![[dr. bob]](/dr-bob-sm.gif)
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 25 of 28. This is the beginning of the thread.
Posted by ixus on June 18, 2005, at 12:00:17
Hi,
who can explain fluoxetine and olanzapine synergy after reading the article below? :-)
/ixus
==============================================
Dopaminergic mechanism of antidepressant action in depressed patients
by
Willner P, Hale AS, Argyropoulos S.
Department of Psychology,
University of Wales Swansea,
Swansea SA2 8PP, UK.
J Affect Disord. 2005 May;86(1):37-45ABSTRACT
Clinical studies have not yet determined a common mechanism of action for antidepressant drugs, which have primary sites of action on a variety of different neurotransmitter systems. However, a large body of evidence from animal studies demonstrates that sensitisation of D2-like dopamine receptors in the mesolimbic dopamine system may represent a 'final common pathway' in antidepressant action. The present study aimed to determine whether, consistent with data from animal studies, the clinical antidepressant action of selective serotonin reuptake inhibitors (SSRIs) is reversed by acute administration of a receptor antagonist selective for D2-like receptors in the mesolimbic dopamine system. The participants were patients diagnosed with major depressive disorder (n=8) who had been treated successfully (Hamilton Depression Scale<10) with selective serotonin uptake inhibitors (fluoxetine, citalopram or paroxetine); and age-matched, non-depressed, untreated volunteers (n=10). They attended a psychiatric research ward on an out-patient basis, and received double-blind acute administration of either placebo, or a low dose of the selective dopamine D2/D3 receptor antagonist sulpiride (200 mg), in a counterbalanced order. Mood and psychomotor effects were assessed using visual analogue scales and the Fawcett-Clark Pleasure Capacity Scale. Sulpiride slightly improved subjective well-being in the control group, but in the antidepressant-treated patients, sulpiride caused a substantial reinstatement of depressed mood. These data are consistent with the hypothesis that sensitisation of D2-like receptors may be central to the clinical action of SSRIs.
================================================
Posted by RetiredYoung on June 18, 2005, at 12:16:13
In reply to Who knows the drug synergy mechanism?, posted by ixus on June 18, 2005, at 12:00:17
Guess my Symbyax isn't working for me, afterall! :)
Posted by linkadge on June 18, 2005, at 16:46:14
In reply to Re: Who knows the drug synergy mechanism?, posted by RetiredYoung on June 18, 2005, at 12:16:13
Contrary to what this article suggests, I think that AD mechanisms can be very diverse.
Even though d2 transmission would be dampened after olanzapine treatment, 5-ht1a transmission would be indirectly enhanced. This would add to the agonistic properties of fluoxetine for the 5-ht1a.
This is just an idea, but 5-ht1a agonists are antidepressants.
Linkadge
Posted by Phillipa on June 18, 2005, at 18:58:01
In reply to Re: Who knows the drug synergy mechanism?, posted by linkadge on June 18, 2005, at 16:46:14
Thanks for the interpretation. I guess I need a good pharmacology book. Fondly, Phillipa
Posted by ixus on June 18, 2005, at 22:47:12
In reply to Re: Who knows the drug synergy mechanism?, posted by linkadge on June 18, 2005, at 16:46:14
> Contrary to what this article suggests, I think that AD mechanisms can be very diverse.
>
> Even though d2 transmission would be dampened after olanzapine treatment, 5-ht1a transmission would be indirectly enhanced. This would add to the agonistic properties of fluoxetine for the 5-ht1a.
>
> This is just an idea, but 5-ht1a agonists are antidepressants.
>
>
> Linkadge
Hi Linkadge,
I am aware of dopamine and serotonin reverse mechanism, but apparently one cannot expect that olanzapine enhances 5-ht1a transmission. This is your own theory which is not supported by either theoretical or experimental research. On which basis do you suggest that 5-HT1a would be indirectly enhanced?
I think we are all messed by f*cked up pharmacy market :-)
It may be that no one knows the explanation, the things may actually work, but why they try to create theory that is not based on anything?
/ixus
Posted by linkadge on June 18, 2005, at 23:29:16
In reply to Re: Who knows the drug synergy mechanism? » linkadge, posted by ixus on June 18, 2005, at 22:47:12
Now, now.
It try hard not to pull this out of nowhere.
--------------------------------------------
from http://www.neurotransmitter.net/onea.html5-HT2A and D2 receptor blockade increases cortical DA release via 5-HT1A receptor activation: a possible mechanism of atypical antipsychotic-induced cortical dopamine release
J Neurochem 2001 76: 1521-1531
"Atypical antipsychotic drugs (APDs), all of which are relatively more potent as serotonin (5-HT)2A than dopamine D2 antagonists, may improve negative symptoms and cognitive dysfunction in schizophrenia, in part, via increasing cortical dopamine release. 5-HT1A agonism has been also suggested to contribute to the ability to increase cortical dopamine release. The present study tested the hypothesis that clozapine, olanzapine, risperidone, and perhaps other atypical APDs, increase dopamine release in rat medial prefrontal cortex (mPFC) via 5-HT1A receptor activation, as a result of the blockade of 5-HT2A and D2 receptors. M100907 (0.1 mg/kg), a 5-HT2A antagonist, significantly increased the ability of both S(–)-sulpiride (10 mg/kg), a D2 antagonist devoid of 5-HT1A affinity, and R(+)-8-OH-DPAT (0.05 mg/kg), a 5-HT1A agonist, to increase mPFC dopamine release. These effects of M100907 were abolished by WAY100635 (0.05 mg/kg), a 5-HT1A antagonist, which by itself has no effect on mPFC dopamine release. WAY100635 (0.2 mg/kg) also reversed the ability of clozapine (20 mg/kg), olanzapine (1 mg/kg), risperidone (1 mg/kg), and the R(+)-8-OH-DPAT (0.2 mg/kg) to increase mPFC dopamine release. Clozapine is a direct acting 5-HT1A partial agonist, whereas olanzapine and risperidone are not. These results suggest that the atypical APDs via 5-HT2A and D2 receptor blockade, regardless of intrinsic 5-HT1A affinity, may promote the ability of 5-HT1A receptor stimulation to increase mPFC DA release, and provide additional evidence that coadministration of 5-HT2A antagonists and typical APDs, which are D2 antagonists, may facilitate 5-HT1A agonist activiy.
-----------------------------------------------Some theorize that an AD's effectivness can be quantified by its ability to activate the 5-ht1a receptors. The 5-ht1a receptors probably represent any neurotrophic action of the drugs.
Linkadge
Posted by linkadge on June 18, 2005, at 23:45:22
In reply to Re: Who knows the drug synergy mechanism? » linkadge, posted by ixus on June 18, 2005, at 22:47:12
Some of the theory is sound, some is not.
I think the reason the drugs f'd us up is more related to the fact that the drugs activate the "feel crappy" receptors just as potently as they activte the "feel good" receptors.
When taking an SSRI, you have to tolerate 5-ht1d,5-ht2a,5-ht2b,-5ht2c,5-ht3,5-ht7 etc activation just to get some 5-ht1a activation.
5-ht1d activation = apathy
5-ht2a activation = anxiety, paranoia, cortisol
issues, melatonin release
problems, migrane, visual
disturbances.
5-ht2b activation = sleep disturbances
5-ht2c activation = agitation/agression, sexual
side effects, less NAA dopamine, movement issues etc.
5-ht3 activation = Social phobia, anxiety, nausia
GI upset, manic behavior.
5-ht7 activation = memory consolidation issues ?
It's really messed up.
Linkadge
Posted by ixus on June 19, 2005, at 3:11:14
In reply to Re: Who knows the drug synergy mechanism?, posted by linkadge on June 18, 2005, at 23:45:22
Thanks Linkadge,
I did not know there are so many serotonin receptor types. So far I knew only the major ones.
/ixus
Posted by linkadge on June 19, 2005, at 5:00:58
In reply to Re: Who knows the drug synergy mechanism? » linkadge, posted by ixus on June 19, 2005, at 3:11:14
Theres more than that too.
5-ht1-7 (I think) with different subtypes for each. These are what has been identified. And they're not sure what they all do. I mean they have some good ideas, but I am guessing a lot is still not concrete.
Medicinal drugs are generally only mild uptake inhibitors (if that). Their actions are more a result of their properties as agonists and antagonists at different receptors. This is why, (for certain individuals), they may do a better job.
A lot of medicinal herbs, ginkgo, SJW, Kava, Dong Quai, Black Cohosh are 5-ht1a agonists. I know SJW has some 5-ht2c antagonistic properties which may be why it lacks prominant sexual side effects.
Its really a strange bag of nails.Linkadge
Posted by SLS on June 19, 2005, at 8:46:59
In reply to Re: Who knows the drug synergy mechanism?, posted by linkadge on June 18, 2005, at 23:29:16
Hi.
Thanks for the summary of receptors, Linkadge.
Does it make sense that 5-HT neurons would want to maintain homeostasis by upregulating 5-HT1a autoreceptors as the activity of the neurons are inhibited by 5-HT2a blockade? I don't know. It would have been pretty cool to have gepirone floating around to test this clinically. 5-HT1a receptors also exist as postsynaptic excitatory receptors that, when stimulated by an agonist, exert anxiogenic effects, so it depends on which receptors have become upregulated as to the net effect. Location, location, location.
"Overall, our results provide evidence that stimulation of the presynaptic 5-HT1A receptors in the MRN results in an anxiolytic action, whereas stimulation of the post-synaptic 5-HT1A receptors in its projection area results in an anxiogenic effect. These results are consistent with an overall reduction in 5-HT neurotransmission in the dorsal hippocampus having an anxiolytic effect, and they explain the relatively weak anxiolytic profile detected when 5-HT1A receptor agonists are given systemically."
http://www.jneurosci.org/cgi/content/abstract/16/15/4810
Perhaps this is why drugs like gepirone and buspirone have not become more popular as anxiolytics. Their efficacy probaby hinges on the individual's ratios of 5-HT1a adaptations between pre- and post-synaptic sensitivity. That anxiolytic activity occurs latently with both of these drugs argues for a reregulation of receptors that would take 2-4 weeks to develop in much the same fashion as an antidepressant.
- Scott
Posted by SLS on June 19, 2005, at 9:11:41
In reply to Re: Who knows the drug synergy mechanism?, posted by linkadge on June 18, 2005, at 23:45:22
> When taking an SSRI, you have to tolerate 5-ht1d,5-ht2a,5-ht2b,-5ht2c,5-ht3,5-ht7 etc activation just to get some 5-ht1a activation.This is a very sound conclusion. You might be right. Are the 5-HT1a receptors you refer to postsynaptic excitatory receptors or somato-dendritic inhibitory autoreceptors? This is a critical distinction that must be described when talking about this receptor subtype.
"Overall, our results provide evidence that stimulation of the presynaptic 5-HT1A receptors in the MRN results in an anxiolytic action, whereas stimulation of the post-synaptic 5-HT1A receptors in its projection area results in an anxiogenic effect. These results are consistent with an overall reduction in 5-HT neurotransmission in the dorsal hippocampus having an anxiolytic effect, and they explain the relatively weak anxiolytic profile detected when 5-HT1A receptor agonists are given systemically."
http://www.jneurosci.org/cgi/content/abstract/16/15/4810
Perhaps this is why drugs like gepirone and buspirone have not become more popular as anxiolytics. Their efficacy probaby hinges on the individual's ratios of 5-HT1a adaptations between pre- and post- synaptic sensitivity. That anxiolytic activity occurs latently with both of these drugs argues for a reregulation of receptors that would take 2-4 weeks to develop in much the same fashion as an antidepressant.
Do you believe that pindolol, a 5-HT1a somato-dendritic autoreceptor antagonist, "hastens" the antidepressant effects of SRIs?
Is there some sort of chart on the Internet that can expand upon what you have provided in your summary below? I'm going to save your post anyway.
- Scott
> 5-ht1d activation = apathy
> 5-ht2a activation = anxiety, paranoia, cortisol
> issues, melatonin release
> problems, migrane, visual
> disturbances.
> 5-ht2b activation = sleep disturbances
> 5-ht2c activation = agitation/agression, sexual
> side effects, less NAA dopamine, movement issues etc.
> 5-ht3 activation = Social phobia, anxiety, nausia
> GI upset, manic behavior.
> 5-ht7 activation = memory consolidation issues ?
>
>
> It's really messed up.
>
>
> Linkadge
>
>
Posted by ed_uk on June 19, 2005, at 9:17:18
In reply to Re: Who knows the drug synergy mechanism? » linkadge, posted by ixus on June 19, 2005, at 3:11:14
Hi Scott!
What do you think of this........
Neuropsychopharmacology. 1997 May;16(5):333-8. Related Articles, Links
Selective activation of postsynaptic 5-HT1A receptors induces rapid antidepressant response.
Blier P, Bergeron R, de Montigny C.
Neurobiological Psychiatry Unit, McGill University, Montreal, Canada.
It has been reported that the 5-HT1A autoreceptor antagonist pindolol can accelerate the antidepressant response to the selective serotonin (5-HT) reuptake inhibitor (SSRI) paroxetine, presumably by preventing the initial decrease in firing activity of 5-HT neurons produced by the SSRI. The present study was aimed at further exploring this treatment strategy in three groups of 10 patients with unipolar major depression allocated sequentially to three treatment arms for 28 days. The administration of the selective 5-HT1A agonist buspirone (20 mg/day for 1 week and 30 mg/day thereafter) with pindolol (2.5 mg TID) was used to activate selectively postsynaptic 5-HT1A receptors. This combination produced a greater than 50% reduction of depressive symptoms in the first week in 8 of 10 patients and the response was sustained for the remainder of the trial. In contrast, the combination of tricyclic antidepressant drugs devoid of effect on the 5-HT reuptake process (desipramine or trimipramine, 75 mg/day for 1 week and 150 mg/day thereafter) with pindolol resulted in only one of ten patients achieving a 50% improvement after 28 days. The combination of the SSRI fluvoxamine (50 mg/day for 1 week and 100 mg/day thereafter) with pindolol produced a marked antidepressant effect but did not act as rapidly as the buspirone plus pindolol combination with none, four, and eight patients achieving a 50% amelioration after 7, 14, and 21 days of treatment, respectively. These results provide further evidence that pindolol may accelerate the antidepressant effect of drugs that alter the function of the 5-HT neurons and that the selective activation of postsynaptic 5-HT1A receptors may induce a rapid and robust antidepressant response.
~Ed
Posted by ed_uk on June 19, 2005, at 9:23:35
In reply to Re: Who knows the drug synergy mechanism? » ixus, posted by ed_uk on June 19, 2005, at 9:17:18
Posted by ed_uk on June 19, 2005, at 9:24:55
In reply to Re: Who knows the drug synergy mechanism?, posted by linkadge on June 18, 2005, at 23:45:22
Hi Link :-)
>5-ht1d activation = apathy
5-ht2a activation = anxiety, paranoia, cortisol
issues, melatonin release
problems, migrane, visual
disturbances.
5-ht2b activation = sleep disturbances
5-ht2c activation = agitation/agression, sexual
side effects, less NAA dopamine, movement issues etc.
5-ht3 activation = Social phobia, anxiety, nausia
GI upset, manic behavior.
5-ht7 activation = memory consolidation issues ?That's a very interesting table. Where did you get it from??
~Ed
Posted by SLS on June 19, 2005, at 10:05:40
In reply to Re: Who knows the drug synergy mechanism? » ixus, posted by ed_uk on June 19, 2005, at 9:17:18
Hi Ed.
Hi Linkadge.
Hi Everyone.
I read this abstract quite awhile ago. I thought the study was well conceived and the results fascinating. It think it goes a long way to validate the thoughts of Linkadge.
- Scott
> What do you think of this........
>
> Neuropsychopharmacology. 1997 May;16(5):333-8. Related Articles, Links
>
> Selective activation of postsynaptic 5-HT1A receptors induces rapid antidepressant response.
>
> Blier P, Bergeron R, de Montigny C.
>
> Neurobiological Psychiatry Unit, McGill University, Montreal, Canada.
>
> It has been reported that the 5-HT1A autoreceptor antagonist pindolol can accelerate the antidepressant response to the selective serotonin (5-HT) reuptake inhibitor (SSRI) paroxetine, presumably by preventing the initial decrease in firing activity of 5-HT neurons produced by the SSRI. The present study was aimed at further exploring this treatment strategy in three groups of 10 patients with unipolar major depression allocated sequentially to three treatment arms for 28 days. The administration of the selective 5-HT1A agonist buspirone (20 mg/day for 1 week and 30 mg/day thereafter) with pindolol (2.5 mg TID) was used to activate selectively postsynaptic 5-HT1A receptors. This combination produced a greater than 50% reduction of depressive symptoms in the first week in 8 of 10 patients and the response was sustained for the remainder of the trial. In contrast, the combination of tricyclic antidepressant drugs devoid of effect on the 5-HT reuptake process (desipramine or trimipramine, 75 mg/day for 1 week and 150 mg/day thereafter) with pindolol resulted in only one of ten patients achieving a 50% improvement after 28 days. The combination of the SSRI fluvoxamine (50 mg/day for 1 week and 100 mg/day thereafter) with pindolol produced a marked antidepressant effect but did not act as rapidly as the buspirone plus pindolol combination with none, four, and eight patients achieving a 50% amelioration after 7, 14, and 21 days of treatment, respectively. These results provide further evidence that pindolol may accelerate the antidepressant effect of drugs that alter the function of the 5-HT neurons and that the selective activation of postsynaptic 5-HT1A receptors may induce a rapid and robust antidepressant response.
>
> ~Ed
>
Posted by ed_uk on June 19, 2005, at 11:11:53
In reply to Re: Who knows the drug synergy mechanism?, posted by SLS on June 19, 2005, at 10:05:40
Hi Scott :-)
Are you interested in trying buspirone/pindolol?
~Ed
Posted by SLS on June 19, 2005, at 11:56:53
In reply to Re: Who knows the drug synergy mechanism? » SLS, posted by ed_uk on June 19, 2005, at 11:11:53
> Hi Scott :-)
>
> Are you interested in trying buspirone/pindolol?
>
> ~Ed
To tell you the truth, Ed, I completely forgot about the combination. Buspar has been on my mind, though.
- Scott
Posted by ed_uk on June 19, 2005, at 12:19:07
In reply to Re: Who knows the drug synergy mechanism? » ed_uk, posted by SLS on June 19, 2005, at 11:56:53
>To tell you the truth, Ed, I completely forgot about the combination.
You could add it to your list of things to try :-)
~Ed
Posted by linkadge on June 19, 2005, at 15:16:57
In reply to Re: Who knows the drug synergy mechanism?, posted by SLS on June 19, 2005, at 8:46:59
It is proposed by some that the theraputic action of SSRI's is due to the activation of the post-synaptic 5-ht1a receptors. Desensitization of the presynaptic autoreceptors may just lead to more post synaptic activity.
I guess the problem with gepirone was that it is more potent for the presynaptic 5-ht1a autoreceptors than the post synaptic receptor.
This may/may not lead to adaptive changes, who knows.One study found a very robust and fast acting AD effect with the combination of pindolol (presynaptic autoreceptor antagonist) and buspar for its post synaptic agonism, in which case presynaptic desensitization would not be necessary.
Linkadge
Posted by linkadge on June 19, 2005, at 16:00:55
In reply to Re: Who knows the drug synergy mechanism? » SLS, posted by linkadge on June 19, 2005, at 15:16:57
Oops, I wrote that above post without even knowing you guys were already ahead on the buspar/pindolol combination.
The problem is that it is so weird the way these drugs affect people.The term "serenics" has been used to describe post synaptic 5-ht1a agonists, because they have anti-agressive actions. But as SLS mentioned, these agents can promote anxiety. But they also have antidepressant action.
It's really dumb, because one doctor says low serotonin causes anxiety, and another says high serotonin causes anxiety.
This is what I think. I think an initial serotogenic challence causes an initial anxiety, but then produces a subsequent change in an organisms coping stradegy. (The reason I say this is because post-synaptic 1a agonists cause an acute increase in hippocampal proliferation) This effect I think is what is responsable for the "anti-panic" effect of the drugs. So its almost like the drug induced anxiety reduces the impact of an environmental anxiety.
But then SSRI's may help anxiety independant of all of this serotonin nonesence as it has been found that all of them inhibit the enzyme that metabolizes allopregnalone, a potent gaba-ergic neurosteroid, enhancing its acton some 20 fold.
But then there are other findings that say that "too much" serotonin at other receptors can cause agressiveness. I read a few studys that suggested when SSRI's were combined with pindolol there was an agressive reaction.
I personally found that lithium (5-ht1 autoreceptor antagonist) and a SSRI made me feel very ANGRY where neither alone cause any of those feelings.
Personally, if you ask me, I think that I have supersensitive serotonin autoreceptors. Of course I have no way of knowing. Some pindolol might sort that out.
I have also thought that pindolol and lithium would be interesting. Lithium is a 5-ht1b autoreceptor antagonists. Both the 5-h1a/b autoreceptors serve to reduce overall serotogenic tone when activated.
Then again what would lithium and buspar do? Since lithium is not a 5-h1a autoreceptor antagonist, but a 5-ht1b autoreceptor antagonist.
How many people on lithium would do as well on a selective 5-ht1b autoreceptor antagonist, without all the extra inositol depleating effects of lithium. I think 5-ht1b autoreceptor antagonist have a strong, "I'm not going to set myself on fire, and jump infront of moving traffic" actionExercise and Shocktreatment and rTMS seem to reduce the sensitivity of the 5-ht1a/b autoreceptors.
Post-synaptic 5-ht1a agonism also reduces acetlycholine release, which may have functionality at the cholinergic/adrenergic axis.
But in some ways ginkgo worked well for me, which is why I'd like to try tianeptine. Ginkgo serves to accelerate 5-ht uptake and also as a fairly potent 5-ht1a post-synaptic agonist.Depressed people have elevated 5-ht2 receptors, but it is interesting to note that post-synaptic 1a agonism is sufficiant to down-regulate the 5-ht2 system. So might not really be direct 5-ht2 agonism that downregulates the 5-ht2 system, which is probably why TCA's downregulate the 5-ht2 system even though they're 5-ht2 antagonists.
But there is such a ballance between the serotogenic system and the dopaminergic system. SSRI's might just serve to even out the ying-yang a little.
But the dumbest thing that I recently read was this. They recently found some sort of depression gene. A short-short varient of the 5-ht transporter. Anyhow, this particular gene codes for a SLOWER serotonin reputake !!. So what good does it do by pumping these individuals full of drugs that serve to futher slow their already slow reputake system???
So I personally prefer the term "placebo's with a buzz"
Linkadge
Posted by Phillipa on June 19, 2005, at 17:27:02
In reply to Re: Who knows the drug synergy mechanism?, posted by linkadge on June 19, 2005, at 16:00:55
Will one of you PLEASE become a pdoc? I'd see any of you. If I were to copy this Thread and give it to my pdoc she wouldn't have the foggiest what it was all about. Seriously. Fondly, Phillipa
Posted by ed_uk on June 19, 2005, at 17:53:42
In reply to Re: Who knows the drug synergy mechanism?, posted by linkadge on June 19, 2005, at 16:00:55
Hi Link,
I didn't know that SSRIs increase allopregnanolone levels, thanks for posting. I've just been reading about it.
Biol Psychiatry. 1998 Nov 1;44(9):865-73.
Can the antidysphoric and anxiolytic profiles of selective serotonin reuptake inhibitors be related to their ability to increase brain 3 alpha, 5 alpha-tetrahydroprogesterone (allopregnanolone) availability?
Guidotti A, Costa E.
Department of Psychiatry, University of Illinois at Chicago, College of Medicine 60612, USA.
Neurosteroids synthesized in the nervous system are potent modulators of synaptic activity. Allopregnanolone (ALLO) is of great significance for neuropsychiatric research because it binds with high affinity at nanomolar concentration to various gamma-aminobutyric acid (GABA)A receptor subtypes and potently facilitates GABA action at these receptors. Fluoxetine and paroxetine, two selective serotonin reuptake inhibitors (SSRIs), when administered to rats increase brain ALLO content without altering the brain content of other steroids, including ALLO's precursor 5 alpha dihydroprogesterone. Moreover the improvement in depression symptomatology following administration of fluoxetine or fluvoxamine to unipolar depressed patients for 8-10 weeks is related to the increase of ALLO content in cerebrospinal fluid. Because ALLO via its action at GABAA receptors may relieve anxiety and dysphoria, the increase in ALLO brain content elicited by fluoxetine or other SSRIs may participate in the beneficial anxiolytic and antidysphoric clinical action of this class of drugs. Preliminary experiments suggest that the effect of SSRIs on ALLO biosynthesis is independent from serotonin reuptake inhibition and may be due to a specific SSRI action on the enzymes that synthesize ALLO from its precursor.
~Ed
Posted by linkadge on June 19, 2005, at 18:49:22
In reply to Allopregnanolone » linkadge, posted by ed_uk on June 19, 2005, at 17:53:42
Crazyness isn't it? I know zyprexa has an effect on this neurosteroid as well.
Its like every time I think I've got myself figured out, they blow my mind again. Somtimes I think things would be clearer on LSD.
I like it when they say things like, "the mechanism of antidepressants is not fully understood", but at the same time that freaks me out.
I'm still up for a Nardil trial sometime. I can't remember if you said that you had been on nardil Ed?
Linkadge
Posted by ed_uk on June 19, 2005, at 20:32:41
In reply to Re: Allopregnanolone, posted by linkadge on June 19, 2005, at 18:49:22
Hi Link,
>Crazyness isn't it?
Crazyness sounds about right. There are soooo many conflicting studies.
>"the mechanism of antidepressants is not fully understood"
Haha, they're not kidding. What about: "the mechanism of action of ADs is barely understood at all".
>I can't remember if you said that you had been on nardil Ed?
I've never tried it. I was thinking about trying it but my OCD came back so I had to return the the wonderful world of the SSRI.
~Ed
Posted by ed_uk on June 19, 2005, at 20:42:46
In reply to Re: Allopregnanolone, posted by linkadge on June 19, 2005, at 18:49:22
>I know zyprexa has an effect on this neurosteroid as well.
You're absolutely right Link........
Biol Psychiatry. 2000 Jun 1;47(11):1000-4.
Olanzapine increases allopregnanolone in the rat cerebral cortex.
Marx CE, Duncan GE, Gilmore JH, Lieberman JA, Morrow AL.
Department of Psychiatry, University of North Carolina at Chapel Hill, 27599-7160, USA.
BACKGROUND: The neurosteroid allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one) has anxiolytic and anticonvulsant properties, potentiating GABA(A) receptor chloride channel function with 20-fold higher potency than benzodiazepines. Behavioral studies demonstrate that olanzapine has anxiolyticlike properties in animals, but the mechanism responsible for these effects is not clear. We examined the effect of acute olanzapine administration on cerebral cortical allopregnanolone and its relationship to serum progesterone and corticosterone levels in rats. METHODS: Male Sprague-Dawley rats were habituated to intraperitoneal (IP) saline injection for 5 days. On the day of the experiment, rats were injected with olanzapine (0, 2.5, 5.0, or 10.0 mg/kg IP, 10-11 rats per condition). Rats were sacrificed 1 hour later, and cerebral cortical allopregnanolone levels and serum progesterone and corticosterone levels were measured by radioimmunoassay. RESULTS: Olanzapine increases cerebral cortical allopregnanolone up to fourfold, depending on dose. Positive correlations were observed between cerebral cortical allopregnanolone and serum progesterone levels and between cerebral cortical allopregnanolone and serum corticosterone levels. CONCLUSIONS: Olanzapine-induced increases in the potent GABA(A) receptor modulator allopregnanolone may alter GABAergic neurotransmission, possibly contributing to antipsychotic efficacy. If allopregnanolone alterations are linked to psychotic symptom relief, neurosteroids may represent molecules for pharmacologic intervention.
Neuropsychopharmacology. 2003 Jan;28(1):1-13.Olanzapine and clozapine increase the GABAergic neuroactive steroid allopregnanolone in rodents.
Marx CE, VanDoren MJ, Duncan GE, Lieberman JA, Morrow AL.
Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina 27705, USA. marx0001@mc.duke.edu
The neuroactive steroid allopregnanolone is a potent gamma-aminobutyric acid type A (GABA(A)) receptor modulator with anxiolytic and anticonvulsant effects. Olanzapine and clozapine also have anxiolytic-like effects in behavioral models. We therefore postulated that olanzapine and clozapine would elevate allopregnanolone levels, but risperidone and haloperidol would have minimal effects. Male rats received intraperitoneal olanzapine (2.5-10.0 mg/kg), clozapine (5.0-20.0 mg/kg), risperidone (0.1-1.0 mg/kg), haloperidol (0.1-1.0 mg/kg), or vehicle. Cerebral cortical allopregnanolone and peripheral progesterone and corticosterone levels were determined. Adrenalectomized animals were also examined. Both olanzapine and clozapine increased cerebral cortical allopregnanolone levels, but neither risperidone nor haloperidol had significant effects. Olanzapine and clozapine also increased serum progesterone and corticosterone levels. Adrenalectomy prevented olanzapine- and clozapine-induced elevations in allopregnanolone. Allopregnanolone induction may contribute to olanzapine and clozapine anxiolytic, antidepressant, and mood-stabilizing actions. Alterations in this neuroactive steroid may result in the modulation of GABAergic and dopaminergic neurotransmission, potentially contributing to antipsychotic efficacy.
Neuropsychopharmacology. 2004 Sep;29(9):1597-609.
Role of neuroactive steroid allopregnanolone in antipsychotic-like action of olanzapine in rodents.Ugale RR, Hirani K, Morelli M, Chopde CT.
University Department of Pharmaceutical Sciences, Nagpur University Campus, Nagpur, Maharashtra, India.
Olanzapine increases brain allopregnanolone (ALLO) levels sufficiently to modulate neuronal activity by allosterically regulating GABAA receptors. Recently, we reported the antipsychotic-like profile of ALLO in rodents. The present study examined the hypothesis that olanzapine-induced elevation of endogenous neurosteroid ALLO is vital for its neuroleptic-like action. The conditioned avoidance response (CAR) and apomorphine-induced climbing behavioral paradigms were used in rodents. Administration of ALLO (1 microg, intracerebroventricular (i.c.v.)) or neurosteroidogenic agents such as the mitochondrial diazepam binding inhibitor receptor agonist, FGIN 1-27 (0.5 microg, i.c.v.) or the ALLO precursor, progesterone (10 mg/kg, i.p.) significantly potentiated olanzapine-induced blockade of CAR and apomorphine-induced climbing. In contrast, these agents failed to alter the antipsychotic-like effect of risperidone and haloperidol. On the other hand, inhibition of the endogenous biosynthesis of neurosteroids by the 3beta-hydroxysteroid dehydrogenase inhibitor, trilostane (30 mg/kg, i.p.), the 3alpha-hydroxysteroid oxidoreductase inhibitor, indomethacin (5 mg/kg, i.p.), or the GABAA receptor antagonist bicuculline (1 mg/kg, i.p.) and dehydroepiandrosterone sulfate (DHEAS) (1 mg/kg, i.p.) blocked the effect of olanzapine, but not of risperidone and haloperidol. Socially isolated animals, known to exhibit decreased brain ALLO and GABAA receptor functions, displayed a shortening in the muscimol-induced loss of righting reflex and an increased susceptibility to apomorphine-induced climbing. Administration of olanzapine, but not of haloperidol and risperidone, normalized the duration of muscimol-elicited loss of righting reflex. Although all three antipsychotics proved capable of antagonizing the apomorphine-induced climbing, a dose almost five times higher of olanzapine was required in socially isolated animals. The data obtained suggest that enhancement of the GABAergic tone plays a key role in the antipsychotic-like effect exerted by olanzapine in rodents, likely as a consequence of augmented levels of neuroactive steroids, in particular ALLO, in the brain. The present findings provide the first specific behavioral evidence in support of the hypothesis that neuroactive steroid ALLO- mediated GABAergic modulation is essential for the antipsychotic-like action of olanzapine.
~Ed
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