Posted by Adam on November 17, 1999, at 16:54:03
In reply to Re: Ketoconazole for depression / DHEA [Long, posted by Scott L. Schofield on November 17, 1999, at 11:23:59
Wow, that's really fascinating. Thanks, Scott. I've never had my cortisol levels checked, only
thyroid, which was normal. I wonder what such a test would find. Unfortunately, the comination of
selegiline and ketoconazole would be a bad one (both pretty potent CYP inhibitors). I think that
property (CYP-inhibition) makes ketoconazole a rather tricky choice as an antidepressant. I would
imagine any augmentation strategy could be frought with difficulties. Are there other, more benign
antiglucocorticoids? What's the mechanistic connection to pregnalone? How does ketoconazole bring
about increases in pregnalone levels?>
> 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
poster:Adam
thread:15312
URL: http://www.dr-bob.org/babble/19991108/msgs/15405.html