Brief

Reports

Dexamethasone A Randomized,
George W. Arana, M.D., Stephen McLeod-Bryant, John M. Roberts, M.D.,

for the Treatment Placebo-Controlled,

of Depression: Double-Blind

Trial

Alberto B. Santos, M.D., Michele T. Laraia, R.N., M.S.N., M.D., Mark D. Beale, M.D., Laura J. Rames, M.D., James K. Dias, Ph.D., and Monica Molloy, R.N., M.S.N.

Objective: The authors goal was to assess dexamethasone for the Method: Thirty-seven outpatients (1 1 men and 26 women) meeting major depressive disorder were randomly assigned to receive either oral with using dexamethasone scores obtained two-sample
t

treatment of depression. DSM-III-R criteria for placebo or 4 mg/day of scores were compared Data were analyzed by Results: Seven (3 7%) of

for 4 days. Baseline Hamilton depression scale 14 days after the first dose ofstudy medication. tests, chi-square methods, but events than study 152:265-267) and only or side Fishers exact test. dexamethasone No adverse effective

the 1 9 patients given responded positively. entered was the significantly study more

one (6%) of the 1 8 patients given placebo effects were reported, and all patients who course 1 4 days outpatients. of oral for the dexamethasone treatment (4 days) of depression

completed double-blind 1995;

it. Conclusions: placebo

A brief within

in a randomized, (Am

of depressed

J Psychiatry

yen the past 25 years, a rich body of research examining the link between depressive illness and hypothalamic-pituitary-adrenal (HPA) axis dysregulation has accumulated (1, 2). Specific abnormalities of the HPA axis that have been associated with affective illness include hypercortisolemia (3), inadequate suppression of cortisol by dexamethasone (4), hypersecretion of cortisol after exogenous ACTH administration (5), and hypersecretion of corticotropin-releasing hormone in CSF (6). Clinical therapeutic studies of depressed patients testing the hypothesis that depression may improve when hypercortisolemia is normalized include the assessment of agents such as ketoconazole (7, 8), aminoglutethimide (9), and metyrapone (10), which are known to reduce serum cortisol in Cushings syndrome ( 1 1 , 12).
Received Feb. 4, 1994; revision received June June 22, 1994. From the Department of Psychiatry Sciences, Medical University of South Carolina. requests to Dr. Arana, Department of Psychiatry Sciences, Medical University of South Carolina, Charleston, SC 29425-0742. 3, 1994; accepted and Behavioral Address reprint and Behavioral 17i Ashley Ave.,

Ketoconazole, a commonly used antifungal medication, has potent cortisol biosynthesis inhibition and glucocorticoid receptor antagonist properties (7). Wolkowitz et al. (8) administered 400-800 mg/day of ketoconazole orally for 3-6 weeks to hypercortisolemic depressed patients and found an average decrease of 30% in Hamilton Depression Rating Scale scores, but the occurrence of liver toxicity and hypoadrenalism led them to condude that safer antiglucocorticoid drugs should be tested as antidepressant agents. The glucocorticoid dexamethasone has been tested in a small number of depressed patients and found to be effective in alleviating depressive symptoms (13, 14). In an uncontrolled, preliminary trial (14), 16 patients given an intravenous infusion of 4-8 mg of dexamethasone demonstrated significant (p<0.0001 ) improvement in Hamilton depression scale scones. In this paper we present data from a double-blind, randomized, placebo-controlled study of 37 depressed outpatients given either dexamethasone or placebo and followed for improvement in depressive symptoms oven a 2-week period.

Am

J Psychiatry

1 52:2,

February

1995

265

BRIEF

REPORTS

TABLE

1. Response

After 14 Days of 37 Depressed

Outpatients

to 4 Days of Treatment
Score 14 Days

With Dexamethasone

or Placebo
Response a t I 4 Daysa None

H amilton Baseline

Dc pression

Positive

Group Dexamethasone
(N=19) Placebo (N=18) Hamilton Fishers depression exact test,

Mean

SD

Mean

SD

26.5 29.4

4.5 4.7

19.2 25.4

7.2 5.2

7 i

36.8k 5.6

12

Total
a2ijtem

(N=37)
scale score one-tailed.

27.9
reduced

4.7
by SO% or to i4.

22.2

8.9

21.6

i7 29

63.2 94.4

78.4

b0.03,

METHOD
Patients meeting DSM-III-R criteria for major depressive episode

were selected

from our outpatient

facilities

for inclusion
years were assistant

in this study.
considered. Pa(M.M.) by tele-

Patients between the ages of 1 8 and 70 tients were screened by the study research

phone L.J.R.,

and then by one of four research and J.M.R.) in person. Diagnosis

psychiatrists (A.B.S., S.M.-B., was determined in a consen-

sus conference in which research psychiatrists reviewed psychiatric history, family history, clinical findings, and mental status findings. Exclusion criteria included active medical illness, endocrinopathy, current treatment with steroids, any contraindication to receiving

tailed). The overall response rate was 22% (eight of 37); seven (88%) of the eight responding patients were in the dexamethasone group. No subjects were eliminated from the study because of side effects on toxicity. Several patients reported transient light-headedness that was not found to be of clinical significance, and none of the patients reported euphoria, central nervous system activation, on other side effects such as headache, gastrointestinal upset, or nausea.

dexamethasone,

treatment

with

antidepressant

medications,

or psy-

chiatric comorbidity (schizophrenia, anxiety disorder, or alcoholism). A 2 1 -item Hamilton depression scale score of >20 was required for inclusion in the study. Of 98 subjects who were screened originally, 61 did not meet inclusion criteria; 37 patients (1 1 men and 26 women), 20-67 years old,

DISCUSSION This placebo-controlled, randomized trial of dexamethasone in the treatment of depression extends our previous finding that glucocorticoids may have antidepressant effects (13, 14). Both earlier reports were anecdotal and lacked uniformity in dose and route of administration of dexamethasone: the dose range was 4-12 mg given intravenously, and some patients received a combination of 4-8 mg of intravenous dexamethasone and an additional 4-mg oral dose on the basis of their clinical status and response ( 14). Having observed that depressive symptoms improved within 10 days after dexamethasone administration, we chose to assess this response by using a treatment design in which medication or placebo was given in the first 4 days of the study followed by a 1 0-day drug-free period after which depression status was assessed. The overall placebo response rate was 6%, which is lower than is often described for studies of antidepressants (20%-40%). The patients studied here were seen only twice by research staff, had brief telephone contact on days 2-4, received medication for 4 days, and completed the study within 14 days. The lack of contact with staff, the brief duration of the study, and the abbneviated use of medication may have reduced the expected response to placebo agents. This finding merits further investigation to assess the antidepressant effects of dexamethasone for the following reasons: 1 ) apparent efficacy for symptoms of depression in a subgroup of depressed patients, 2) possible utility of glucocorticoids as a novel class of antidepressant drugs, 3) rapid response (within 14 days) profile, which may shorten morbidity, 4) low risk for suicide by drug overdose with dexamethasone, and 5) lack

were

included

in the study.

The

mean

baseline

Hamilton

depression

scale score for the patients was 27.9 (SD=4.7). After providing informed consent, the 37 patients were randomly assigned to receive either placebo or 4 mg/day of oral dexamethasone for 4 days. Patients, clinical investigators, and the research assistant were blind to the treatment condition during the study period. All patients were telephoned daily on days 2, 3, and 4 by the research assistant for a brief checkup and reminded to take their study medication to ensure compliance. At the end of 14 days, patients returned for an exit interview and completion of a final Hamilton depression scale. Response was defined as a SO% reduction in Hamilton depression scale score from baseline or a terminal Hamilton depression scale score of 14. Patients needing further treatment were referred for an appropriate standard treatment of depression. The significance of differences between patients given dexamethasone and those given placebo in quantitative variables (age, baseline Hamilton depression scale score, i4-day Hamilton depression scale score) was assessed by using two-sample t tests; for qualitative vanables (sex, race, marital status, education, employment, medical history, psychiatric history, and medications), chi-square tests were used. Fishers exact test was used to test for equality of response nate for the two groups.

RESULTS There were no statistically significant differences between the drug and placebo groups in the qualitative variables. Seven (37%) of the 19 patients in the dexamethasone group, compared with one (6%) of the 18 patients in the placebo group, responded with a S0% reduction in Hamilton depression scale score or a scone of14 (table 1). The percent of responding patients in the dexamethasone group was significantly greaten than the percent in the placebo group (p=O.O3, Fishers exact test, one-

266

Am

J Psychiatry

1 52:2,

February

1995

BRIEF

REPORTS

of toxicity duration

or substantial of dexamethasone

side

effects treatment.

with

this

dose

and

7. Sonino
duction. 8.

N: The use of ketoconazole

N EnglJ Med 1987;

as an inhibitor
18

of steroid

proL,

317:812-8

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J Psychiatry

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1995

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