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Valdoxan/Agomelatine & Melatonin


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#1 OneScrewLoose

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Posted 14 January 2010 - 10:21 PM


I will be trying Valdoxan soon, right now I am taking 3mg of time released melatonin at night, and low doses of Lamictal (125), Amitrytiline(25), and Seroquel(100), for sleep and anxiety. Will it cause a problem to take it with the Melatonin? Should I be worried about any other interactions?

#2 BadPlasmid

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Posted 15 January 2010 - 12:44 AM

I will be trying Valdoxan soon, right now I am taking 3mg of time released melatonin at night, and low doses of Lamictal (125), Amitrytiline(25), and Seroquel(100), for sleep and anxiety. Will it cause a problem to take it with the Melatonin? Should I be worried about any other interactions?


Due to the fact that Valdoxan is a strong melatonin agonist I would personally avoid taking additional melatonin. The reality is that you probably won't need it. That being said, I am very interested in where you got it. I have been looking around to try it but haven't found it available anywhere. Feel free to PM me if you are comfortable with sharing that info.

I am dealing with anxiety myself, but am not interested in trying tricyclics or SSRI's.

Admittedly, I am a little concerned about the liver toxicity (and would be monitored) and it's been shown to be oncogenic at high doses - but I still find it interesting and possibly worth considering. Still reading through the literature.

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#3 OneScrewLoose

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Posted 15 January 2010 - 02:42 AM

I am currently in Spain where it can be purchased at any pharmacy. :)

Links to liver and oncogenic effects, please.

Why aren't you willing to try tricyclics or SSRIs?

#4 jackinbox

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Posted 15 January 2010 - 03:48 AM

I take agomelatine and routinely combine melatonin with it. I didn't experience any side effect. They might potentiate each other a bit. Agomelatine is great for have virtually no side effect.

#5 BadPlasmid

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Posted 15 January 2010 - 04:28 AM

I am currently in Spain where it can be purchased at any pharmacy. :)

Links to liver and oncogenic effects, please.

Why aren't you willing to try tricyclics or SSRIs?


Tried SSRI's years ago, didn't work for me and the erectile dysfunction was bad enough to say 'no way in hell'. Beyond that, I am one of the growing group who aren't sold on the serotonergic description of depression/anxiety and feel that while lower HT receptor activity is obviously involved in the pathogenesis of some of these diagnosis, it is not the cause. If it were, atypical antidepressants that raise synaptic serotonin such as tianeptine or MDMA would make the problem worse, not better. In addition, studies on cognition are a mixed bag, but generally I have found that those focused on subjects not suffering from Major Depression have declines in memory. Being in academia, I need my mental faculties intact until I am completely done with school (which still looks years away /sigh ). My anxiety is problematic at times, but retaining full cognitive function is more important to me than stopping the racing thoughts/worries.

Tricyclics simply have too many side effects for my taste. I also don't need or want the noradrenal reuptake inhibition that comes along with them.

The reason Agomelatine appeals to me is due to the sleep enhancement on top of the anxiolytic effects. I have problems sleeping which likely contribute to my mood and anxiety problems - it would be worth it to try and kill two birds with one stone. Given the genetic links between depression/bipolar/ADHD/circadian rhythm and certain neurological disorders (like restless legs syndrome) I would be surprised if melatonin didn't play a role somehow.

As far as the liver/oncogenic issue - I don't have links handy, but there are studies available through pubmed that have that info if you search for agomelatine. I got most of the info browsing my campus library and med school. If you can't find info on pubmed or google scholar, let me know and I will try and get info on which publications they can be found in when I am on campus tomorrow or next week (time permitting).

Would look on pubmed for you, but have to get my kids in to bed and then watch a sappy romantic comedy I committed to. (one of the Cons of married life :( )

Either way, I am interested in hearing how your trial goes if you do start it. It's in Stage III trials here and isn't likely to be released (if it wins approval) until 2012.

#6 robbs

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Posted 26 January 2010 - 05:08 PM

I take Agomelatine and 0,5mg Melatonin (time released) every evening, agomelatine sometimes makes me wake up early (although refreshed! It's amazing that it can lower your need for sleep about 25%).

It lost it's effectiveness a month ago, but then I added a minute amount of lithium carbonate (read on a pubmed article that lithium salts increase sensitivity of melatonergic receptors) and the effect returned and increased by about 25-50%!

This is of course my own subjective experience, but adding a small amount of lithium (that increases melatonergic sensitivity) or perhaps a small amount of valeric acid (which increases melatonin production AND melatonin receptor sensitivity) could produce som pronounced results in others, as it did with me.

#7 OneScrewLoose

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Posted 27 January 2010 - 12:19 AM

BadPlasmid, you seem to have a really oversimplified view of neurotransmitters (I need x and not y). I had the same kind of viewpoint when I first got on these forums, but it's always more complicated than that. Have you ever tried an NRI?

Also, amitryptiline might be worth a look for you. It is a 5HT2c inverse agonist and tends to block the side-effects of the SRI part of that drug.

It's always more complicated...

Anyway, I did start the agomelatine. Tonight will be my fifth dose. I took a half a pill the first 2 nights, and likewise lowered my melatonin. I often take naps during the day from chronic fatigue. At first, the ago made it worse. I couldn't stay awake after going out and doing something. But now it seems to be making it better, my anxiety is going down and things exhaust me less. Plus it's easier to do things I don't normally want to. I'll keep everyone updated.

Edited by OneScrewLoose, 27 January 2010 - 12:23 AM.


#8 OneScrewLoose

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Posted 29 January 2010 - 12:09 AM

I've been feeling pretty damn good today. This might be the real deal.

#9 Cappa

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Posted 29 January 2010 - 07:50 AM

Ignore. Was concerned about prolactin. Did more research.

Edited by Cappa, 29 January 2010 - 08:17 AM.


#10 OneScrewLoose

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Posted 29 January 2010 - 09:52 AM

Went to bed with less insomnia and woke up automatically with only 7 hours sleep (I usually wake up at 9 hours unless I put an alarm).

#11 OneScrewLoose

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Posted 07 February 2010 - 03:50 PM

Just went up to 50mg. That stuff always leaves me tired for 2-3 days on it when I go up, but then it goes away. Feeling less anxious and less resistant to doing stuff I normally don't want to.

#12 bluebird2

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Posted 19 February 2010 - 02:26 PM

Someone requested link to liver/oncogenic data...

i haven't found the oncogenic data but this site mentions liver damage as exacerbating side effects from valdoxan. the data seems to show that liver impairment may cause excessive blood levels of the medication and this could have an oncogenic effect.

#13 OneScrewLoose

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Posted 19 February 2010 - 04:46 PM

Update: Last weekend I had a GREAT time in Carnaval in Spain. I loved being around there, loved the music, went for 16 hours. This would not have happened before the Valdoxan. For the first time I was fine being in a huge crowd. Well, there was some anxiety, but it was minimal.

#14 KimberCT

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Posted 19 February 2010 - 06:16 PM

Interesting. You have social anxiety, right? Did you suffer from symptoms of agoraphobia?

I've been considering a agomelatine trial, but I don't know if it works for "panic"-type anxiety or "worry"-type anxiety. It's expensive to import into the USA.

#15 OneScrewLoose

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Posted 19 February 2010 - 08:56 PM

Never had agoraphobia, though I generally get tired easily being in places I am used to. I've always loved nature though. Just peoplephobia.

#16 mwasnidge

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Posted 02 March 2010 - 07:51 PM

OneScrewLoose: How is it going with the Valdoxan? This stuff intrigues me. My sleep quality is garbage, and if this could combat that along with daytime sleepiness and anxiety and/or depression, then it could be a winner. Is it available in Spain without prescription? I have a friend in Madrid that I'll get in touch with if that's the case. I wonder if it's readily available in the UK too (i'm from the UK, but live in the US).

There are people raving about it over at addforums, and that it could be synergistic with ADHD stims--what would be your thoughts on that?

#17 OneScrewLoose

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Posted 02 March 2010 - 08:11 PM

First of all in my last post I meant places I am NOT used to.

It helps me in my fatigue in the sense that I don't get tired as easily, but it doesn't help with my baseline fatigue. It just makes life more enjoyable, but that is a lot. I took some Vyvanse when I was on it. Not that big a difference. But the stims never really helped me much anyway.

#18 chrwe

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Posted 05 May 2010 - 08:18 AM

Also started taking 25mg Valdoxan (without melantonine) and it works wonders, strangely enough (I was resistant to all other anti-depressants). I`m going to experiment with adding 0,5mg Melatonine.

The oncogenic and hepatotoxic effects worry me greatly - so does the hint "do not take in cases of dementia" (I mean: Why?). But when push comes to shove, sleep deprivation and bad anxiety also lowers the quality of life a lot and will in my opinion severely shorten your life due to insane levels of stress. So it`s a risk worth taking if you suffer badly enough.

OneScrewLoose, how is it one month later? Do you know how long you will have to take the medication?

#19 Thorsten3

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Posted 02 June 2010 - 07:54 PM

BUMP

ScrewLoose are you concerned about the issues with liver toxicity? Is there anyone here who takes this drug that actually takes this issue seriously? Even if it is a remote thing it still concerns the hell out of me.

I've been taking Tianeptine recently with good results - Thinking it could be a long term thing for me (combined with 2g of EPA daily, good diet and regular exercise and the occasional trip to keep spiritual perception - I no longer see the point in looking for anything else - I'm not 100% happy but my cognition is so much sharper, depression non existent and no more anxiety so progress has been made :) )

....The only reason I am going to try agomelatine is purely for a trial. If it really is as good as they say and I discover it kicks Tianeptine's ass then i'll have to reconsider. They're both expensive so we'll have to see.

If anyone from the UK is reading this do you know if a liver test is generally free through the NHS? I have some agomelatine on the way but I would like regular checks if possible.
I am quite appreciative of how hard it can be liasing with the medical profession when it comes to self medicating. Is there a clinic I can go to or are there ways around this? (short of visiting my local GP)

Edited by Thorsten, 02 June 2010 - 07:55 PM.


#20 chrwe

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Posted 03 June 2010 - 04:21 AM

I`m off Agomelatine again since it stopped working for me after about a month.

Also, I was too concerned about the liver toxicity - especially since I still could not sleep through the night on Valdoxan.

I wonder if there is any sleep aid out there that is safe and still lets me sleep for 6-8 hours again without waking up in sweat and anxiety in the middle of the night :(

#21 OneScrewLoose

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Posted 04 June 2010 - 12:26 AM

I got a liver test a month back and it turned out fine. I am still on the 50mg. It's not the be-all-end-all that the above posts made it seem like (some placebo), but it does make things enjoyable and, above all, it countered the horrible mind-numbing side effects of the Lamictal. I could talk to people again!

Before anyone else posts about this, the current pros of the Lamictal outweigh the cons, though I will be trying Memantine to replace it in August.

#22 Thorsten3

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Posted 05 June 2010 - 12:44 PM

I got a liver test a month back and it turned out fine. I am still on the 50mg. It's not the be-all-end-all that the above posts made it seem like (some placebo), but it does make things enjoyable and, above all, it countered the horrible mind-numbing side effects of the Lamictal. I could talk to people again!

Before anyone else posts about this, the current pros of the Lamictal outweigh the cons, though I will be trying Memantine to replace it in August.


Cool memantine is a good drug although anything less than 30mg no longer provides positive effects for me so it's become quite an expensive one. I haven't been taking it for about 6/7 weeks now due to the tolerance that crept up on me.

As for agomelatine I think it arrived this morning but the post office is closed so I have to wait till monday morning until I can try it.

#23 curious_sle

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Posted 08 June 2010 - 08:20 PM

I got Agomelatine since friday... have to buy it in germany but that is just one commuter rail stop from my home so...
Can't say i feel like i sleep better... i do seem to wake up several times and falling asleep doesn't seem easier but... i am fairly well during the day (varies) plus i am still taking for a few days only. Certainly not much of a hypnotic... Mirtazapin used to make me sleep fairly well, not so with Agomelatin but then again i never responded well to 5-htp, melatonin etc so why would it?

Still... so far not bad... if it improves all the better... had like one especially well day hehe.

#24 FunkOdyssey

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Posted 25 July 2010 - 04:23 PM

Any of you still taking agomelatine? I'm about to go on it again (starting this evening), along with tianeptine this time which I've been on nearly a week.

#25 John Barleycorn

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Posted 26 July 2010 - 05:09 AM

Any of you still taking agomelatine? I'm about to go on it again (starting this evening), along with tianeptine this time which I've been on nearly a week.


There is a possibility the two could clash, at least as far as memory and plasticity goes:

Abstract

Recent studies using invertebrate and mammal species have revealed that, endogenous serotonin (5-hydroxytryptamine, 5-HT) modulates cognitive processes, particularly learning and memory, though, at present, it is unclear the manner, where, and how long 5-HT systems are involved. Hence in this work, an attempt was made to study the effects of 5-HT endogenous on memory formation, using a 5-HT uptake facilitator (tianeptine) and, selective 5-HT(1-7) receptor antagonists to determine whether 5-HT uptake sites and which 5-HT receptors are involved, respectively. Results showed that post-training tianeptine injection enhanced memory consolidation in an autoshaping Pavlovian/instrumental learning task, which has been useful to detect changes on memory formation elicited by drugs or aging. On interaction experiments, ketanserin (5-HT(1D/2A/2C) antagonist) slightly enhanced tianeptine effects, while WAY 100635 (5-HT(1A) antagonist), SB-224289 (5-HT(1B) inverse agonist), SB-200646 (5-HT(2B/2C) antagonist), ondansetron (5-HT(3) antagonist), GR 127487 (5-HT(4) antagonist), Ro 04-6790 (5-HT(6) antagonist), DR 4004 (5-HT(7) antagonist), or fluoxetine (an inhibitor of 5-HT reuptake) blocked the facilitatory tianeptine effect. Notably, together tianeptine and Ro 04-6790 impaired learning consolidation. Moreover, 5-HT depletion completely reversed the tianeptine effect. Tianeptine also normalized an impaired memory elicited by scopolamine (an antimuscarinic) or dizocilpine (non-competitive glutamatergic antagonist), while partially reversed that induced by TFMPP (5-HT(1B/1D/2A-2C/7) agonist/antagonist). Finally, tianeptine-fluoxetine coadministration had no effect on learning consolidation; nevertheless, administration of an acetylcholinesterase inhibitor, phenserine, potentiated subeffective tianeptine or fluoxetine doses. Collectively, these data confirmed that endogenously 5-HT modulates, via uptake sites and 5-HT(1-7) receptors, memory consolidation, and are consistent with the emerging notion that 5-HT plays a key role on memory formation.

PMID: 12034133


However, the clash mechanism isn't really spelt out. My understanding is that agomelatine, by antagonising 5HT-2C, increases limbic dopamine downstream. The nice part is that those 5HT receptors downregulate in response to antagonism, and they have this dopaminergic effect on a continuous basis. With tianeptine, everyone remarks that it transports serotonin, but as far as I can tell from the research, its effects are actually on the glutamate system. Doesn't appear to be grounds for a clash on the face of it.

Oh, and another speculation is that agomelatine may not feel like it is doing much if someone's basal limbic dopamine system is already in good shape. In other words, it could work best on those who need it.

#26 FunkOdyssey

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Posted 26 July 2010 - 12:23 PM

There is a possibility the two could clash, at least as far as memory and plasticity goes:

Abstract

Recent studies using invertebrate and mammal species have revealed that, endogenous serotonin (5-hydroxytryptamine, 5-HT) modulates cognitive processes, particularly learning and memory, though, at present, it is unclear the manner, where, and how long 5-HT systems are involved. Hence in this work, an attempt was made to study the effects of 5-HT endogenous on memory formation, using a 5-HT uptake facilitator (tianeptine) and, selective 5-HT(1-7) receptor antagonists to determine whether 5-HT uptake sites and which 5-HT receptors are involved, respectively. Results showed that post-training tianeptine injection enhanced memory consolidation in an autoshaping Pavlovian/instrumental learning task, which has been useful to detect changes on memory formation elicited by drugs or aging. On interaction experiments, ketanserin (5-HT(1D/2A/2C) antagonist) slightly enhanced tianeptine effects, while WAY 100635 (5-HT(1A) antagonist), SB-224289 (5-HT(1B) inverse agonist), SB-200646 (5-HT(2B/2C) antagonist), ondansetron (5-HT(3) antagonist), GR 127487 (5-HT(4) antagonist), Ro 04-6790 (5-HT(6) antagonist), DR 4004 (5-HT(7) antagonist), or fluoxetine (an inhibitor of 5-HT reuptake) blocked the facilitatory tianeptine effect. Notably, together tianeptine and Ro 04-6790 impaired learning consolidation. Moreover, 5-HT depletion completely reversed the tianeptine effect. Tianeptine also normalized an impaired memory elicited by scopolamine (an antimuscarinic) or dizocilpine (non-competitive glutamatergic antagonist), while partially reversed that induced by TFMPP (5-HT(1B/1D/2A-2C/7) agonist/antagonist). Finally, tianeptine-fluoxetine coadministration had no effect on learning consolidation; nevertheless, administration of an acetylcholinesterase inhibitor, phenserine, potentiated subeffective tianeptine or fluoxetine doses. Collectively, these data confirmed that endogenously 5-HT modulates, via uptake sites and 5-HT(1-7) receptors, memory consolidation, and are consistent with the emerging notion that 5-HT plays a key role on memory formation.

PMID: 12034133


However, the clash mechanism isn't really spelt out. My understanding is that agomelatine, by antagonising 5HT-2C, increases limbic dopamine downstream. The nice part is that those 5HT receptors downregulate in response to antagonism, and they have this dopaminergic effect on a continuous basis. With tianeptine, everyone remarks that it transports serotonin, but as far as I can tell from the research, its effects are actually on the glutamate system. Doesn't appear to be grounds for a clash on the face of it.

Oh, and another speculation is that agomelatine may not feel like it is doing much if someone's basal limbic dopamine system is already in good shape. In other words, it could work best on those who need it.


How did you arrive at the two clashing based on that abstract? There were no selective 5-HT2C antagonists tested. A 5-HT2B/5-HT2C antagonist blocked tianeptine's effect while a 5-HT1D/5-HT2A/5-HT2C antagonist enhanced it. It seems just as likely based on this information that 5-HT2C antagonism is helpful but 5-HT2B is problematic, or that 5-HT2C is simply neutral. Antagonism of 5-HT2B autoreceptors would affect 5-HT release so I could see the possibility for a negative interaction there.

Plus I woke up this morning and my memory seems excellent. :-D

Edited by FunkOdyssey, 26 July 2010 - 12:29 PM.


#27 Animal

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Posted 26 July 2010 - 04:59 PM

There is a possibility the two could clash, at least as far as memory and plasticity goes:

Abstract

Recent studies using invertebrate and mammal species have revealed that, endogenous serotonin (5-hydroxytryptamine, 5-HT) modulates cognitive processes, particularly learning and memory, though, at present, it is unclear the manner, where, and how long 5-HT systems are involved. Hence in this work, an attempt was made to study the effects of 5-HT endogenous on memory formation, using a 5-HT uptake facilitator (tianeptine) and, selective 5-HT(1-7) receptor antagonists to determine whether 5-HT uptake sites and which 5-HT receptors are involved, respectively. Results showed that post-training tianeptine injection enhanced memory consolidation in an autoshaping Pavlovian/instrumental learning task, which has been useful to detect changes on memory formation elicited by drugs or aging. On interaction experiments, ketanserin (5-HT(1D/2A/2C) antagonist) slightly enhanced tianeptine effects, while WAY 100635 (5-HT(1A) antagonist), SB-224289 (5-HT(1B) inverse agonist), SB-200646 (5-HT(2B/2C) antagonist), ondansetron (5-HT(3) antagonist), GR 127487 (5-HT(4) antagonist), Ro 04-6790 (5-HT(6) antagonist), DR 4004 (5-HT(7) antagonist), or fluoxetine (an inhibitor of 5-HT reuptake) blocked the facilitatory tianeptine effect. Notably, together tianeptine and Ro 04-6790 impaired learning consolidation. Moreover, 5-HT depletion completely reversed the tianeptine effect. Tianeptine also normalized an impaired memory elicited by scopolamine (an antimuscarinic) or dizocilpine (non-competitive glutamatergic antagonist), while partially reversed that induced by TFMPP (5-HT(1B/1D/2A-2C/7) agonist/antagonist). Finally, tianeptine-fluoxetine coadministration had no effect on learning consolidation; nevertheless, administration of an acetylcholinesterase inhibitor, phenserine, potentiated subeffective tianeptine or fluoxetine doses. Collectively, these data confirmed that endogenously 5-HT modulates, via uptake sites and 5-HT(1-7) receptors, memory consolidation, and are consistent with the emerging notion that 5-HT plays a key role on memory formation.

PMID: 12034133


However, the clash mechanism isn't really spelt out. My understanding is that agomelatine, by antagonising 5HT-2C, increases limbic dopamine downstream. The nice part is that those 5HT receptors downregulate in response to antagonism, and they have this dopaminergic effect on a continuous basis. With tianeptine, everyone remarks that it transports serotonin, but as far as I can tell from the research, its effects are actually on the glutamate system. Doesn't appear to be grounds for a clash on the face of it.

Oh, and another speculation is that agomelatine may not feel like it is doing much if someone's basal limbic dopamine system is already in good shape. In other words, it could work best on those who need it.


How did you arrive at the two clashing based on that abstract? There were no selective 5-HT2C antagonists tested. A 5-HT2B/5-HT2C antagonist blocked tianeptine's effect while a 5-HT1D/5-HT2A/5-HT2C antagonist enhanced it. It seems just as likely based on this information that 5-HT2C antagonism is helpful but 5-HT2B is problematic, or that 5-HT2C is simply neutral. Antagonism of 5-HT2B autoreceptors would affect 5-HT release so I could see the possibility for a negative interaction there.

Plus I woke up this morning and my memory seems excellent. :-D


I expect the tianeptine will attenuate any long term benefit (or any benefit at all) of the agomelatine administration, since tianeptine primarily functions by increasing the sensitivity of all 5-HT receptors; the enabling of DA and NE release being comparatively weak . Since the 5-HT2C receptors only express a sustained but gradual downregulation response to antagonism, but more readily upregulate in response to reverse-agonism (i.e. tianeptines MOA)I think the agomelatine's MOA will simply be overwhelmed by the more rapid but transient effects of the tianeptine.

Basically every time you take a dose of the tianeptine you are counteracting the benign but sustained effects of the agomelatine. Of course, there could be some sort of novel synergy that can't be predicted, simply due to the more mysterious nature of some of tianeptine's effects.

I love tianeptine, I think it's a fantastic molecule and a superb anti-depressant, but it just has too short of a half-life for me to be comfortable taking it. I mean, if you stay up late one night, or miss a dose, or for some other reason leave longer then about 6 hours between doses (while you're awake obviously) then the depression and anxiety will start to creep back in no matter how long you've been on it. I think one of the most therapeutic effects of one day dosing with AD's is that they can make you feel you don't even suffer from a mood disorder.

Why the fuck Servier can't just make an extended release >37.5mg tablet is beyond me. Anyway, try an keep us updated please funk, I'm really interested in how this combo plays out. The only problem being it'll take a couple of months of consistent dosing for you to be fully aware of whether or not the agomelatine is functioning correctly.

#28 FunkOdyssey

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Posted 26 July 2010 - 09:54 PM

I expect the tianeptine will attenuate any long term benefit (or any benefit at all) of the agomelatine administration, since tianeptine primarily functions by increasing the sensitivity of all 5-HT receptors; the enabling of DA and NE release being comparatively weak . Since the 5-HT2C receptors only express a sustained but gradual downregulation response to antagonism, but more readily upregulate in response to reverse-agonism (i.e. tianeptines MOA)I think the agomelatine's MOA will simply be overwhelmed by the more rapid but transient effects of the tianeptine.

Basically every time you take a dose of the tianeptine you are counteracting the benign but sustained effects of the agomelatine. Of course, there could be some sort of novel synergy that can't be predicted, simply due to the more mysterious nature of some of tianeptine's effects.

I love tianeptine, I think it's a fantastic molecule and a superb anti-depressant, but it just has too short of a half-life for me to be comfortable taking it. I mean, if you stay up late one night, or miss a dose, or for some other reason leave longer then about 6 hours between doses (while you're awake obviously) then the depression and anxiety will start to creep back in no matter how long you've been on it. I think one of the most therapeutic effects of one day dosing with AD's is that they can make you feel you don't even suffer from a mood disorder.

Why the fuck Servier can't just make an extended release >37.5mg tablet is beyond me. Anyway, try an keep us updated please funk, I'm really interested in how this combo plays out. The only problem being it'll take a couple of months of consistent dosing for you to be fully aware of whether or not the agomelatine is functioning correctly.


A couple thoughts, first tianeptines MOA according to more recent thinking is primarily modulation of glutamatergic neurotransmission, second I don't think it reduces synaptic serotonin so much as it accelerates turnover, because the increased rate of uptake is compensated for by additional release of serotonin. However assuming for a moment it does appreciably reduce serotonin's agonism of 5-ht2c receptors, they would likely upregulate if tianeptine was used as monotherapy, which would be all the more reason to antagonize them periodically with agomelatine to keep them pinned down.

The half-life thing doesn't bother me because the acute effects aren't the important thing, its the long-term adaptation and remodeling that is taking place in response to the drug. Same reason agomelatine's once daily, 2.5 hour half-life is irrelevant. You care about sustained plasma levels of things like stimulants, painkillers, drugs that you depend on for their acute effects, not these type of antidepressants.

Edited by FunkOdyssey, 26 July 2010 - 09:55 PM.


#29 Animal

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Posted 26 July 2010 - 11:34 PM

A couple thoughts, first tianeptines MOA according to more recent thinking is primarily modulation of glutamatergic neurotransmission, second I don't think it reduces synaptic serotonin so much as it accelerates turnover, because the increased rate of uptake is compensated for by additional release of serotonin. However assuming for a moment it does appreciably reduce serotonin's agonism of 5-ht2c receptors, they would likely upregulate if tianeptine was used as monotherapy, which would be all the more reason to antagonize them periodically with agomelatine to keep them pinned down.

The half-life thing doesn't bother me because the acute effects aren't the important thing, its the long-term adaptation and remodeling that is taking place in response to the drug. Same reason agomelatine's once daily, 2.5 hour half-life is irrelevant. You care about sustained plasma levels of things like stimulants, painkillers, drugs that you depend on for their acute effects, not these type of antidepressants.


Tianeptine's action on serotonin receptors is almost identical to sulbutiamine's action on dopamine receptors, look it up, it doesn't increase the release of serotonin at all, the mechanism is receptor regulated. You may be right about agomelatine keeping the 5HT-2C receptors from upregulating substantially in response to the tianeptine's reverse-agonism but since agomelatine has such a gradual and benign effect, and 5HT-2C receptors respond more readily to reverse-agonism I can see it simply being made ineffective. Also you should keep in mind that an excessive reduction in 5HT-2C receptor activity proportional to overall 5-HT activity can cause an excess of excitatory neurotransmission, resulting in excitotoxicity and seizures.

What I'm saying is that agomelatine is a long term and gradual antidepressant, while tianeptine has primarily short term effects on serotonin, but is extremely potent in comparison. It only has long term effects on D1 + D2 auto-receptors, which are irrelevant to the MOA of agomelatine.

The reuptake effects of tianeptine only last as long as the drug is in your system at active levels, whereas the irreversible antagonism of 5-HT2C receptors by agomelatine lasts well beyond it's half-life, though it's melatonin agonism decreases in proportion to plasma concentration. You're totally wrong about plasma concentration of antidepressants being irrelevant, this may be true in some cases, but not in all. For example, Buproprion requires maintained plasma concentrations to be effective, which is why there is an SR and XR version of the pill, tianeptine is the same.

I simply think you're wasting the agomelatine, and I'm not sure why you're taking both at once when you recently claimed to be fully satisfied with your regime. These are significant additions, and starting them both only weeks apart is irresponsible in my opinion, you haven't even waited for tianeptine to exhibit long term effects. It's not as simple as 'the more antidepressants the better', you should be aiming to be on the least amount of pharmaceuticals necessary to achieve a remission in whatever condition you are suffering from, which in your case is what?

These drugs won't permanently 'remodel' your brain, all the receptors will re-regulate after discontinuation within a couple of months. The reason why antidepressants can result in an individual being 'cured' of depression is because the individual makes tangible changes to their life and thought processes while being enabled by the drug, resulting in a sustained change in neurochemistry (exempting neuro-regeneration). If you just sit on your arse while taking these drugs, whatever issues you have will return gradually after you discontinue their use. Try missing a tianeptine dose, the mood elevating effects will wear off rapidly.

Edited by Animal, 26 July 2010 - 11:44 PM.


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#30 John Barleycorn

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Posted 27 July 2010 - 01:25 AM

What I'm saying is that agomelatine is a long term and gradual antidepressant, while tianeptine has primarily short term effects on serotonin, but is extremely potent in comparison. It only has long term effects on D1 + D2 auto-receptors, which are irrelevant to the MOA of agomelatine.


My understanding is that the short-term, mood elevating effects of tianeptine are also dopaminergic. PMID: 1630590 suggests acute administration raised DA levels in the NA (which of course agomelatine is also supposed to do more gradually). They also looked at chronic administration. I have seen a throwaway suggestion on medline that pramipexole might work as a tianeptine augmentor.

My second understanding is that tianeptine long-term is some unspecified type of glutamate modulator, presumably in the same ballpark as NMDA antagonists or AMPA agonists/modulators (eg, aniracetam).

Whilst I'm free-associating, anyone here considered low dose atypical antipsychotics (for DA inhibitory autoreceptor downregulation)? Come on Funk, you know you want to try it. :)




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