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Dr. Bob is Robert Hsiung, MD,
[email protected]Shown: posts 1 to 5 of 5. This is the beginning of the thread.
Posted by Scott L. Schofield on November 16, 1999, at 14:22:26
Ketoconazole (oral) has actually been investigated for its usefulness in major depression. The results of controlled trials are equivocal. It is thought that a disturbance in CRH - ACTH - cortisol function may play a part in, or be a result of, major depression.
Cortisol is secreted by the adrenal glands and is said to be a "stress" hormone. What this means is that in a healthy person, the experience of stress will cause levels of cortisol to rise in the blood-stream. I don't know what function cortisol has in a stressful situation, but I imagine it has its benefits. One measure of cortisol function is the dexamethasone-suppression test (DST). When given dexamethasone (fake cortisol?), the rate of cortisol secretion is suppose to be suppressed so as to keep blood-levels stable. In many people with major depression, this control system seems to be out-of-whack. 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.
Ketoconazole has properties other than those that act as an antifungal. Among them is the ability to inhibit the biosynthesis of cortisol (antiglucocorticoid). It is used in diseases in which excessive levels of cortisol occur (hypercortisolemia). Cushings disease is an example of this.
If elevated levels of cortisol in the blood-stream cause or contribute to depression, shutting down the cortisol factories (adrenal glands) should help. Right? Well...
I'm glad the *topical* ketoconazole thread was running. I had no idea that cytochrome P450 inhibition was another of ketoconazole's properties. Is it possible to compensate for this by adjusting the dosage of those drugs with which it competes?
Anyway, you can find articles in the literature regarding the use of ketoconazole in major depression and treatment-resistant depression. The most recent one I found on Medline is from October 1999.
- Scott
Posted by Adam on November 16, 1999, at 15:49:46
In reply to Ketoconazole for depression, posted by Scott L. Schofield on November 16, 1999, at 14:22:26
Wow, that's new to me. I remember this conversation I had with a dermatologist years ago where there was some
excitement about ketoconazole because it appeared to be an antiandrogen, and maybe could be used for baldness,
though it seemed doubtful; not in a shampoo, because it wasn't absorbed well, and not orally because chronic
treatment caused so many problems with drug interactions, but maybe in a cream. Don't know what happened to that
idea. The cortisol/steroid connection is interesting vis-a-vis its "antiandrogen" properties. Anyway, it is, I
guess, a very potent inhibitor of some CYPs, and is sometimes used in research for that purpose alone.> Ketoconazole (oral) has actually been investigated for its usefulness in major depression. The results of controlled trials are equivocal. It is thought that a disturbance in CRH - ACTH - cortisol function may play a part in, or be a result of, major depression.
>
> Cortisol is secreted by the adrenal glands and is said to be a "stress" hormone. What this means is that in a healthy person, the experience of stress will cause levels of cortisol to rise in the blood-stream. I don't know what function cortisol has in a stressful situation, but I imagine it has its benefits. One measure of cortisol function is the dexamethasone-suppression test (DST). When given dexamethasone (fake cortisol?), the rate of cortisol secretion is suppose to be suppressed so as to keep blood-levels stable. In many people with major depression, this control system seems to be out-of-whack. 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.
>
> Ketoconazole has properties other than those that act as an antifungal. Among them is the ability to inhibit the biosynthesis of cortisol (antiglucocorticoid). It is used in diseases in which excessive levels of cortisol occur (hypercortisolemia). Cushings disease is an example of this.
>
> If elevated levels of cortisol in the blood-stream cause or contribute to depression, shutting down the cortisol factories (adrenal glands) should help. Right? Well...
>
> I'm glad the *topical* ketoconazole thread was running. I had no idea that cytochrome P450 inhibition was another of ketoconazole's properties. Is it possible to compensate for this by adjusting the dosage of those drugs with which it competes?
>
> Anyway, you can find articles in the literature regarding the use of ketoconazole in major depression and treatment-resistant depression. The most recent one I found on Medline is from October 1999.
>
>
> - Scott
Posted by Ant-z on November 17, 1999, at 9:46:18
In reply to Re: Ketoconazole for depression, posted by Adam on November 16, 1999, at 15:49:46
>
>
> Wow, that's new to me. I remember this conversation I had with a dermatologist years ago where there was some
> excitement about ketoconazole because it appeared to be an antiandrogen, and maybe could be used for baldness,
> though it seemed doubtful; not in a shampoo, because it wasn't absorbed well, and not orally because chronic
> treatment caused so many problems with drug interactions, but maybe in a cream. Don't know what happened to that
> idea. The cortisol/steroid connection is interesting vis-a-vis its "antiandrogen" properties. Anyway, it is, I
> guess, a very potent inhibitor of some CYPs, and is sometimes used in research for that purpose alone.
>
>
>
> > Ketoconazole (oral) has actually been investigated for its usefulness in major depression. The results of controlled trials are equivocal. It is thought that a disturbance in CRH - ACTH - cortisol function may play a part in, or be a result of, major depression.
> >
> > Cortisol is secreted by the adrenal glands and is said to be a "stress" hormone. What this means is that in a healthy person, the experience of stress will cause levels of cortisol to rise in the blood-stream. I don't know what function cortisol has in a stressful situation, but I imagine it has its benefits. One measure of cortisol function is the dexamethasone-suppression test (DST). When given dexamethasone (fake cortisol?), the rate of cortisol secretion is suppose to be suppressed so as to keep blood-levels stable. In many people with major depression, this control system seems to be out-of-whack. 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.
> >
> > Ketoconazole has properties other than those that act as an antifungal. Among them is the ability to inhibit the biosynthesis of cortisol (antiglucocorticoid). It is used in diseases in which excessive levels of cortisol occur (hypercortisolemia). Cushings disease is an example of this.
> >
> > If elevated levels of cortisol in the blood-stream cause or contribute to depression, shutting down the cortisol factories (adrenal glands) should help. Right? Well...
> >
> > I'm glad the *topical* ketoconazole thread was running. I had no idea that cytochrome P450 inhibition was another of ketoconazole's properties. Is it possible to compensate for this by adjusting the dosage of those drugs with which it competes?
> >
> > Anyway, you can find articles in the literature regarding the use of ketoconazole in major depression and treatment-resistant depression. The most recent one I found on Medline is from October 1999.
> >
> >
> > - ScottI 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.
If anyone has any input or suggestions I would love to hear them. Thanx, Ant-z
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
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
This is the end of the thread.
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Dr. Bob is Robert Hsiung, MD,
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