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Re: Ketoconazole for depression / DHEA [Long

Posted by Scott L. Schofield on November 17, 1999, at 11:23:59

In reply to Re: Ketoconazole for depression, posted by Ant-z on November 17, 1999, at 9:46:18

> > In many people with major depression,... levels of cortisol can be abnormally high. In addition, the production of cortisol is not suppressed by dexamethasone. In the past, this has been used as a diagnostic test for depression. I don't know if it is anymore.

> I recently had the DST cortisol test, and it came back my cortisol level is low. The endocronologist(sp?) said that he's not convinced that this is causing my fatigue/depression/muscle-tiredness. After reading the DHEA post, I might consider experimenting with this substance, seeing that the symptoms it was so helpful with are my biggest problem.(Anhedonia, fatigue, emotional numbness). I'm also considering thyroid augmentation, even though my levels were in the normal range.

When you mentioned DHEA, a little bell went off inside my head (not tinnitus). I read some ketoconazole stuff yesterday and remembered seeing references to androsteroids and DHEA. It seems that ketoconazole *decreases* levels of DHEA and testosterone, but increases levels of pregnenolone. I dug a little deeper and voila...

I have always thought that dopamine plays a more significant role in affective-disorders than the lack of literature regarding this topic would indicate. I would like to see it looked at a bit more closely, especially in bipolar depression and retarded-type uniplolar depression. I get the feeling that it might be involved in a sort of primary vs. secondary site(s) of dysregulation.


Biol Psychiatry 1999 Apr 15;45(8):1070-4

Antiglucocorticoid treatment of depression: double-blind ketoconazole.

Wolkowitz OM, Reus VI, Chan T, Manfredi F, Raum W, Johnson R, Canick J

Department of Psychiatry, University of California at San Francisco Medical
Center, USA.

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.

Publication Types:
Clinical trial
Randomized controlled trial

PMID: 10386195, UI: 99313973


Eur J Neurosci 1999 Oct;11(10):3757-3760

The neurosteroid pregnenolone sulphate increases dopamine release and the dopaminergic response to morphine in the rat nucleus accumbens.

Barrot M, Vallee M, Gingras MA, Le Moal M, Mayo W, Piazza PV
[Record supplied by publisher]

Neurosteroids are a subclass of steroids that can be synthesized in the central nervous system independently of peripheral sources. Clinical studies in humans have associated some of these hormones with a generic sensation of 'well-being' and with pathologies such as depression. In rodents, the neurosteroid pregnenolone sulphate (Preg-S) has been shown to present antidepressant-like effects. These observations suggest that neurosteroids could interact with reward-related processes, mood and motivation. However, the possible neural substrates of such an effect remain unclear. In this report, we studied the action of Preg-S on the activity of the mesencephalic dopaminergic projection to the nucleus accumbens which is considered one of the biological substrates of motivation and reward. Both the direct effect of Preg-S and the influence of this hormone on the dopaminergic response to the pharmacological reward provided by the opiate morphine, were studied by means of microdialysis. Pregnenolone sulphate dose-dependently increased dopamine release in the nucleus accumbens. Furthermore, this hormone doubled the dopaminergic response to morphine. These effects were observed for Preg-S doses of 100, 200, and 400 pmol injected intracerebroventricularly. The stimulant effect of Preg-S on dopamine could mediate some of the behavioural effects of neurosteroids and in particular the interaction of these hormones with mood and motivation.

PMID: 10564382


Don't blame me. I'm only the messenger.

- Scott




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