adreno-corticotrophic hormone levels. Arch Intern Med1981;191:215–9.
11.
DubrovskyB.Effects of adrenal cortex hormones on limbic structures: Some experimental and clinical correlations related to depression. J Psychiatry Neurosci1993;18:4–16.
12.
DubrovskyB.Adrenal steroids and the physiopathology of a subset of depressive disorders. Med Hypotheses1991;36:300–5.
13.
GibbonsJL. Cortisol secretion rate in depressive illness. Arch Gen Psychiatry1964;10:572–5.
14.
GibbonsJL. Plasma cortisol in depressive illness. J Psychiatry Res1962; 1:162–71.
15.
Pearson-MurphyBE. Steroids and depression. J Steroid Biochem Mol Biol1991;38:537–59.
16.
NemeroffCB. The role of corticotropin-releasing factor in the pathogenesis of major depression. Pharmacopsychiatry1988;21:76–82.
17.
SwannACStokesPECasperRSecundaSKBowdenCLBermanN, and others. Hypothalamic-pituitary-adrenocortical function in mixed and pure mania. Acta Psychiatr Scand1992;85:270–4.
18.
PerskyH.Blood corticotropin and adrenal weight-maintenance factor levels of anxious patients and normal subjects. Psychosom Med1959;21:379–86.
19.
BornJde KloetERWenzHKernWFehmHL. Gluco- and antiminaralocorticoid effects on human sleep: A role for central corticosteroid receptors. Am J Physiol1991;260:E183–E188.
20.
WolkowitzOMRubinowDDoranARBreierABerrettiniWHKlingMA, and others. Prednisone effects on neurochemistry and behavior. Arch Gen Psychiatry1990;47:963–8.
21.
FilipiniDGijsbersKBirminghamMKKraulisIDubrovskyB.Modulation by adrenal steroids of limbic function. J Steroid Biochem Mol Biol1991;39:245–52.
22.
SchatzbergAFRothschildAJLanglaisPJBirdEDColeJO. A corticosteroid/dopamine hypothesis for psychotic depression and related states. J Psychiatry Res1985;19:57–64.
23.
SchatzbergAFRothschildAJ. The roles of glucocorticoid and dopaminergic systems in delusional (psychotic) depression. Ann N Y Acad Sci1988;537:462–71.
24.
GiffordSGundersonJG. Cushing's disease as a psychosomatic disorder: A selective review of the clinical and experimental literature and a report of ten cases. Perspect Biol Med1970;Winter:169–221.
25.
RederATThaparMJensenMA. A reduction in serum glucocorticoids provokes experimental allergic encephalomyelitis: Implications for treatment of inflammatory brain disease. Neurology1994;44:2289–94.
26.
SapolskyRM. Is this relevant to the human? In: SapolskyRM, editor. Stress, the aging brain and the mechanism of neuron death. Boston: MIT; 1992. p 315–7.
27.
YoungEAKwakSPKottakJ.Negative feedback regulation following administration of chronic exogenous corticosterone. J Neuroendocrinol1995;7:37–45.
28.
CohenS.Cushing's syndrome: A psychiatric study of 29 patients. Br J Psychiatry1980;136:120–4.
29.
CleghornRA. Adrenal cortical insufficiency: Psychological and neurological observations. Can Med Assoc J1951;65:449–54.
30.
McEwenBS. Glucocorticoid-biogenic amine interactions in relation to mood and behaviour. Biochem Pharmacol1987;36:1755–63.
31.
AbramoviczM.Drugs that cause psychiatric symptoms. The Medical Letter1993;35:65–70.
32.
NewcomerJWCraftSHersheyTAskinsKBardgettME. Glucocorticoid induced impairment of declarative memory performance in adult humans. J Neurosci1994;14:2047–53.
33.
McEwenBS. Steroid hormones are multifunctional messengers of the brain. Trends in Endocrinology and Metabolism1991;2:62–7.
34.
SapolskyRM. Glucocorticoids endanger hippocampal neurons. In: SapolskyRM, editor. Stress, the aging brain and the mechanism of neuron death. Boston: MIT; 1992. p 119–258.
35.
UnoHEiseleSSakaiASheltonSBakerEDeJesusO, and others. Neurotoxicity of glucocorticoids in the primate brain. Horm Behav1994;28:336–48.
36.
PapezJA. A proposed mechanism for emotion. Archives of Neurology and Psychiatry1937;38:725–49.
37.
MilnerB.Disorders of learning and memory after temporal lobe lesions in man. Clin Neurosurg1972;19:421–46.
38.
CohenNJEichenbaumH.Memory, amnesia and the hippocampal system. Cambridge: MIT; 1994.
39.
SchumacherM.Rapid membrane effects of steroid hormones: An emerging concept in neuroendocrinology. Trends Neurosci1990;13:359–62.
40.
MajewskaMD. Neurosteroids: Endogenous bimodal modulators of the GABAa receptor: Mechanism of action and physiological significance. Prog Neurobiol1992;38:379–95.
41.
StarkmanMN. Hippocampal formation volume, memory dysfunction and cortisol levels in patients with Cushing's syndrome. Biol Psychiatry1992;32:756–65.
42.
HeinzREMartinezJHaenggelliA.Reversibility of cerebral atrophy in anorexia nervosa and Cushing's syndrome. J Comput Assist Tomogr1977;1:410–4.
43.
MomoseKJKjellbergRNKlimanB.High incidence of cortical atrophy of the cerebral and cerebellar hemispheres in Cushing's disease. Radiology1971; 99:341–8.
44.
BentsonJRWinterJWilsonG.Steroids and apparent cerebral atrophy on computed tomography scans. Assist J Comput Tomogr1978;2:16.
45.
JensenTGenefkeIHildebrandtN.Cerebral atrophy in young torture victims. N Engl J Med1982;307:1341–2.
46.
ThygesenPHarmannKWillangerR.Concentration camp survivors in Denmark; persecution, disease, disability, compensation. Dan Med Bull1970;17:65–7.
47.
CorkinSRosenTSullivanECleggR.Penetrating head injury in young adulthood exacerbates cognitive decline in later years. J Neurosci1989;9:3876–7.
48.
KraepelinE.Manic depressive insanity and paranoia. BarclayRM, translator. Edinburgh: E & S Livingstone; 1921.
49.
SternES. The psychopathology of manic depressive disorder and involutional melancholia. Br J Med Psychol1944;20:20–32.
50.
PostRM. Transduction of psychosocial stress into the neurobiology of recurrent affective disorder. Am J Psychiatry1992;149:999–1010.
51.
LinkowskyPMendleewiczJKerkhofsMLeClercqRGolsteinJBrasseurM, and others. 24-hour profile of adrenocorticotropin, cortisol and growth hormone in major depressive illness: Effect of antidepressant treatment. J Clin Endocrinol Metab1987;65:141–8.
52.
WolkowitzOMReusVIWeingartnerHThompsonKBreierADoranA, and others. Cognitive effects of corticosteroids. Am J Psychiatry1990;147:1297–303.
53.
RubinowDRPostRMSavardRGoldPW. Cortisol hypersecretion and cognitive impairment in depression. Arch Gen Psychiatry1984;41:279–83.
54.
AranaGW. Intravenous dexamethasone for symptoms of major depressive disorder. Am J Psychiatry1991;148:1401–2.
55.
AranaGW. Dexamethasone for the treatment of depression: A preliminary report. J Clin Psychiatry1991;52:304–6.
56.
AranaGWSantosABLaraiaMTMcLeod-BryantSBealeMDRamesLJ. Dexamethasone for the treatment of depression; a randomized, placebo-controlled, double-blind trial. Am J Psychiatry1995;152:265–7.
57.
BealeMDAranaGW. Dexamethasone treatment of major depression in patients with bipolar disorder. Am J Psychiatry1995;152:959–60.
58.
TurnerWJ. Dexamethasone suppression test: Problems and promise [editorial]. Biol Psychiatry1982;17:1–2.
59.
JeffcoateWJSilverstoneJTEdwardsCRWBesserGM. Psychiatric manifestations of Cushing's syndrome: Response to lowering of plasma cortisol. Q J Med1979;48:465–72.
60.
SemenkovichCF. Endocrine diseases. In: WoodleyMWhelanA, editors. Manual medical therapeutics. Boston: Little, Brown & Company; 1993. p 414–6.
61.
LandfieldPWEldridgeJC. Evolving aspects of the glucocorticoid hypothesis of brain aging; hormonal modulation of neuronal calcium homeostatsis. Neurobiol Aging1994;15:579–88.
62.
ColemanPFloodD.Neuron numbers and dendritic extent in normal aging and Alzheimer's disease. Neurobiol Aging1987;8:521–40.
63.
LandfieldPW. Nathan Shock Memorial Lecture 1990: The role of glucocorticoids in brain aging and Alzheimer's disease: An integrative physiological hypothesis. Exp Gerontol1994;29:3–11.
64.
ReusVI. Hormonal mediation of the memory disorder in depression. Drug Development and Research1984;4:489–500.
65.
GredenJFlegelPHaskettR.Age effects in serial hypothalamic-adrenal-pituitary monitoring. Psychoneuroendocrinology1986;11:195–203.
66.
APA Task Force on Laboratory Tests in Psychiatry. The dexamethasone suppression test: An overview of its current status in psychiatry. Am J Psychiatry1987;144:1253–68.
67.
FeldmanD.Ketoconazole and other imidazole derivatives as inhibitors of steroidogenesis. Endocr Rev1986;7:409–20.
68.
AngeliAFrairiaR.Ketoconazole therapy in Cushing's disease. Lancet1985;1:821.
69.
SoninoN.The use of ketoconazole as an inhibitor of steroid production. N Engl J Med1987;317:812–8.
70.
SoninoNBoscaroMFavaGAManteroF.Prolonged treatment of Cushing's disease with metyrapone and glutethimide. IRCS Med Sci1986;14:485–6.
71.
MurphyBE PearsonFilipiniDGhadirianAM. Possible use of glucocorticoid receptor antagonists in the treatment of major depression: Preliminary results using RU 486. J Psychiatry Neurosci1993;18:209–13.
72.
KramlingerKGPetersonGCWatsonPKLeonardLL. Metyrapone for depression and delirium secondary to Cushing's syndrome. Psychosomatics1985;26:67–71.
73.
RavarisCLSateiaMJBerozaKWNoordsyDLBrinck-JohnsenT.Effect of ketoconazole on a hypophysectomized, hypercortisolemic, psychotically depressed woman. Arch Gen Psychiatry1988;45:966–7.
74.
Pearson-MurphyBEDharVGhadirianAMChouinardGKellerR.Response to steroid suppression in major depression resistant to antidepressant therapy. J Clin Psychopharmacol1991;11:121–6.
75.
AnandAMalisonRMcDougleCJPriceLH. Antiglucocorticoid treatment of refractory depression with ketoconazole: A case report. Biol Psychiatry1995;37:338–40.
76.
ThakoreJHDinanTG. Cortisol synthesis inhibition: A new treatment strategy for the clinical and endocrine manifestations of depression. Biol Psychiatry1995;37:364–8.
77.
DallmanMF. Regulation of adrenocortical function following stress. In: BrownMRKoobGFRiverC, editors. Stress: Neurobiology and neuroendocrinology. New York: Marcel Dekker; 1991. p 173–92.
78.
WeissJM. The effects of coping on stress. Journal of Comparative and Physiological Psychology1968;65:251–60.
79.
WeinbergJLevineS.Psychobiology of coping in animals: The effects of predictability. In: LevineSUrsinH, editors. Coping and health. New York: Plenum; 1980. p 39–59.
80.
BreierAAlbusMPickarDZahnTPWolkowitzOMPaulSM. Controllable and uncontrollable stress in humans: Alterations in mood and neuroendocrine and psychophysiological function. Am J Psychiatry1987;144:1419–25.
81.
VoigtKZieglerMGrunert-FuchsMBickelUFehm-WolfsdorfG.Hormonal responses to exhausting physical exercise: The role of predictability and controllability of the situation. Psychoneuroendocrinology1990;15:173–84.
82.
GunnarMR. Reactivity of the hypothalamic-pituitary-adrenocortical system to stressors in normal infants and children. Pediatrics1992;90(Suppl):491S–497S.
83.
SapolskyRM. Why zebras don't get ulcers. New York: WH Freeman and Company; 1994.
84.
AbelsonJLCurtisJC. Hypothalamic-pituitary-adrenal axis activity in panic disorder: Prediction of long-term outcome by pretreatment cortisol levels. Am J Psychiatry1996;153:69–73.
