Natural steroids counteracting some actions of putative depressogenic steroids on the central nervous system: Potential therapeutic benefits

Psychological similarities in the symptomatology of Cushing's and depressive diseases led to repeated attempts of treatment of the affective disease by suppression of adrenocortical secretion. While successful in many patients, all drugs employed - metyrapone, ketoconazole and aminoglutethimide - carry the danger of inducing adrenal insufficiency. In addition, their undesirable side effects were also a main reason for treatment suspension. In our 1990 proposal for the treatment of depression through control of adrenal steroid levels, we set as one of the goals the identification of steroids which can antagonize each other on their effects on the central nervous system. Specifically, we looked first at steroids that could counter each other's effects on long-term potentiation, a putative memory mechanism in the central nervous system. One reason for this was the consensus that memory mechanisms are affected in both Cushing's and depressive patients. Another was the fact that cortisol-type hormones which underlie, at least in part, the depressogenic actions of adrenal steroids also have inhibitory effects on LTP. We conjectured, then, that a steroid with opposite effects, one that could enhance long-term potentiation and, further, that could counter the depressant effects of corticosterone on long-term potentiation, could be of use in the treatment of depression. Dehydroepiandrosterone sulfate increases long-term potentiation in a dose-related manner, and preliminary data suggest that it also counteracts the depressant effects of corticosterone on long-term potentiation when injected simultaneously on experimental animals. Potentially at least, rather than resort to total suppression of adrenocortical activity, it may be possible to treat depression just by counteracting some of the effects of cortisol-like hormone actions in the central nervous system. Further, both in clinical trials as well as in experimental animals, dehydroepiandrosterone sulfate has been shown to enhance performance in memory-requiring tasks.