Rapid Reversal of Acute Psychosis
`in the Cushing Syndrome with the
`Cortisol-Receptor Antagonist
`Mifepristone (RU 486)
`Aart-Jan van der Lely, MD; Karin Foeken, MD;
`Roos C. van der Mast, MD; and
`Steven W. J. Lamberts, MD
`
`Annals of Internal Medicine. 1991;114:143-144.
`
`The progesterone-receptor antagonist, RU 486 (mife(cid:173)
`pristone), is also, at higher concentrations, an effective
`antagonist of glucocorticoid action in vitro and in vivo
`(1-3). In normal humans, RU 486 blocks glucocorticoid
`negative feedback at the hypothalamic-pituitary level,
`inducing a compensatory increase in plasma adrenocor-
`ticotropin (ACTH) and Cortisol levels (4, 5). In previous
`studies, patients with the Cushing syndrome caused by
`
`From Erasmus University, Rotterdam, The Netherlands. For current
`author addresses, see end of text.
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`15 January 1991 • Annals of Internal Medicine • Volume 114 • Number 2
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`Table 1. Serum Cortisol Levels in the Two Study Pa(cid:173)
`tients
`
`Patient
`
`Before
`Treatment
`
`<
`
`Serum Cortisol*
`During
`During Therapy
`o,p'-DDD
`with o,p'-DDD
`Therapyt
`and RU 486
`nmollL
`>
`
`mg/d) resulted in improvement within 24 hours, with the
`complete disappearance of psychiatric symptoms within
`3 days. These symptoms did not recur during the last 2
`months of her life. Cortisol levels remained unchanged,
`and no evidence of relative adrenal insufficiency (hypo(cid:173)
`glycemia or eosinophilia) was observed. Other signs and
`symptoms of the Cushing syndrome decreased during
`this period.
`
`tt
`2§
`
`2000-2500
`1000-1500
`
`1800-2200
`800-1100
`
`1800-2200
`800-1100
`
`* Normal level at 0800 hours is less than 450 nmol/L.
`t o,p'-DDD = 1,1-dichlorophenyldichloroethane (mitotane).
`$ Male; age, 43 years.
`§ Female; age, 32 years.
`
`ectopic ACTH secretion or by adrenocortical carcino(cid:173)
`mas who received therapy with RU 486 (5 to 22 mg/kg
`body weight per day) showed clinical improvement, and
`no compensatory increases in plasma ACTH or cortisoj
`levels were noted, probably because of ongoing hypo(cid:173)
`thalamic and corticotroph suppression (6-8). In our
`study, RU 486 had a rapid, beneficial effect in reversing
`acute psychosis and preventing further psychiatric
`symptoms in two patients with inoperable end-stage
`cortisol-secreting adrenal cancers.
`
`Case Reports
`Patient 1, a 43-year-old man, had inoperable left-sided
`adrenal cancer with extensive metastases to the liver
`and lungs. Very high circulating Cortisol (Table 1) and
`undetectable ACTH levels confirmed the clinical diag(cid:173)
`nosis of the Cushing syndrome. After receiving therapy
`with o,p'-DDD (1,1-dichlorodiphenyldichloroethane; mi(cid:173)
`totane) for 2 weeks (12 g/d; body weight, 74 kg), his
`mental state deteriorated acutely. Different psychiatric
`states were observed during a period of 8 to 12 hours;
`these included consecutively severe clouding of con(cid:173)
`sciousness, mutism, and psychosis with nihilistic delu(cid:173)
`sions. The patient's behavior was unpredictable, and he
`was considered to be at high risk for suicide. Psychiat(cid:173)
`ric symptoms improved within 12 hours after 800 mg of
`RU 486 was administered, and all mental abnormalities
`disappeared within 24 hours. Therapy with RU 486 (800
`mg daily) was continued but after 5 days hypoglycemic
`episodes occurred and eosinophilia reappeared. The
`daily dose of RU 486 was lowered to 400 mg without
`side effects. The patient died 2 weeks later from renal
`insufficiency caused by tumor obstruction of the inferior
`vena cava. Plasma Cortisol levels remained elevated and
`unchanged until death, but no psychiatric symptoms
`recurred. Other signs and symptoms of the Cushing
`syndrome had started to subside.
`Patient 2, a 32-year-old woman, also developed the
`Cushing syndrome because of an inoperable left-sided
`adrenal cancer with metastases to the liver and lungs.
`Her circulating Cortisol level remained elevated (Table
`1) and her ACTH level undetectable after 7 weeks of
`therapy with o,p'-DDD (8 g/d; body weight, 52 kg). She
`was admitted with rapidly developing signs and symp(cid:173)
`toms of paranoid psychosis, including depression, agi(cid:173)
`tation, and hallucinations. Treatment with RU 486 (400
`
`Discussion
`Patients with the Cushing syndrome show a wide
`range of mental abnormalities. Depression, often of a
`psychotic nature, is the most frequent symptom and is
`accompanied by a high risk for suicide (9). These symp(cid:173)
`toms of psychosis are difficult to treat and in most
`instances do not respond to antipsychotic drugs (9).
`It has been previously reported that RU 486 results in
`clinical and biochemical improvement of patients with
`the Cushing syndrome (6-8). We found that RU 486 was
`probably useful in rapidly reversing the severe acute
`psychiatric symptoms in two patients with end-stage
`metastatic adrenal cancers. We chose a dose of 400 to
`800 mg/d of RU 486 on empiric grounds. There is cur(cid:173)
`rently no way to distinguish between adequate or ex(cid:173)
`cessive blockade of glucocorticoid action, making the
`recognition of adrenal insufficiency in these patients
`difficult (10).
`
`Requests for Reprints: A. J. van der Lely, MD, Department of Medi(cid:173)
`cine, University Hospital Dijkzigt, 40 Dr. Molewaterplein, 3015 GD
`Rotterdam, the Netherlands.
`
`Current Author Addresses: Drs. van der Lely, Foeken, van der Mast,
`and Lamberts: University Hospital Dijkzigt, 40 Dr. Molewaterplein,
`3015 GD Rotterdam, The Netherlands.
`
`References
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`ticoid in vivo [Abstract]. International Congress of Pharmacology,
`Tokyo, Japan; 1981:1463.
`2. Proux-Ferland L, Cote J, Philibert D, Deraedt R. Potent antigluco-
`corticoid activity of RU 38486 on ACTH secretion in vitro and in
`vivo in the rat [Abstract]. / Steroid Biochem. 1982;17:xvii.
`3. Lamberts SW, Bons EG, Uitterlinden P. Studies on the glucocorti(cid:173)
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`secreting human pituitary tumor cells and normal rat pituitary cells.
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`6. Bertagna X, Bertagna C, Laudat MH, Husson JM, Girard F, Luton
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`7. Nieman LK, Chrousos GP, Nisula BC, et al. Successful treatment of
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`8. Nieman LK, Udelsman R, Loriaux DL, Chrousos CP. Antiglucocor-
`ticoids: basic and clinical studies. In: D'Agata R, Chrousos GP,
`eds. Recent Advances
`in Adrenal Regulation and Function. New
`York: Raven Press; 1987:235-58.
`9. Haskett R. Diagnostic categorization of psychiatric disturbance in
`Cushing's syndrome. Am J Psychiatry. 1985;142:911-6.
`10. Laue L, Callucci W, Loriaux DL, Udelsman R, Chrousos GP. The
`antiglucocorticoid and antiprogestin steroid RU 486: its glucocorti(cid:173)
`coid agonist effect is inadequate to prevent adrenal insufficiency in
`primates. J Clin Endocrinol Metab. 1988;67:602-6.
`
`© 1 9 91 American College of Physicians
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