Antiglucocorticoid treatment of depression: double-blind ketoconazole.
BACKGROUND
Hypercortisolemia is frequently observed in major depression but its pathophysiologic significance is unknown. In patients in whom hypercortisolism contributes to depressive symptomatology, antiglucocorticoid agents should have antidepressant effects.


METHODS
Twenty medication-free depressed patients (eight of whom were hypercortisolemic and twelve of whom were not) received either the cortisol biosynthesis inhibitor, ketoconazole (400-800 mg/d p.o.) or placebo for 4 weeks in a double-blind manner, and behavioral ratings were performed weekly.


RESULTS
Ketoconazole, compared to placebo, was associated with improvements in depression ratings in the hypercortisolemic, but not in the non-hypercortisolemic patients. The hormonal changes seen (decreased dehydroepiandrosterone and testosterone levels and increased pregnenolone and pregnenolone-sulfate levels) are consistent with enzymatic blockade of C17,20-lyase, 11-hydroxylase, and 17-hydroxylase. Ketoconazole was generally well tolerated with no occurrence of significant side effects or laboratory abnormalities.


CONCLUSIONS
This small-scale double-blind study suggests that antiglucocorticoids have antidepressant activity in hypercortisolemic depressed patients. The data are consistent with a causal role of adrenocortical dysfunction in some depressed patients and suggest the need for larger-scale trials.
Wolkowitz
O M
OM
Department of Psychiatry, University of California at San Francisco Medical Center, USA.
Reus
V I
VI
Chan
T
T
Manfredi
F
F
Raum
W
W
Johnson
R
R
Canick
J
J
D000328:Adult; D003865:Major Depressive Disorder / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*; D004311:Double-Blind Method; D005260:Female; D005938:Glucocorticoids / Q000037:antagonists & inhibitors; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D007654:Ketoconazole / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D011569:Psychiatric Status Rating Scales; D012720:Severity of Illness Index
D005938:Glucocorticoids; D007654:Ketoconazole; D006854:Hydrocortisone