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RU486 IN DEPRESSION

K.

RANGA

RAMA KRE%NAN’, DEBORAH REED*, WILLIAM H. WILSON', WILLJAH B. SAUNDERS',JAMES C. RITCHIE', CNARLgS 8. NEMRROFP, and BERNARD J. CARROLL'

'Department of Psychiatry, Duke University Medical Center, Durham, NC, 2Department of Psychiatry, Emory University School of Medicine, Atlanta, GA, USA. (Final form, January 1992)

Abstract Krishnan, K. Ranga R., Deborah Reed, William H. Wilson, William Saunders, James G. Ritchie, Charles 8. Nemeroff and Bernard J. Carroll: RU486 in depression. Prog. Neuro-Psychopharmacol.& Biol Psychiat. 1992, 1~~913~~ 1.

2. 3.

RU486 is a synthetic glucocortfcoid antagonist. The authors used RU486 to examine the hypothesis that the elevated plasma cortisol and ACTH in patients is due to suprahypophysealstimulation of the anterior pituitary, Seven patients and matched controls were studied before and after the administration of RU486. RU486 producedan increase inHPAactivity in depressed patients. Thus providing support for the hypothesis that there is increased suprahypophyseal stimulation of the anterior pituitary.

Kevworda: depression, plasma ACTH, plasma cortisol, RU486. Sbbreviations* adrenocorticotropin (ACTH), corticotropin releasing factor (CRF), hypothalamo-pituitary-adrenal (HPA), coefficient of variation (CV), dexamethasone suppression test (DST).

LnfroductioU Gold et al. (1984) and Holsboer et al. (1984) noted that depressed patients have a blunted adrenocorticotropin (ACTH) response to corticotropin releasing factor (CRF). This blunting is believed to be secondary to the hypercortisolemiaseen in depression. RU486 is a synthetic steroid with a high affinity for glucocorticoid receptors [Chobert et al. 1983; Moguilesky and Philibert, 19841. It produces a dose dependent increase in plasma concentrationsof

ACTH,

Betaendorphin, Beta lipotropin andcortisol

[Bertagna et al. 1984, Gaillard et al. 19881. RU486 also blocks 1 mg dexamethasone induced suppression of coxtisol [Bertagna et al. 19841. These findings clearly indicate that RU486 blocks the negative feedback of cortisol. When RU486 was given in the evening to normal controls, no change in plasma adrenocorticotropin(ACTN) and plasma cortisol concentrationswere noted [Bertagna et 913

914

K. R R. KrlshnanetaL

al. 19841. This suggested that there was little or no hypothalamic drive on the pituitary through CRF and/or vasopressin in the evening in normal volunteers.

All the

evidence points to increased cortisol and ACTH secretion in the evening in depressed patients [Krishnan et al. 19861. Thus, administrationof RU486 in the evening should allow us to test whether the increased plasma ACTH and cortisol at that time in depressed patients result from suprahypophysealstimulation of the anterior pituitary. The authors tested the hypothesis that the rise in plasma ACTH concentration after RU486 administration in the evening will be higher in depressed patients than in normal subjects. Methods Subiects The authors studied seven patients (6 male, 1 post-menopausal female) who satisfied DSM-III criteria for major depression and seven age- and sex-matched controls after obtaining informed consent. The diagnosis of major depression was made on the basis of semistructured interviews, clinical interviews, interviews with family members and review of all available KeCOKdS. RU486 was generously provided by DK. E. Beaulieu and Roussell-Uclaf.

All patients were drug free for at least one week

prior

to the study. The study was

conducted in two sessions. On the first session an intravenous catheter was placed at 1300 h.

Placebo was administered orally at 1400 h.

Blood was drawn for plasma

cortisol and ACTH determination at 30 minute intervals between 1800 h and 0200 h the next day.

In the second session which was conducted the next day, RU486, 400 mg, was

administered orally at 1400 h. The catheter was placed at 1300 h.

Blood was collected

at the same time points as in session 1. All patients had a standard dexamethasone suppression test on the following day. The test was conducted as follows: One mg of dexamethasone, p.o., was given at 11 pm.

The next day blood was drawn for plasma

cortisol concentration at 3 pm and 10 pm the next day. Assavs Plasma ACTH was measured by radioimmunoassay [Krishnan et al. 19861. assay CV was 7X, the interassay C.V. was 12%.

Plasma

competitive protein binding method [Ritchie et al. 19851.

COKtiSOl

The intra-

was measured by

The intraassay C.V. was

5.6X, the interassay C.V. was 12.6%. Data Analvsis Repeated measures analysis of variance was used to compare response levels before and after loglo transformation pre and post RU486 in both patients and controls. In addition, appropriate parametric and nonparametric tests were also used.

915

RU486indepreaaion

Results Three patients were nonsuppressors on the DST. suppressors.

Table

I

All

provides the demographic and

of

mean

the controls were cortisol and

ACTR

concentrations in each subject before and after RU486. In one subject, plasma samples were obtained only for 6 hours on day 2. Depressed patients had higher plasma cortisol

Table 1 Mean Plasma Cortisol and ACTH Concentration in Patients and Controls before (Day 1) and after RU486 Administration (Day 2)

CORTISOL (nmol/L). Controls # Age 1

43

ACTH (vmol/L)

Day 1

Day 2

Day 1

Day 2

65.2 + 27.7

248.3 + 216.8

0.6 + 0.9

1.2 + 2.1

2

36

95.5 + 69.8

46.1 + 29.4

0.6 + 0.3

0.5 + 0.3

3

28

107.7 + 113.5

52.4 + 55.7

0.7 + 0.8

1.1 + 1.5

4

67

82.1 + 61.4

38.1 + 22.2

1.5 f 1.1

0.9 + 0.7

5

40

159.8 + 93.2

118.6 + 65.5

1.2 + 0.8

1.4 + 0.7

6

32

74.2 + 36.8

96.7 + 56.0

2.8 f 0.7

2.9 + 1.1

42

70.3 + 40.9

112.5 + 97.5

3.3 + 1.7

0.6 f 0.4

93.5 f 32.7

101.8 + 72.4

1.5 f 1.1

1.2 + 0.8

7

(n-7)

CORTISOL (nmol/L) Patients # Age 1

29

ACTH (omol/L)

Day 1

Day 2

Day 1

Day 2

203.1 + 103.6

334.2 + 237.5

1.9 + 1.5

2.9 + 1.8

2

43

317.0 f 173.2

218.5 k 124.9

2.1 + 1.2

2.0 + 0.8

3

68

175.5 + 69.6

178.7 + 88.8

2.5 + 1.4

2.8 f 3.1

4

47

157.8 + 131.8

273.7 + 142.5

0.9 + 1.3

0.6 + 0.4

5

43

88.1 + 85.2

49.1 + 17.1

0.5 + 0.4

0.5 + 0.5

7

34

145.4 f.84.8

(93.8 + 46.0)

2.5 f 1.9

(1.8 + 1.0)

34

160.2 + 132.6

234.4 + 154.5

(7.1 + 2.3)

(42.3 + 21.4)

178.2 + 70.5

197.5 + 99.5

2.5 + 2.2

7.5 f 15.3

*(210.8 A 107.7)

*(1.6 + 0.8)

a

(n-7)

*(188.3 k 83.6)

* - only patients l-5 Subjects 1, 2, and 7 were nonsuppressors

*(1.8 f 1.2)

K. R.R KrlshnanetaL

916

concentration (178.2k70.53) nmol/L than controls (93.Q32.8) patients alsohadhigher cortisol

nmol/L.

Depressed

levels (197.5k99.5)nmol/Lthan controls (101.8t72.4)

nmol/L following RU486. These results were confirmed by a repeated measures ANOVA on the logI, transformed data which indicated an overall difference between patients [F-7.4, ~1.021, but no difference between days and no day by group interaction. A similar analysis of the ACTIiconcentrationssuggested that patients had about the same levels (2.5k2.16) fmol/ml as controls (1.5kl.l) fmol/ml on the placebo day, but had slightly higher levels (7.6k15.4) fmol/ml than controls (1.2kO.8) fmol/ml after RU486. However, repeated measures AROVA failed to show any statistically significant differences. The extreme variability was due to one subject who had very high plasma ACTR concentrations.

ACTH n - Dar1

for Conwob - Day 2 for conwob +- Day 1 for P~tbnu A - Day 2 lor Patbnta

l

5

El-

8 0.0-

I 0

I

I

I

I

I

III

II

11

I”’

30 60 90 120 150 160 2x) 240 270 300 330 360 390 420450480

Time (minutes)

Fig 1. Plasma ACTH concentrations in &pressed patients and controls before (day 1) and after (day 2) RU486.

917

RU486indepression

400

CORTISOL L \

n l + A

\

350 c Bs

Day1 forCoatrob

300 ‘.

gj 250 c 0

;

-

- Dal 2 for Controls = Day 1 far Patients - Day 2 for PNknts

‘. +.

\ \ \ ‘A \

‘.

200

.s & IX 0 g

101

; a 5

5(

3

( I

0

I

III

1

““““’

I

I

30 60 90 120 150 180 2lO 240 270 300 330 360 390 420 450480

Time (minutes)

Plasma cortisol concentrations in &pressed patients and controls before Fig 2. (day 1) and after (day 2) RU486.

Inspection of the data in

Fig

1

and 2 suggests that effects of RU486 may occur

within the early period after administration,with the effect on ACTR preceding the change in cortisol.

To explore this possibility, mean plasma concentrations were

determined over 1800 to 2030 hours for ACTR and from 1900 to 2130 hours for cortisol, and loglo transformed data were analyzed. 'Iheresult for the cortisol did not change from that of the total period. Patients had significantly higher levels before and after RU486 than did controls, but there was no difference between days.

For ACTH,

patients have higher levels on both days than controls, and appear to have higher levels following RU486 than after placebo when compared to controls (t--2.5 df-11.8 FO.03).

When the difference after placebo is covaried from these after RU486, the

effect approached significance (F-4.2 ~~0.06). There was no difference in the number of cortisol and ACTR pulses between patients and controls on both day 1 and 2 (Table 2).

K.R.R. KrishnanetaI.

918

Table 2 Number of Pulses in Individual Subjects

W&

ACTH

Control #

Day 1

Day 2

Day 1

Day 2

41

5

5

4

6

2

5

6

7

5

3

5

3

6

5

4

5

4

8

6

5

3

3

5

4

6

5

3

4

6

7 (n-7)

6

7

4.86 + 0.90

4.43 + 1.62

7

7

5.86 + 1.57

CORTISOC

5.86

+ 1.07

ACTH

Patient #

Day 1

Day 2

Day 1

Day 2

11

5

4

7

7

12

3

4

6

7

13

3

2

7

5

14

4

2

3

5

1s

3

7

6

5

16

3

NA

4

NA

17

6

4

NA

NA

(n-7)

3.86 + 1.21

3.83 r.1.83

5.50 + 1.64

5.80 + 1.10

piscussion

The finding of higher plasma cortisol and a trend towards higher plasma ACTH concentration in depressed patients in the evening is similar to an earlier report [Krishnanet al. 19861 and those of others [Linkowskiet al., 19851. Our findings confirm the earlier reports of Gaillard et al. (1984) that RU486 administration in the evening does not cause any change in corticotropinor cortisol concentration in normal volunteers.

The finding of an increase in plasma corticotropin and cortisol

concentration after the administration of RU486 suggests that there is a suprahypophyseal drive of the hypothalamo pituitary adrenal axis in depression. In addition, the study confirms in part the results of Kling et al. (1989) demonstrating an increase in hypothalamo pituitary adrenal activity after RU486 in depressed patients; although, the time at which this occurred was later in their study.

RU486indepression

919

The mechanisms underlying the suprahypophysealdrive of the hypothalamo-pituitaryadrenal (HPA) axis in depression remains uncertain. A recent study by Nemeroff et al. (1984) showing elevated cerebrospinal fluid (pituitary) concentration of CRF in depressed patients has led to the speculation that CRF may play a role.

Further

studies are needed to elucidate the mechanisms underlying the suprahypophysealdrive.

Conclusion RU486 administrationwas used to test the hypothesis that there is suprahypophyseal stimulation of the pituitary adreno cortical system in depression. The results from this preliminary study is consistent with this hypothesis.

Acknowledeement The authors gratefully acknowledge the secretarial assistance provided by Mary Hunt and assistance with data analysis provided by Linda Patterson.

References BFRTAGNA, X., BERTAGNA, C.. LUXTON, J. P., HUSSON, J. M. andGIRARD, F. (1984) The new steroid analog RU486 inhibits glucocorticoid action in man. J. Clin. Endocrinol. Metab. s.: 25-28. CHOBERT, M. N., BAROUKI, R., FINIDON, J., AGGERBAgCK, H., HANOUNE, J., PHILIBERT, D. and DERAEDT, R. (1983) Antiglucocorticoidproperties of RU486 in a differentiated hepatoma cell line. Biochem. Phanaacol. 2: 3481-3485. GAILLARD, R. C., RIONDE, L. A., HULLER,A. F. HERMANN, W., BEAULIEU, E. E. (1984) RU486: A steroid with antiglucocorticoidactivity that disinhibits the HPA axis at a specific time of the day: Proc. Natl. Acad. Sciences. h: 3879-3882. GOLD, P. W., CHROUSOS, G., KELINER, C., POST, R., AUGERINOS P., SCHULTE, H., OLDFIELD, E. and LORIAUX, D. L. (1984) Psychiatric implicationsof basic and clinical studies with corticotropin releasing factor: Am. J. Psychiat. 141: 619-627. HOLSBOER, F., BARDELEBEN, U., GERKEN, A., STALLA G. K. and MULLER, 0. A. (1984) Blunted corticotropin and normal cortisol response to human corticotropin releasing factor in depression: N. England J. Med. 311: 1127-1130. KLING, M. A., WHITFIELD, J. W., BRANDT, H. A., DEMITRACK, M. A., KAMGERAS, K., GERACIOTI, T., PERINI, G. I., CALABRESE, J. R., CHROUSAS, G. P., and GOLD, P. W. (1989) Effects of glucocorticoid antagonism with RU486 on pituitary adrenal function inpatients with major depression:PsychopharmacologyBulletina: 466-472. KRISHNAN, K. R. R., RITCHIE, J. C., HANEPALLI, A. N., FRANCE, R. D., CARROLL, B. J. (1986) What is the relationshipbetween plasma cortisol and plasma ACTH in normal humans and depressed patients. In: HPA Physiology and Pathophysiology, A. F. Schatxberg and C. 8. Nemeroff (Eds.), Raven Press, New York. LINKOWSKI, P., MENDELEWICZ, J., LECLERG, R., DORASSEUR, R., HUBAIN, P., GOLSTEIN, J., COPINSCHI, G.. VANCOUTER, E. (1985) 24 hour profile of ACTH and cortisol in depressive illness: J. Clin. Endo. Metab. 61: 429-438. MOGUILESKY, M. and PHILIBERT, D. (1984) RU486 potent antiglucocorticoid activity correlated with strong binding to the cytosolic glucocorticoidreceptor followed by an impaired activation. J. Steroid Biochem. a: 271-276.

K.R.R.Krishnan etal.

920

NEMEROFF, C. B., WIDERLGV, E., BISSETTE, G., WALLENS, H., KARLSSON, I., KILTS C.D., VALE W., LOOSEN, P.T. (1988) Elevated concentrations of CSF corticotropin releasing factor in depressed patients. Science: m, 1342-1344. RITCHIE, J. C., CARROLL, B. J., OLTON, P., SHIVELYV., and FEINBERG, H. (1985) Plasma cortisol determination for the dexamethasone suppression test. Arch. Gen. Psychiat.: u, 493-496.

Inquiries and reprint requests should be addressed to: K. Ranga R. Krishnan, M.D. Department of Psychiatry Box 3215 Duke University Medical Center Durham, NC 27710 U.S.A.

RU486 in depression.

RU486 is a synthetic glucocorticoid antagonist. The authors used RU486 to examine the hypothesis that the elevated plasma cortisol and ACTH in patient...
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