Neuroendocrine responses to inhibitors of steroid biosynthesis in patients with major depression resistant to antidepressant therapy.
OBJECTIVE
Patients with major depression frequently have high cortisol levels and resistance to dexamethasone. We sought to determine to what extent major depression might be influenced by inhibitors of steroid biosynthesis and to study the endocrine changes produced.


METHODS
After drug washout, 20 treatment-resistant patients with major depression were given aminoglutethimide, metyrapone, and/or ketoconazole, along with a small dose of cortisol for 8 weeks. Hamilton Depression Rating Scale (HDRS) ratings, 8:00 AM cortisol dehydroepiandrosterone sulfate (DHAS), adrenocorticotropin (ACTH), and testosterone levels were followed weekly or oftener. A dexamethasone suppression test (DST) was conducted before and after treatment.


RESULTS
Seventeen patients (85%) completed the course of treatment, and a significant mean drop (P < or = 0.0001) of 50% in the HDRS score occurred by 7 weeks of treatment. Cortisol levels fluctuated widely and were often still high after the patient had improved clinically. Dehydroepiandrosterone sulfate levels fell more uniformly and were found to be a useful indicator of compliance and, to some extent, efficacy with aminoglutethimide and ketoconazole therapy. The correlation between DHAS and HDRS (r = 0.94) was significant (P = 0.02). Testosterone levels in men fell with ketoconazole but returned promptly to normal at the end of treatment. Adrenocorticotropin levels were normal or elevated, depending on the assay used, and rose (P = 0.07; n = 13) in most subject during therapy. Of the 6 responders who had nonsuppressor DSTs before starting therapy, 5 had reverted to normal 1 to 2 weeks following cessation of therapy (P = 0.0006).


CONCLUSIONS
Abnormal metabolism of adrenocortical steroids may perpetuate depression, and alterations of synthesis or metabolism of these steroids may lead to a remission.
Murphy
B E
BE
McGill University, Montreal, Quebec. md98@musica.mcgill.ca
Ghadirian
A M
AM
Dhar
V
V
D000328:Adult; D000616:Aminoglutethimide / Q000627:therapeutic use*; D000704:Analysis of Variance; D000726:Androgen Antagonists / Q000627:therapeutic use; D000928:Antidepressive Agents / Q000627:therapeutic use*; D019314:Dehydroepiandrosterone Sulfate / Q000037:antagonists & inhibitors / Q000097:blood; D003866:Depressive Disorder / Q000097:blood / Q000188:drug therapy*; D003907:Dexamethasone; D004351:Drug Resistance; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D006727:Hormone Antagonists / Q000627:therapeutic use*; D006801:Humans; D006854:Hydrocortisone / Q000037:antagonists & inhibitors / Q000097:blood; D007654:Ketoconazole / Q000627:therapeutic use*; D008297:Male; D008797:Metyrapone / Q000627:therapeutic use*; D008875:Middle Aged; D013256:Steroids / Q000037:antagonists & inhibitors* / Q000097:blood; D016896:Treatment Outcome
D000726:Androgen Antagonists; D000928:Antidepressive Agents; D004791:Enzyme Inhibitors; D006727:Hormone Antagonists; D013256:Steroids; D000616:Aminoglutethimide; D019314:Dehydroepiandrosterone Sulfate; D003907:Dexamethasone; D007654:Ketoconazole; D006854:Hydrocortisone; D008797:Metyrapone