Antiglucocorticoid therapies in major depression: a review

In major depression there are two well-documented biochemical abnormalities: hypercortisolism, and its resistance to dexamethasone suppression. It therefore seems reasonable to see if giving drugs which interfere with cortisol biosynthesis might bring about a remission. An open trial was begun in our institution of 20 refractory patients with major depression. Aminoglutethimide, metyrapone, ketoconazole or combinations of these drugs along with a maintenance dose of cortisol were used for eight weeks. Of the 17 completers, eleven patients were considered to have good responses and two partial responses. Four had complete remissions lasting several years. A similar study of four patients who received oral RU 486 also gave encouraging results. Two patients with obsessive compulsive disorder associated with depression showed striking improvement on aminoglutethimide combined with a serotonin re-uptake inhibitor. In addition to a case report in 1988 by Ravaris et al. of a patient hypophysectomized for previous Cushing's syndrome whose depression responded to ketoconazole, several other studies over the past five years have had similar favorable results. Wolkowitz et al. (1993) gave oral ketoconazole to 10 depressed patients for three weeks which resulted in a significant drop in their Hamilton Depression Scale ratings. O'Dwyer et al. (1995) conducted a placebo-controlled single-blind crossover study using lifetyrapone and maintenance cortisol in eight inpatients for two weeks; six responded. Thakore and Dinan (1995) studied eight inpatients using ketoconazole for four weeks; there were five responders and three partial responders. Anand et al. (1995) conducted a four-week double-blind trial of ketoconazole in a single treatment-refractory patient with good results. Arana et al. (1995) used a different approach but one which also leads to suppression of endogenous corticosteroids-i.e. short-term dexamethasone suppression (4 mg/day for four days). When tested at 14 days, 7/19 of the dexamethasone group had responded well while only 1/18 of the placebo group had responded. While these studies have shortcomings, antiglucocorticoid therapy appears to be an effective tool in the treatment of major depression. Possible mechanisms are discussed, and a unifying hypothesis is attempted.