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Dr. Bob is Robert Hsiung, MD,
[email protected]Shown: posts 1 to 25 of 52. This is the beginning of the thread.
Posted by psychobot5000 on December 20, 2008, at 19:19:26
So, just to pose a thought--looks like those of us in Europe will soon have Agomelatine as another pharmacalogical tool. Great. One of its benefits is that it may be helpful for sleep, very useful considering how sensitive a bunch depressives and bipolars can be about sleep. But couldn't the increase in frontal cortex activation caused by its serotonin receptor effects (5HT (2c)) disrupt sleep also? Would anyone who knows about this sort of thing care to comment? Is there anything specific that could be done to help with this (other than the usual assortment of sleep drugs like ambien, lunesta and benzodiazepines)?
Psychbot
Posted by linkadge on December 20, 2008, at 20:34:03
In reply to Agomelatin: could 5HT(2c) action be bad for sleep?, posted by psychobot5000 on December 20, 2008, at 19:19:26
5-ht2c antagonism tends to increase slow wave sleep.
I suppose, depending on the state, it could increase prefrontal cortex activity too much.
Its like remeron I guess. For most people, it improves sleep, but for some people it can actually cause insomnia.
Linkadge
Posted by Marty on December 21, 2008, at 1:15:03
In reply to Agomelatin: could 5HT(2c) action be bad for sleep?, posted by psychobot5000 on December 20, 2008, at 19:19:26
5-HT2c antagonism is activating, especially just before bed which is the case with Agomelatine. So activating as to become an obstacle to sleep.Ever read Prozac being the most activating of the SSRIs ? That's because it isn't an SSRI in the first place: Prozac main antidepressant mechanism of action is now recognized as being 5-HT2c antagonism. Prozac's SRI is only secondary and so today, because of it's rockstar status in the history of SSRI development, it's usually classified as an atypical SSRI.
Apart from Prozac and Agomelatine, most 5-HT2c antagonist usually benefit from some 5-HT2a antagonism which, contrary to 5-HT2c ANT, is very pro sleep.
It is my opinion that if someone on Agomelatine is sensitive to 5-HT2c antagonism to the point of rendering its MT1/MT2 agonistic action insufficient to sleep, adding an 5-HT2a antagonist could be a good move: it calms and improve sleep while being pro-DA in some regions of the brain where Agomelatine is also pro-DA. (A different kind of pro-DA that is. Not one that is even remotely as activating)
As I don't believe in DA antagonism in the treatment of depression, I'd go with low dose Trazodone (which is good regarding insomnia) instead of Seroquel or any other atypical neuroleptic. Trazodone metabolite m-CPP is reported to be an agonist of 5-HT2c and 5-ht2b, but is in fact a partial agonist weaker than serotonin at those receptors. m-CPP from 50 mg of metabolized Trazodone should be insignificant in the scheme of things.
Especially if you believe a 2003 study reporting Trazodone as having an 5-HT2c antagonistic profile equivalent to what's reported of Agomelatine.
(6.4 vs 6.2 pKi) ... But I, for one, call b*llsh*t on this one./\/\arty
Posted by SLS on December 21, 2008, at 5:28:33
In reply to Re: Agomelatin: could 5HT(2c) action be bad for sl » psychobot5000, posted by Marty on December 21, 2008, at 1:15:03
Hi Marty.
How do you think one would respond to a drug that antagonizes 5-HT2a/b/c ?
I hope all is well with you.
- Scott
Posted by Marty on December 21, 2008, at 13:10:35
In reply to Re: Agomelatin: could 5HT(2c) action be bad for sl » Marty, posted by SLS on December 21, 2008, at 5:28:33
Hi Scott,
> How do you think one would respond to a drug that antagonizes 5-HT2a/b/c ?
Coming from you, I'd guess you have something in mind asking me this catch-21 question ... ;) As you know, many drugs antagonize those 3 and many feel different from each others.
I'd think that a selective 5-HT2a, 2b and 2c antagonist without any other affinity for other receptors/transporter ESPECIALLY anything related to DA, could be a great drug -for a subset- of depression/anxiety afflicted. The increased tendency in the last couple years of neuroleptic prescription for depression/anxiety is, IMO, hinting at this potential. The only problem with those, again IMO, is mainly DA antagonism. While it works great for some, most are let down because of the -DA effect and others non 5-HT2 antagonism action.
Is the perfect 5-HT2a,b,c would be any good for treatment resistant people ? I doubt it. But that said, it's pretty good for the subset of treatment intolerant people as it comes with very few side-effects compared to much everything else when prescribed at low dose. Treatment intolerants being very sensitive to drugs (all effects, not only the undesirable one), that low dose would likely be sufficient for a good proportion of them.
In any case, it's working great for me as I consider myself in total remission, ZERO side effects since a couple days and the core of my combo is 5-HT2a,b,c antagonism, a combo I designed with frontal cortex focalized +DA/NE tonic enhancement by way of DA neurons disinhibition rather than too much brutal DA/NE reuptake inhibition:
Agomelatine 25 mg : 5-HT2c antagonism / cortico frontal +DA/NE.
Trazodone 50 mg : 5-HT2a/b(c) antagonism / orbitofrontal +DA
Wellbutrin 100 mg at night : NE/DA RI enhancing the frontal cortex focalized pro-DA effect of the 2 first I guess.
Lamictal 100 mg and Clonazepam .25 : for good mesure .. without them I think I may not be able to handle the +DA/+NE in some regions which directly or indirectly leads to increased anxiety in my type.
My design was probably flawed to many extent regarding what I wanted to modulate and how I planned my cocktail would succeed, but in any case the effects are exactly the one I was 'dreaming of' and I can't care less if I'm only a dumb lucky bastard. :P
And, you.. what's your feeling about 5-HT2 'triple subtype antagonism' ?
/\/\arty
Posted by SLS on December 21, 2008, at 14:10:00
In reply to Re: Agomelatin: could 5HT(2c) action be bad for sl » SLS, posted by Marty on December 21, 2008, at 13:10:35
Hi Marty.
Thanks for your input.
It was not a trick question! ;-)
I genuinely wanted to know your thoughts on the matter as it seems you are more knowledgeable than me in this area. I am amazed how accurate your appraisal is regarding dopamine function. I am extremely happy that you are feeling so well. I am very impressed with the intellect you demonstrated by actually designing your own successful treatment regime based upon combining drugs with complementary properties.
BRILLIANT!!!
My motivation for asking the question is that there has existed for many, many years a drug called ritanserin. It is a selective 5-HT2a/b/c antagonist that has shown itself to promote DA neurotransmission. Off patent, no drug compnay is interested in developing it for marketing. However, ritanserin is the paradigm agent for assaying 5-HT2 function and is used as a biological probe around the world.
- Scott
Posted by SLS on December 21, 2008, at 14:17:57
In reply to Re: Agomelatin: could 5HT(2c) action be bad for sl » SLS, posted by Marty on December 21, 2008, at 13:10:35
Hey Marty.
Check this out:
http://www.nature.com/mp/journal/v5/n6/full/4000804a.html
- Scott
Posted by Marty on December 21, 2008, at 15:08:00
In reply to Re: Agomelatin: could 5HT(2c) action be bad for sl » Marty, posted by SLS on December 21, 2008, at 14:10:00
Thanks for the compliments Scott :)
Again, coming from you, it's very appreciable. I use to remember a couple years ago when I knew nothing about psychopharmacology and I were reading almost everything you were posting on this board.. (you and 2 or 3 others I can't remember.. Linkadge was of the bunch for sure) I was very impressed to say the least. I'm glad I'm now to the point of being able to discuss this subject with you and the like s of you. :) .. Now if only I could get the courage to return to school to study properly neuroscience. Maybe one day I'll do.. depends on how stable I'll be in the next couple years.
> My motivation for asking the question is that there has existed for many, many years a drug called ritanserin.Ritanserin is an interesting drug for sure. Probably far too strong for me! .. especially with its DRI properties comparable to cocaine. But I wonder .. If one day I fall back into depression and I have the chance to put my hand upon it (very improbable OR EXPANSIVE!) I would love to give it a fair trial.
How are you doing lately Scott ?
/\/\arty
Posted by Marty on December 21, 2008, at 15:10:00
In reply to Re: Agomelatin: could 5HT(2c) action be bad for sl, posted by SLS on December 21, 2008, at 14:17:57
> Check this out:
http://www.nature.com/mp/journal/v5/n6/full/4000804a.html
> - ScottLOL! This is precisely the link I've just been too 5 minutes ago to make sure I didn't dream about it's DRI properties. :P
Viva Google! ;)
Later,
/\/\arty
Posted by SLS on December 21, 2008, at 15:38:16
In reply to Re: Agomelatin: could 5HT(2c) action be bad for sl » SLS, posted by Marty on December 21, 2008, at 15:08:00
> How are you doing lately Scott ?
:-)
Very well. Thanks for asking. My switching from Nardil to Parnate has made a significant difference. So far, I have not reached a plateau. I keep feeling better and better. I am blessed.
- Scott
Posted by psychobot5000 on December 21, 2008, at 16:08:20
In reply to Re: Agomelatin: could 5HT(2c) action be bad for sl » psychobot5000, posted by Marty on December 21, 2008, at 1:15:03
>
> 5-HT2c antagonism is activating, especially just before bed which is the case with Agomelatine. So activating as to become an obstacle to sleep.
>
> Apart from Prozac and Agomelatine, most 5-HT2c antagonist usually benefit from some 5-HT2a antagonism which, contrary to 5-HT2c ANT, is very pro sleep.> As I don't believe in DA antagonism in the treatment of depression, I'd go with low dose Trazodone
> /\/\arty
>Many thanks, all. The 2c receptors seem to have some paradoxical effects (don't they?), and I was hoping to hear a bit from people about them.--I found this from some study or other:
"This notion is supported by findings that 5-HT2C receptor antagonists stimulate dopaminergic and adrenergic pathways, exert antidepressant and anxiolytic actions in behavioural paradigms, and favour sleep and sexual function."
Sounds great--every one of those effects would be a positive for most depressives, wouldn't they? I suppose the only way to find out how Agomelatine or another antagonist will work (with or without other 5ht2-affecting meds like Traz.), is a personal trial. Glad to hear yours is going so damned well, Marty.
Regards,
Psychbot
Posted by Marty on December 21, 2008, at 17:02:09
In reply to Re: Agomelatin: could 5HT(2c) action be bad for sl » Marty, posted by SLS on December 21, 2008, at 15:38:16
> Very well. Thanks for asking. My switching from > Nardil to Parnate has made a significant
> difference. So far, I have not reached a
> plateau.
>I keep feeling better and better. I am blessed.Wow. I'm glad to hear that Scott!
Parnate is good stuff, wasn't for me, but this doesn't change a thing: Parnate is outstanding.I was chatting with a Psychiatrist which is 2 years into retirements and he told me that if anyone in his family were to fall into depression, Parnate would be his first choice. That says alot about it ...
I wish you a persistent and constant progress toward remission Scott and have some nice holidays!
/\/\arty
Posted by Marty on December 21, 2008, at 17:10:44
In reply to Re: Agomelatin: could 5HT(2c) action be bad for sl » Marty, posted by psychobot5000 on December 21, 2008, at 16:08:20
> The 2c receptors seem to have some paradoxical
> effects (don't they?), and I was hoping to hear
> a bit from people about them.2c is especially complex I've read. An example is that 5-HT2c antagonism seems to be favorable sexually, but 5-HT2c agonism is necessary to achieve erection. Another proof is there's some 5-HT2c AGONIST in the pipeline/clinical trials for depression/anxiety (Wyeth's Vabicaserin phase 2 or 3).. and even some prospect for psychosis if I remember well..
Later,
/\/\arty
Posted by linkadge on December 21, 2008, at 21:49:27
In reply to Re: Agomelatin: could 5HT(2c) action be bad for sl » psychobot5000, posted by Marty on December 21, 2008, at 1:15:03
>Especially if you believe a 2003 study reporting >Trazodone as having an 5-HT2c antagonistic >profile equivalent to what's reported of >Agomelatine.
Trazodone itself has 5-ht2a/b/c antagonist properties. mcpp is a 5-ht2b/c agonist however, so the net effect on 5-ht2c ? Who knows.
Posted by linkadge on December 21, 2008, at 21:51:21
In reply to Re: Agomelatin: could 5HT(2c) action be bad for sl » Marty, posted by SLS on December 21, 2008, at 5:28:33
Ritanerin is a 5-ht2a/b/c antagonist and has beneficial effects on sleep.
5-ht2b/c antagonism can have stimulating propteriies in certain paradigms and anxiolytic effects in others.
Linkadge
Posted by linkadge on December 21, 2008, at 22:08:33
In reply to Re: Agomelatin: could 5HT(2c) action be bad for sl » SLS, posted by Marty on December 21, 2008, at 13:10:35
Too much frontal cortex activity can actually cause a certain form of depression too.
Certain depressive states are associated with frontal cortex hyperactivity.
Also, the 5-ht2c receptors exert anticonvulsant effects. Too much 5-ht2c antagonism could decrease the seizure threshhold. For instance, 5-ht2c antagonism can increase the convulsant effects of cocaine. You may want to watch with the combination of a 5-ht2c antagonist and bupriopion (on a theoretic level). Too much 5-ht2c antagonism apparently can cause agression too. Remeron rage is probably due to a combination of the 5-ht2c antagonism and alpha-2 antagonism. 5-ht2c receptors also exert some effects on neurogenesis. 5-ht2c receptor antagonists block the neurotrophic effects of serotonin in certain hippocampal subfields.
The 5-ht2c receptors also control appetite. Too much 5-ht2c antagonism could lead to an inability to supress appetite.
Actually, if I recall, agomelatine is also a 5-ht2b antagonist. This might be good to take in combination with trazodone since mcpp is a 5-ht2b antagonist and could have negative hypertrophic effects on cardiac valvles.
Just thinking aloud.
Linkadge
Posted by linkadge on December 21, 2008, at 22:34:13
In reply to Re: Agomelatin: could 5HT(2c) action be bad for sl » psychobot5000, posted by Marty on December 21, 2008, at 17:10:44
Yes, 5-ht2c agonists have antidepressant properties too. I personally think that there is a normal circadian regulation of 5-ht2c function which may become disturbed in depression. I know that HGH acts as a functional 5-ht2c antagonist.
5-ht2c agonists increase climbing behavior in the forced swim test in mice.
A 5-ht2c agonist might have more application in depression associated with hyperactive frontal cortex function (for instance OCD/Depression). A 5-ht2c agonist might also work well with atypical depression depression that is associated with overeating etc.
The other thing too is that a 5-ht2c agonist would likely downregulate these receptors so that DA output is enhanced as the drug starts to wear off. Thats why I really think it is more about regulation. You need the receptors to be active at certain times of the day and then less responsive at others.
The 5-ht2c receptors are involved in declarative memory. 5-ht2c receptor antagonists can block declaritive memory retrieval they can also block the memory for certain escape related behaviors in mice.
I see it like this, you need the 5-ht2c antagonist so that you have enough executive function to sustain certain tasks. After an activity is sustained for a period of time, the 5-ht2c receptors kick in so that you can 'pull out' of the behavior and 'reflect' on the processes that you have been performing. 5-ht2c agonism is only good for memory retrieval if you have learned the task, it can also increase the ability to think abstractly and laterally to help compare and relate ideas.
So if you're one of those people who doesn't want to initiate a task because you think you know it all, you might need some 5-ht2c antagonism. However if you are not getting enought 5-ht2c antagonism you might have trouble stopping behaviors and/or realizing what you have learned / the bigger picture.
Also, there is crosstalk between the 5-ht2c receptors and 5-ht1b receptors. Apparently 5-ht2c agonism decreases the responsiveness of postsynaptic 5-ht2b receptors which are involved in reward function and certain spatial memory functions. So althought 5-ht2c antagonism acutely decreases declaritive memory, it may increase performance in certain spacial learning tasks.
So, the antideprssant effects of 5-ht2c antagonism may infact be partially mediated by a corresponding increase in 5-ht1b receptor function.
The reason that a 5-ht2c agonist might help in schizohprenia is perhaps due to an anticonvulsant effect. Also, the 5-ht2c receptors are involved in some form of synaptic pruning if I recall.
Posted by linkadge on December 21, 2008, at 22:37:06
In reply to Re: Agomelatin: could 5HT(2c) action be bad for sl, posted by linkadge on December 21, 2008, at 22:34:13
Also, lithium and valproate indirectly decrease the activity of 5-ht2c related receptor function.
I wonder if a 5-ht2c agonist antidepressant would have psychedelic properties?
Linkadge
Posted by mav27 on December 21, 2008, at 23:39:00
In reply to Re: Agomelatin: could 5HT(2c) action be bad for sl, posted by linkadge on December 21, 2008, at 22:37:06
Im currently on valproate and prozac.. does that mean each one is fighting each other at 5ht2c, could they sort of cancel each other out ?
Valproate is a funny thing because there was no specific reason for taking it.. i've tried all the anti-depressents without any luck and asked the doc if i could try valproate to see what happens and found it gives me the mental energy/motivation to finally do things other than lay in bed. Prozac has just been added recently for the depression.> Also, lithium and valproate indirectly decrease the activity of 5-ht2c related receptor function.
>
> I wonder if a 5-ht2c agonist antidepressant would have psychedelic properties?
>
> Linkadge
Posted by Trotter on December 22, 2008, at 2:36:18
In reply to Re: Agomelatin: could 5HT(2c) action be bad for sl » psychobot5000, posted by Marty on December 21, 2008, at 1:15:03
There is a study that claims to prove Trazodone is a potent 5-HT2c agonist. http://www.ncbi.nlm.nih.gov/pubmed/9618398?dopt=Abstract
If this is true, then doesn't this mean adding Trazodone to Agomelatine reduces its effectiveness?
Trotter
Posted by linkadge on December 22, 2008, at 9:18:26
In reply to Re: Agomelatin: could 5HT(2c) action be bad for sl, posted by Trotter on December 22, 2008, at 2:36:18
Interesting, I have seen other studies suggesting it is an antagonist at 5-ht2c.
Anyhow, I don't think they would completely block eachother's effects since trazodone has other targets ie 5-ht1a, which could be more responsable for its effects.
Linkadge
Posted by psychobot5000 on December 22, 2008, at 10:56:32
In reply to Re: Agomelatin: could 5HT(2c) action be bad for sl, posted by linkadge on December 21, 2008, at 22:34:13
Hi Link,
>
> I wonder if a 5-ht2c agonist antidepressant would have psychedelic properties?Like in that pilot study indicating psilocybin had a positive acute effect on OCD symptoms? I knew a guy with severe OCD who continually self-medicated with psilocybin mushrooms, by the way. At least that was my interpretation of his situation...
> A 5-ht2c agonist might have more application in depression associated with hyperactive frontal cortex function (for instance OCD/Depression). A 5-ht2c agonist might also work well with atypical depression depression that is associated with overeating etc.
So is OCD thought to be related to frontal cortex overactivity? (I have both OCD and severe difficulty with executive function...so I'm very curious...) It's worth mentioning, that (I read in one article) some patients find Remeron (5HT2c antagonist, no?) highly effective for OCD symptoms. I also found this to be the case from my personal experience. Any ideas what might explain the (apparent) paradox that both 5HT2c agonists and antagonists can be effective on OCD? Granted, mirtazipine (like most antidepressants) takes several days to have its positive effects, whereas presumably psilocybin gives its benefits almost immediately, when the user takes them, leaving open the question of whether mirtazipine's positive effects are due to some sort of re-regulation... But should one look to the medications' effects on other targets as well (i.e. 5HT-2a)? How well understood is the 5HT-2c link?
(and if frontal cortex activation is bad for OCD...what is someone like myself with both OCD and cognitive dysfunction/executive dysfunction supposed to do, I wonder?)
I'd be very curious to hear any insight anyone might have, of course. I suppose the practical answer to such questions is: take agomelatine and see what happens. But it sure is all confusing.
Psychbot
Posted by desolationrower on December 22, 2008, at 12:32:52
In reply to Re: Agomelatin: could 5HT(2c) action be bad for sl » linkadge, posted by psychobot5000 on December 22, 2008, at 10:56:32
IIRC 5ht2c also exhibits downregulation in the face of both agonism and antagonism. I think there was some evidence some of the psychedelics exhibit functional agonism at 5ht2a at least; my suspicion is that a number of drugs acting at ht52 receptors have these complicated actions; it woudl explain some of the contradictory findings. So i'd be quite wary of drawing conclusion of what one drug will do based on what another one does at this receptor. It doesn't seem this set of recptors is very well understood yet. lots of clues, not many real maps. Lots of info in this thread.
-d/r
Posted by linkadge on December 22, 2008, at 14:05:59
In reply to Re: Agomelatin: could 5HT(2c) action be bad for sl » linkadge, posted by psychobot5000 on December 22, 2008, at 10:56:32
>So is OCD thought to be related to frontal >cortex overactivity? (I have both OCD and severe >difficulty with executive function...so I'm very >curious...)
Generally yes, but it may depend on the nature of the OCD. If it is more rumanative, then there may not be frontal hyperactivity. If your OCD involves repetitive motor behaviors then perhaps this is associated with hyperactivity.
OCD and attention problems can certainly coexist and then it is probably more complex.
I do know that 5-ht1a receptor stimulation apparently has some anti-OCD effects. Remeron indirectly increases 5-ht1a receptor activity through the alpha-2 antagonism which may mediate some effects in OCD. I do know that in some studies potent and selective 5-ht2a/c antagonists can abololish or greatly reduce the anti OCD effects of SSRI's.
>It's worth mentioning, that (I read in one >article) some patients find Remeron (5HT2c >antagonist, no?) highly effective for OCD >symptoms. I also found this to be the case from >my personal experience.Remeron is not generally a first line OCD medication, but you are right there are case reports of it both improving (and worsening OCD). Remeron can have strong anxolytic effects which may indrectly improve OCD. Also, the enhanced 5-ht1a receptor stimulation could underly a theraputic effect in OCD.
>(and if frontal cortex activation is bad for >OCD...what is someone like myself with both OCD >and cognitive dysfunction/executive dysfunction >supposed to do, I wonder?)Again its hard to say. Activating the frontal cortex can actually supress certain limbic activity. I think there are probably subtle different neurobiological underpinnings of varients in OCD.
Do you mind me asking if your OCD is more classic (i.e. specific obsessions with associated specific behaviors indented to prevent the behaviors) or more ruminative?
Linkadge
Posted by psychobot5000 on December 22, 2008, at 19:27:55
In reply to Re: Agomelatin: could 5HT(2c) action be bad for sl, posted by linkadge on December 22, 2008, at 14:05:59
> Again its hard to say. Activating the frontal cortex can actually supress certain limbic activity. I think there are probably subtle different neurobiological underpinnings of varients in OCD.
>
>
> Do you mind me asking if your OCD is more classic (i.e. specific obsessions with associated specific behaviors indented to prevent the behaviors) or more ruminative?
>
>
> Linkadge
>
>Not at all, and thanks for all your thoughts. I suppose my personal OCD symptoms are mixed, including both behavioral and ruminative aspects--and both entangled with other anxiety symptoms. A bit of a mess, like many of us here, of course.
But, re 5HT2c and frontal cortex dopamine, I've decided to take some heart from the fact that stimulants (dexamph and methylphenidate) never made my OCD worse. So perhaps in my case increased stimulation of the frontal cortex would be fine, and there would be no conflict with improving executive function.
I didn't know that remeron/mirtazipine made some patients' OCD worse. Perhaps it's as you say, that Remeron only helps largely by reducing anxiety in-general (it did do that in my case). I wonder if ritanserin might have had similar beneficial effects on anxiety, without some of Remeron's drawbacks (sedation etc)--I suppose we'll never know). But with any luck, pharmacologists will get some helpful tools from the small slew of 5ht2 affecting meds in the pipeline.
Psychbot
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