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.

Method: 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.