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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 28 to 52 of 52. Go back in thread:
Posted by Marty on December 23, 2008, at 9:14:46
In reply to Re: 5HT(2c), remeron and etc, posted by linkadge on December 22, 2008, at 20:55:59
Linkage is in fire or what ? :) Very interesting collection of abstract Link, I'm bookmarking some for latter.What is your opinion regarding antagonizing 5-HT2a and 5-HT2c at the same time (without -DA) ? I think you find it counter intuitive, right ?
/\/\arty
Posted by linkadge on December 23, 2008, at 9:35:47
In reply to Re: Agomelatin: could 5HT(2c) action be bad for sl » Marty, posted by SLS on December 23, 2008, at 7:16:15
Theres more than that which could be considered ideal.
For instance, there are some compounds with 5-ht uptake inhibition and 5-ht1a/b autoreceptor antagonism which apprently bypass the need for long term drug administration to desensitize these receptors.
If you take into acount the mood modulating effects of all 5-ht receptors you'd have some agent which might do the following:5-ht1a/b post synaptic agonism
5-ht1a/b autoreceptor antagonism
5-ht2a/c antagonism
5-ht3 antagonism
5-ht4 agonism
5-ht7 antagonism+ 5-ht uptake inhibition (or not)
etc. etc.
(but I still don't think that 5-ht uptake inhibition is at all relatant to the antidepressant effects of SSRI's.Linkadge
Posted by SLS on December 23, 2008, at 9:38:23
In reply to Re: Agomelatin: could 5HT(2c) action be bad for sl » Marty, posted by SLS on December 23, 2008, at 7:16:15
> Interesting:
> http://www.nature.com/npp/journal/v28/n2/full/1300057a.html
> To produce a treatment - whether monotherapy or polypharmacy - that will inhibit the reuptake of 5-HT and simultaneously antagonize 5-HT2a and 5-HT2c receptors in the absence of DA antagonism might be ideal to treat depression.Oops.
I managed to overlook the role that 5-HT2c receptors are suggested to play. The authors conclude that 5-HT2c agonism, and not antagonism, can act as a synergist to SRIs.
Geodon is an interesting drug. I didn't think much of it as an antidepressant augmenter when it first appeared. However, I have come to believe that it possesses an array of properties, including selective 5-HT2a receptor antagonism, that serves to explain its antidepressant properties. It really is the most antidepressant-like of the neuroleptic antipsychotics. I've seen it work wonders in TRD when added to a combination of Lexapro and Wellbutrin.
Antidepressant properties of Geodon:
5-HT1a agonist ++
5-HT1d antagonist
5-HT2a antagonist +++
NE reuptake inhibition
5-HT reuptake inhibition
- Scott
Posted by linkadge on December 23, 2008, at 9:42:05
In reply to Oops., posted by SLS on December 23, 2008, at 9:38:23
I made a typo in the following:
>Apparently 5-ht2c agonism decreases the >responsiveness of postsynaptic 5-ht2b receptors >which are involved in reward function and >certain spatial memory functions.
Which should read:
Apparently 5-ht2c agonism decreases the responsiveness of postsynaptic *5-ht1b* receptors which are involved in reward function and certain spatial memory functions.
Posted by Marty on December 23, 2008, at 9:51:29
In reply to Re: Agomelatin: could 5HT(2c) action be bad for sl » Marty, posted by SLS on December 23, 2008, at 7:16:15
> Interesting.
>http://www.nature.com/npp/journal/v28/n2/full/130>0057a.htmlYes, great paper indeed. Makes me think the team who develop Trazodone were on a good track: 5-HT2a antagonist, 5-HT2c agonist (via m-CPP) AND some SRI. If it wasn't of the side effects, in particular the hangover, and if the SRI was stronger it could be an awesome antidepressant if you embrace the thesis discussed in your paper.
That, said I wonder if my Agomelatine/Trazodone combo isn't working against each other in some way s while being completive in others. That paper suggest it would somehow, or did I badly interpret ? (I just woke up, my eyes are still glued)
Something happened yesterday that made me wonder even more: I took Agomelatine and .25mg Clonazepam but forgot to take my other meds (Trazo, Wellbutrin, Lamictal, Chromium).. 1 hour later I feel good and go to bed. Time pass by and I'm still not sleeping completely (unusual for me) but I wasn't caring because I was feeling GREAT.. even better than since I started Agomelatine. After a while I got up to go to the bathroom and realized how terrific I was feeling and when going back to my bed I saw on my desk the pills I forgot to take... and so I took them. This morning I wake up feeling not that great.. just normal hangover from Trazo and while I want to go out of the bed and do something of my day (this wasn't the case before Agomelatine) I don't feel excited about life like I do when I take Agomelatine alone...
While I strongly believe the thesis of the paper you sent me, my beliefs in my Ago/Trazo combo are shaky right now. I'm wondering if I should try reducing Trazodone .. in the last 3 days I realized my Agomelatine miracle wasn't 'constant' (consistency of Ago effect is a recurring theme in discussion between people who are currently on it BTW)
I scratch my head over this today. If you have an opinion whatsoever, even if the strong, I'm interested.
> To produce a treatment - whether monotherapy or >polypharmacy - that will inhibit the reuptake of >5-HT and simultaneously antagonize 5-HT2a and 5->HT2c receptors in the absence of DA antagonism >might be ideal to treat depression.I think it's a great strategy for a lot of people. But I'm still not sure about which are the best complement to 5-HT2a antagonism.. 5-HT2c antagonism OR agonism ? Linkage seems to eat for breakfast the right kind of papers lately to express an interesting opinion. I've ask him in my last post on this thread. What about yours ?
> I hate when researchers feel it necessary to
>search for a single molecule that will combine
>all the relevant mechanisms of action. Just give
>us multiple drugs that are highly specific,
>complementary, and synergistic.So do I. I wish our 'drug palette' would be more complete and specific. I feel the day we'll have the likes of 5-HT5/6/7 agonists, for example, developed and marketed is far, far away.
/\/\arty
Again, sorry for the long post.. hope you're good are reading diagonally. ;)
Posted by SLS on December 23, 2008, at 10:30:08
In reply to Re: Oops., posted by linkadge on December 23, 2008, at 9:42:05
> Apparently 5-ht2c agonism decreases the responsiveness of postsynaptic *5-ht1b* receptors which are involved in reward function and certain spatial memory functions.
Hmm.
Are these heteroreceptors?
- Scott
Posted by linkadge on December 23, 2008, at 11:14:25
In reply to Re: Oops. » linkadge, posted by SLS on December 23, 2008, at 10:30:08
No, I don't think so.
http://www.ihop-net.org/UniPub/iHOP/pm/718965.html?nr=2&pmid=8863849
Linkadge
Posted by linkadge on December 23, 2008, at 11:16:40
In reply to Re: Oops. » linkadge, posted by SLS on December 23, 2008, at 10:30:08
Here's another study:
http://www.ihop-net.org/UniPub/iHOP/pm/7983944.html?nr=4&pmid=7935328
You can probably find more info too on ihop.
http://www.ihop-net.org/UniPub/iHOP/gs/89250.html
Linkadge
Posted by desolationrower on December 23, 2008, at 11:18:32
In reply to Re: Agomelatin: could 5HT(2c) action be bad for sl » Marty, posted by SLS on December 23, 2008, at 7:16:15
> Hi Marty.
>
> Interesting.
>
> http://www.nature.com/npp/journal/v28/n2/full/1300057a.html
>
> To produce a treatment - whether monotherapy or polypharmacy - that will inhibit the reuptake of 5-HT and simultaneously antagonize 5-HT2a and 5-HT2c receptors in the absence of DA antagonism might be ideal to treat depression.
>
> I hate when researchers feel it necessary to search for a single molecule that will combine all the relevant mechanisms of action. Just give us multiple drugs that are highly specific, complementary, and synergistic.
>
>
> - Scottit sort of goes to many parts of the industry - fda wants a drug that is more effective than other treatments, not just part of a an effective coctail. And doctors want to prescibe one drug not polypharmacy. And the pharm companies don't want a drug that only works when taken with their competitor's drug.
also marty, how has the agometaline affected weight/appetite/metabolism?
I hope researchers beging to look at conditional effects of recptors more as i don't think the always have simple linear reltaionship: MORE agonism=MORE activation or whatever. I would like if there was a wiki database of research - as a researcher publishes their study, they must update the encyclopedia - less to create articles, but to have references to the relevant research. I'm sure there are many problems with such an idea.
-d/r
Posted by psychobot5000 on December 23, 2008, at 12:08:43
In reply to Re: Agomelatin: could 5HT(2c) action be bad for sl » Marty, posted by SLS on December 23, 2008, at 7:16:15
>
> To produce a treatment - whether monotherapy or polypharmacy - that will inhibit the reuptake of 5-HT and simultaneously antagonize 5-HT2a and 5-HT2c receptors in the absence of DA antagonism might be ideal to treat depression.
>
> I hate when researchers feel it necessary to search for a single molecule that will combine all the relevant mechanisms of action. Just give us multiple drugs that are highly specific, complementary, and synergistic.
>
>
> - ScottI agree (for what that's worth)--that would allow for more flexible and specific treatment for those of us who are resistant, while presumably also making drug development easier. However, I would suggest that almost any agent with significant serotonin reuptake inhibition would not be 'ideal,' (even assuming Linkadge is wrong and it -is- a significant AD mechanism), simply because the mechanism causes so many damned side-effects.
Posted by linkadge on December 23, 2008, at 12:17:13
In reply to Re: Agomelatin: could 5HT(2c) action be bad for sl, posted by desolationrower on December 23, 2008, at 11:18:32
These drugs are still more discovered than designed.
Linkadge
Posted by psychobot5000 on December 23, 2008, at 12:23:31
In reply to Re: Agomelatin: could 5HT(2c) action be bad for sl » SLS, posted by Marty on December 23, 2008, at 9:51:29
>
> > Interesting.
> >0057a.html" target="_blank">http://www.nature.com/npp/journal/v28/n2/full/130>0057a.html
>
> Yes, great paper indeed. Makes me think the team who develop Trazodone were on a good track: 5-HT2a antagonist, 5-HT2c agonist (via m-CPP) AND some SRI. If it wasn't of the side effects, in particular the hangover, and if the SRI was stronger it could be an awesome antidepressant if you embrace the thesis discussed in your paper.
>This is all sort of above my head, of course, but isn't nefazodone pretty much what you're describing: trazodone, only with less sedation/hangover, and a (modestly) stronger SRI effect?
Posted by psychobot5000 on December 23, 2008, at 16:46:37
In reply to Re: Agomelatin: could 5HT(2c) action be bad for sl, posted by linkadge on December 23, 2008, at 9:35:47
> Theres more than that which could be considered ideal.
>
> For instance, there are some compounds with 5-ht uptake inhibition and 5-ht1a/b autoreceptor antagonism which apprently bypass the need for long term drug administration to desensitize these receptors.
>
>Suppose we take this in a slightly different direction: What might be the properties of an 'ideal' agent (acting on 5HT receptors) to be combined with a serotonin-reuptake -enhancer-, rather than an SSRI? 5HT1a agonism? Something else? Mightn't one make a more effective or targeted drug combination by -reducing- synaptic serotonin, and then targeting certain specific receptor subgroups for -increased- action, rather than the reverse?
(disclaimer: I am a tianeptine loyalist)
Posted by iforgotmypassword on December 24, 2008, at 4:33:31
In reply to Re: Agomelatin: could 5HT(2c) action be bad for sl » Marty, posted by psychobot5000 on December 23, 2008, at 12:23:31
and i was hoping that the nefazodone SRI effect was weak enough that i wouldn't have to worry about it.
(sorry i just realized my whole post from here on in was my babbling about me and my nefazodone rx i hope to fill in the states, but want to post it to see if anyone finds it relevant and has a response.)
i have suspicions my problems are of the hyperserotonergic-hypodopaminergic domino effect type, and exacerbated by previous SSRI use. i am worried about increasing serotonin, i worry that i either have too much of it, or i am hypersensitve, or that i have receptor or transpoter genotypes i could benefit knowing more about, if it were possible.
i was under a faint impression that not only did 5-HT1a autoreceptor agonism decrease serotonin (an increase catecholamines), but that 5-HT2a antagonism did this as well (decrease serotonin, increase NE DA) and that 5-HT2c seemed to as well, but that it has complexities with regards to executive function (that it seemed to be the opposite of 5-HT2a in some ways).
i guess they may all be different in where their action is prominent. if i remember correctly (i may not), buspirone's anti-bruxism effect was due to its serotonin depleting and dopamine enhancing effect in the VTA. i *think* they tagged the mesocortical tract as being implicated in bruxism.
the final effect of nefazodone, and increase or decrease in serotonin, i am not sure of, and it bothers me. i know that the drug paradoxically increases REM by a small amount, whereas trazodone decreases REM, i think. i don't know the significance of this, if any, in determining what the broad chemical effect of nefazodone is.
both the hard to figure out SRI effect, and the 5-HT2c and mCPP issue bother me a lot. as does the 5HT-2b agonist property of mCPP, and how it's levels may depend on certain liver enzyme genotype(s) one has. (i think there was one or two enzymes that may be specifically relevant.)
the occupancy* of 5-HT2a by nefazodone is lower than i would have expected, making me wonder if it the recognition of nefazodone "having an effect" relied significantly on other properties of the drug, like its mCPP metabolite, or a possibility that it's SRI effect wasn't that weak at the dosage range that the drug ended up being rx'd at. but then again, i do not know what levels of antagonistic occupancy of 5-HT2a is associated with which types of responses.
i do not know anything about what type of occupancy profile trazodone has. it would be interesting to know how it compares, and which drug metabolizes into more mCPP at the dosage ranges that are used clinically.
* a single dose of 200mg nefazodone apparently creates ~39% occupancy of 5-HT2a receptors, and "less than 50% after 6 weeks of treatment with an average dose of approximately 450mg"
Posted by psychobot5000 on January 22, 2009, at 14:53:54
In reply to Re: Agomelatin: could 5HT(2c) action be bad for sl, posted by linkadge on December 22, 2008, at 14:05:59
For those few who might be interested in 5ht(2c) and its effects on OCD, here's a brief account of 5ht(2c) antagonist Agomelatine's effects on my symptoms thus far...
I has had dramatic effects. And yet, I am not entirely certain I would recommend it to someone else. The ruminative components of my OCD are gone or severely reduced. Concerns with things like, say, handwashing, are more or less gone. However, a certain -feeling of obsessive urgency- has arisen or been magnified, and it's connected to a certain physical obsessiveness...repetitive and unnecessary movements, like winking (not at someone--just on my own). Thinking back, this reaction is somewhat similar to my reaction to Remeron, though more dramatic. It's probably less unpleasant than the previous incarnation of my OCD, but it's always present, and disrupts my ability to work without distraction.
Problematic. I have no idea what it means in neurobiological terms, but I thought I'd throw it out there, for those with an interest in this stuff: ruminative symptoms largely eliminated, physical obsessiveness much increased. Patient claims subjective similarity to previous experience with Remeron.
(incidentally, I more recently added low-dose nefazodone to my regimen, but I attribute most of the change to Agomelatine, as it started before the second drug was added)
Psychbot
Posted by SLS on January 22, 2009, at 15:05:21
In reply to Re: Agomelatine effects on OCD..., posted by psychobot5000 on January 22, 2009, at 14:53:54
How about adding Luvox for the OCD? Prozac might aggravate things with its 5-HT2c antagonism.
- Scott
Posted by desolationrower on January 23, 2009, at 1:43:13
In reply to Re: Agomelatine effects on OCD..., posted by psychobot5000 on January 22, 2009, at 14:53:54
that sounds a bit like tics, more than OCD?
-d/r
Posted by SLS on January 23, 2009, at 2:45:48
In reply to Re: Agomelatine effects on OCD..., posted by desolationrower on January 23, 2009, at 1:43:13
> that sounds a bit like tics, more than OCD?
That's a great observation.
Often OCD and tics go together. Maybe the melatonin receptor agonism has muted the OCD and left the tics? Just a guess.
I found no evidence that 5-HT2c receptors are involved in either OCD or tics. Investigations designed to look for this concluded that there was no association with either one.
- Scott
Posted by psychobot5000 on January 23, 2009, at 12:07:18
In reply to Re: Agomelatine effects on OCD..., posted by desolationrower on January 23, 2009, at 1:43:13
> that sounds a bit like tics, more than OCD?
>
> -d/r
Mmm. Good thought, d/r--Now, I don't know how ironclad this is, but as I understand it, there is a distinction between tics and 'tic-like' behaviors in OCD, and I think my behavior falls into the latter category. Tics are supposed to be involuntary, whereas OCD repetitive movements are ultimately under voluntary control. In my case, the movements are easily suppressed, and are the result of a feeling of...compulsion, which can manifest in a variety of ways. Its that -feeling- that's the root problem, as far as I can tell, and it can manifest in other irritating behavioral compulsions.Still, I'd like to know how well-established the distinction is. They say tics involve dysfunction in the same brain-regions as OCD, and some articles seem to lump them together, though perhaps this is just sloppy terminology.
Psychbot
PS - Scott, thanks for your note on 5HT-2c and OCD etiology. That's good to know. I'm not at all convinced that this won't ultimately work out somehow. Maybe nefazodone and its 5ht-2a effects could even be the actual cause...
Posted by desolationrower on January 23, 2009, at 12:49:44
In reply to Re: Agomelatine effects on OCD...(?), posted by psychobot5000 on January 23, 2009, at 12:07:18
I'm not sure where tic activity originates; i think d2 antagonists are used for it though, so i guess i was wondering if the DA disinhibition from agometatine might be allowing it despite overall benefit...i don't think genetic correlative studies are the last word, there is the developmental effects of genes which is much different from the effect of manipulating the receptors in a mature brain
-d/r
Posted by psychobot5000 on January 23, 2009, at 15:50:30
In reply to Re: Agomelatine effects on OCD... » desolationrower, posted by SLS on January 23, 2009, at 2:45:48
Did a google search and found this on an odd site which doesn't give its research sources. I haven't the time to find a better source, but I've read very similar things elsewhere recently. This one is better, though because it has a list of the neurological targets involved in OCD, segregated by their positive or negative correlation with OCD symptoms. Though I'm assuming much of their conclusions are unconfirmed, it makes me wonder what might be done with all this information to throw together a makeshift treatment or two. If I come up with anything, I'll mention it.
http://www.k12academics.com/ocd_neuropsychiatry.htm
________________________________________________
"OCD primarily involves the brain regions of the striatum and the cingulate cortex, especially the striatum. OCD involves several different receptors, mostly H2, M4, nk1, NMDA, and non-NMDA glutamate receptors. The receptors 5-HT1D, 5-HT2C, and the mu opioid receptor exert a secondary effect. The H2, M4, nk1, and non-NMDA glutamate receptors are active in the striatum, whereas the NMDA receptors are active in the cingulate cortex.The activity of certain receptors is positively correlated to the severity of OCD, whereas the activity of certain other receptors is negatively correlated to the severity of OCD. Those correlations are as follows:
Activity positively correlated to severity:
H2
M4
nk1
non-NMDA glutamate receptorsActivity negatively correlated to severity:
NMDA
mu opioid
5-HT1D
5-HT2CThe central dysfunction of OCD involves the receptors nk1, non-NMDA glutamate receptors, and NMDA, whereas the other receptors exert secondary modulatory effects.
Pharmaceuticals that act directly on those core mechanisms are aprepitant (nk1 antagonist), riluzole (glutamate release inhibitor), and tautomycin (NMDA receptor sensitizer). The drugs that are popularly used to fight OCD lack efficacy because they do not act upon the core mechanisms."
__________________________________________(endquote)
Posted by SLS on January 23, 2009, at 17:16:40
In reply to Re: 5HT-2c and other receptors and targets in OCD, posted by psychobot5000 on January 23, 2009, at 15:50:30
Interesting stuff. They sound pretty confident in their commentary.
Look into memantine (Namenda) for OCD. It is a non-competitive NMDA glutamatergic receptor antagonist.
Ever try magnesium?
- Scott
Posted by psychobot5000 on January 24, 2009, at 14:59:29
In reply to Re: 5HT-2c and other receptors and targets in OCD » psychobot5000, posted by SLS on January 23, 2009, at 17:16:40
> Interesting stuff. They sound pretty confident in their commentary.
>
> Look into memantine (Namenda) for OCD. It is a non-competitive NMDA glutamatergic receptor antagonist.
>
> Ever try magnesium?
>
>
> - ScottThey do sound confident, don't they.
I'm glad to hear you suggest memantine--I spent last night (obsessively) looking into what I might do about this--and came across a psychobabble post from a Tourette's sufferer
http://www.dr-bob.org/babble/neuro/20080204/msgs/820576.html
...which quotes that same confident but unsourced passage--among many other articles and medication posts. But the sum of it all was that this poster was helped greatly by Memantine. Looking into all these potential pathways...I had drawn up a list of potential drugs when I read your post, SLS. Memantine was already at the top, followed by tramadol and potentially a low-dose atypical antipsychotic. --It makes me feel much more comfortable to hear someone add their recommendation of it, though--seriously, thank you.
As for antipsychotics for OCD, this 2008 abstract seems to claim they may be the treatment of choice for the 'tic-related' subtype of OCD, which seems relevant.
...From what I read elsewhere, risperidone has the best evidence supporting its use--checked its binding affinities, and it looks like it might have the most 5ht2a action in comparison to 2c and D2. Maybe that could be why. But in any case, memantine seems a safer and possibly more effective option.
As for magnesium--I did try it, a few times, actually--several years ago--for depression, mostly. I Don't remember much about the experience, except that I felt it didn't work very well--I imagine I would have noticed if it had positive effects on OCD, though. ...Interestingly, that unsourced passage that names all the alleged OCD pathways (the one that's so confident) also indicates that NMDA activity is -negatively- correlated to OCD severity--meaning you'd actually want an NMDA AGONIST! Some say that memantine is not an antagonist (as it usually seems to be called), but rather a partial agonist--so perhaps that's why it seems to work better than other NMDA agents for OCD. Here's a quote from the p-babble post I named above, from a quoted a section of another post, touting NMDA antagonists to prevent stimulant tolerance:
"The article goes on to mention DXM, another NMDA antagonist, which I tried, and personally had negligeable success with, and was eventually hospitalized while on it.. it may have exacerbated OCD/schizo-xx tendencies, delusions in my case." (endquote)
Anecdotal evidence that NMDA antagonists ARE in fact bad for OCD? (excluding memantine, obviously) Maybe. In any case, for the moment, Memantine seems the one to try...
Posted by psychobot5000 on January 24, 2009, at 15:23:09
In reply to Re: Agomelatine effects on OCD...(?), posted by desolationrower on January 23, 2009, at 12:49:44
> I'm not sure where tic activity originates; i think d2 antagonists are used for it though, so i guess i was wondering if the DA disinhibition from agometatine might be allowing it despite overall benefit...
> -d/rThat would seem to make sense, wouldn't it--a hard situation when I need more DA in the frontal cortex to help my depression and other issues...
Your hypothesis would make sense given that (I've read) antipsychotics may be the 'treatment of choice' for 'tic-related OCD.'
Maybe....theoretically it makes one think there could be a way of targeting the area of the brain responsible for OCD/Tics/whatever, and reducing activity there while leaving most of the rest functioning. But I imagine such a thing hasn't been invented yet (maybe deep-brain stimulation is the way to go for such relatively precise targeting...)
What you say makes good sense.
Posted by SLS on January 24, 2009, at 15:47:53
In reply to Re: Agomelatine effects on OCD...(?) » desolationrower, posted by psychobot5000 on January 24, 2009, at 15:23:09
Referring to DesolationRower:
> What you say makes good sense.
He has an annoying habit of doing that.
:-)
- Scott
This is the end of the thread.
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