Agomelantine antidepressant-Half life 2 hours?

[Alexander16]

So I got scripted Agomelantine (valdoxan) today, to the best of my knowledge it worked on M1 and M2 receptors and supposedly increases dopamine and noradrenaline through stimulating 5ht2c receptors...How does this work given the halflife is 2 hours? Isn't the whole reason SNRI's/SSRI's effexor IR and paroxetine got such a bad rap...because the drug was out of their system and causing withdrawals upon stopping?

Also, anyone any experience on this medication?

 

[sekio]

just because it has a short half life doesn't mean it will be totally eliminated and having no effect on you in 2 hours.

consider that it may induce downstream changes in signalling (e.g. alteration of normal melatonin biosynthesis, perhaps) in response to temporary stimulation of melatonin receptors... see also, cocaine produces a tolerance that lasts even when you're not doing cocaine any more - drugs don't have to stay present in your body to cause changes.

Also, anyone any experience on this medication?

i'm sure you can find something if you search in the usual places (Trip Reports board, erowid etc)

 

[Cotcha Yankinov]

I believe that paroxetine also has one of the worst withdrawals as far as SSRIs go so that could've been a factor in specifically that drug getting a bad rep for IR, but I think Sekio is right. Might have something to do with the general concept of a feedback loop. Once you calm the neurons down (over simplification but whatever) they will stay calmed down for a while after the drug that originally did the trick is out of your system. But as far as Agomelatine goes I can really seem to find many reviews but weird seeing as its melatonergic actions should be sedating but the 5-ht2c action should be anti-depressing (Which seemed to keep some people awake). Hope it works for you but the couple random reviewers I found didn't like it at all kept some awake, one said it really messed with their sleep after they got off of it and one of their doctors said OTC melatonin would be better. Also apparently an agency in France listed Valdoxan as the 8th most dangerous drug and that they demanded its withdrawal. So tread carefully I guess, melatonin is an interesting receptor.
Personally my sleep doctor said that melatonin agonists "don't work very well at all" so I never tried them wanting to keep my melatonin receptors drug naive.
My specialty is sleep so if you have any questions fire away, although I guess some people aren't taking this for sleep.

 

[Flynnal]

Cotcha, I believe sleep is the main theme at the heart of my problems. I currently take 60mg Avanza at night, about 1 hour before retiring. It works beautifully...not just on sleep but also on my depression as well...I am generally more positive, especially in the morning. Afternoon I'm always feeling a bit off.

Is there anything that causes this?

The drug also causes pretty serious food cravings, and even though I try to keep it under control, I find that I am putting on some weight. Roughly 1kg since I started taking it, which was about 5 weeks ago.

 

[adder]

Paroxetine has a long half-life comparable to sertraline, venlafaxine has a shorter half-life and is to be taken twice a day if it's immediate release, but the bad reputation has certainly nothing to do with it. Paroxetine's bad reputation is, I believe, due to GlaxoSmithKline's marketing, they withheld the information that discontinuation of paroxetine may cause withdrawal symptoms and claimed it didn't. Well, I was on paroxetine for half a year, it seemed to work exceptionally well, my depression and anxiety were gone, I could approach anyone and talk to them, but then I realized it didn't cure my depression, it just made me extremely manic, I decided to quit and it was a hellish withdrawal indeed, the worst SSRI withdrawal I ever went through. Obviously, my depression and anxiety were back as soon as I quit it.

 

[IndustrialStrength]

@Cotcha Yankinov

Sorry to go slightly off topic in the thread but you mentioned your expertise in sleep matters.
And my question relates to that & somewhat also throws in AD's so perhaps it fits?
Since you mentioned melatonin receptors though don't have personal experience...
For those of us who have not kept said receptors naive, perhaps naively
What's your take on melatonin as a sleep aid?
Dosage, daily usage, etc.
As personally I use it, in what is probably overly high dosages & am not sure how much it benefits.

I know my sleep architecture is generally a mess, due to years of benzo usage.
Sadly doctor's put me on them 15 years ago before I knew any better.
Though I have managed to reduce from 6mg Klonopin daily to 3mg & may consider reducing it.
Though it's prescribed for anxiety, I find I use it just as much to fall asleep.
After all these years of various benzo's & at high doses it doesn't seem to do much for anxiety.
As a side note I was also prescribed other benzo's on top of the 6mg Klonopin previously.
I also take Mirtazapine 15mg nightly, as a sleep aid/appetite enhancer.
Supposedly also for Anti-Depressant properties, but I have not noticed any.
Even at a 30mg dose, which I lowered due to side effects & lack of benefits.

If this post is inappropriate for the thread or to off topic to stand I apologize.
Just let me know & I'll delete, or a Mod can feel free to delete & I'll switch to PM.
Thanks.

 

[adder]

I was on benzodiazepines, mostly clonazepam, for 9 years before I quit it. When you've been on benzodiazepines for many years, they hardly do anything good for you and your problems with sleep are definitely largely due to clonazepam. I didn't even realize how much clonazepam was negatively affecting me until I got off it. I thought it didn't have much effect on me, I was on 6mg for ~5-6 years and I didn't feel much from such a high dose. When I finally quit, my memory started working much much better, I didn't know why I had problems with maths while I was on benzos as I had always been good at it. The impact on memory is huge, I guess it has a lot to do with REM phase during which new memories are formed, and benzodiazepines reduce REM sleep, it's evident in the first few months after quitting when one has very vivid dreams, often nightmares (of course there is scientific evidence for it).

Chronic benzodiazepine usage and withdrawal in insomnia patients.
Medications for the Treatment of Sleep Disorders: An Overview

I highly recommend further reducing your clonazepam dose and quitting completely when your dose is low enough.

 

[IndustrialStrength]

@Adder thanks for the references & your post.
I have a few questions for you but rather than cluttering the thread I will PM you directly.
I don't have the time atm but will do so as soon as time allows. Thanks again for the insight.

 

[Cotcha Yankinov]

Hi there flynnal, sorry mods not trying to clutter thread, just delete or whatever and I will happy to PM and what have you instead, but anyways Avanza/mirtazapine is a unique drug, worked a while for sleep especially at a lower dosage for myself. It functions more as a sedating antihistamine at lower dosage but as the dosage gets higher (30mg+) its effects get stronger at other brain sites so key point is the effects aren't linear and you'll get different effects at 60mg, which would be more serotonin/dopamine/mood effects. I don't know for sure what to make of your mood drop off in the afternoon but a guess is that it could be related to the higher dosage and that by the time afternoon rolls around the dosage in your system is getting down to the point where that dosage isn't boosting your serotonin/dopamine as much and helping your mood but is still hitting your histamine making you feel a little under the weather, idk what your mood is like for you though I guess. Could also be your brain running out of steam towards the end of the day. The antihistamine effects will fade one of these days though if you've only been on it for 5 weeks, also 60mg seems to me to be a high dosage to be at for 5 weeks, I should mention just like Seroquel (somewhat similar anyways) lower dosages are sedating but higher dosages can actually give people insomnia. Oh and the appetite stuff seems to be commonplace with drugs that affect some of these serotonin receptors and histamine, and it boosts dopamine a bit too which can cause cravings for lots of things. Weight gain on mirtazpine is really common. But yeah mirtazapine is really complicated, not like a benzo/ambien that just shuts down your brain.
I see that you mention it does wonders for your sleep as well as depression, makes me wonder how much of your depression and related problems are from your sleep issues?? I personally think sleep is definitely at the heart of most peoples problems but there might be a few people who are the other way around, other problems cause their sleep problems. Hard to say what the mirtazapine is doing for you without knowing what just better sleep could do for you depression (something like ambien that wouldn't be messing with all your other brain cells, just giving you better sleep). Any questions feel free to PM me anyone.

 

[Cotcha Yankinov]

Sorry mods for cluttering thread!
Hi industrial, we actually relatively don't know that much about melatonin at this time (new discovery) but from what we know so far small amounts work better than large amounts and large amounts can actually work negatively. For some .1mg to .3mg is their sweet spot, I wouldn't take more than 10mg or any of that kind of dosage. In my opinion daily usage isn't going to be that bad and if its that or insomnia its definitely the lesser of two evils. I wonder to myself since melatonin is a hormone if you supplement long enough, like other hormones your body will you cease to make it naturally?? but I think that would be decades down the line before you saw any of that (studies looked good for 12 months), and just purely as a substance it is very good for you. Your brain is naturally supposed to make melatonin out of serotonin so it works very well for people having serotonin problems, serotonin essentially regulates your sleep cycle/circadian rhythms and supplementing melatonin is awesome for artificially making a rhythm (for example in blind people or people with non 24 hour rhythms) if your brain is outta whack. One thing is for sure, many people have melatonin problems because their surroundings aren't dark for the whole night and at LEAST an hour before bed time. Light inhibits melatonin production fiercely so even phone light is no bueno. For computer work I would recommend a program called Flux, changes the spectrum of light on your computer so that it doesn't stop melatonin production very much When the sun starts going down it'll turn off the blue spectrums so your melatonin can start building up a couple hours before bed, sunglasses will also help. The thing is melatonin has a very short half life
The question in my mind if you don't know if you're benefiting from melatonin is "Is melatonin your problem?".

Sorry to hear you were on benzos so much man, that's horrible and I get the feeling your main problems isn't melatonin though it might help a bit. Your brain will be recovering for a while... Klonopin also has a very long half life and not so normal mechanism of action, so some people can't tell its in their system very well it seems.. I hope you can taper the dosage but I would definitely consider Z-class ambien CR and related drugs for long term over regular benzos and maybe while you're tapering... There are also new options like Belsomra that work for some people and don't seem to cause addiction, I would be hard pressed to think that they would work very well for a heavy benzo user though, but better than nothing for sure. Benzos are kind of a shotgun approach where as ambien just targets a small portion of brain cells (that benzos affect as well so it should help with withdrawals a bit.). Ambien type drugs usually preserve REM sleep pretty well so you aren't driven into the alzheimers and brain shrinkage arena of things like you are with benzos long term. Benzos really are horrible for your brain long term, most of it really does have to do with suppression of REM sleep as Adder mentions, they can also make sleep breathing disorders worse and I think you would be surprised how many people are suffering from sleep apnea.. I encourage everybody suffering from sleep issues to get a sleep study to check that out, 100%. Mirtazapine's mood effects are very complicated and only really pop up at higher dosages, probably closer to 60mgs. but its not like it straight up increases serotonin so idk what the timeline would be like to notice improvement, it does help even out sleep architecture for some people though and helps sedate at lower dosages for a little while. Brain gets used to that eventually though. A word on the depression... Benzos essentially are downers and to me logically would cause a bit of a depression if its stopping all your brain cells from firing it could stop your happy brain cells from firing too, especially a downer like Klonopin that is in your system 24/7 and never lets up (compared to something like ambien that is still a downer in some sense but is out of your system during the day).

ALSO, klonopin has some very complicated effects on serotonin that I wish I understood better... If I had to guess though I would say that overall Klonopin decreases your brain's serotonin, and that's essentially what Wikipedia says "clonazepam decreases the utilization of 5-HT (serotonin) by neurons". So you could be having melatonin problems and depression problems because of klonopin's effect on serotonin in theory.

 

[Flynnal]

Cotcha, I'm still on 60mg...it works wonders for sleep. It always works well for sleep, from what I am told, especially if the dose is kept high, ie, 60mg. Some people I'm told are as high as 120mg, but this is unusual.

60mg works well, and helps keep the depression at bay. I still get agitation during the afternoon for some reason, and I wish it wasn't so. I have thought about asking my doctor to put in some Lexapro, just a small dose, say 10mg, a day, to see if that helps with the intrusive thoughts and agitation during the afternoon.

Once I'm home I feel better, but still the agitation can get to me at times.

 

[Cotcha Yankinov]

Hey flynnal, I really think that Lexapro is a good SSRI for some people because it has really high affinity for serotonin and not adrenaline (no need to make you more agitated with adrenaline) so it could give you some more patience when you get to your crappy part of the day but I would remember to think about the root cause of your agitation if I were in your shoes. Avanza and Lexapro might not combine well though too, Lexapro will increase your serotonin across the board and if it is a serotonin mediated effect from Avanza that is contributing to your agitation this could make it worse. SSRIs also cause people insomnia and Lexapro is no exception. This SSRI is something that's going to be in your system 24/7 too so not necessarily a great choice for an issue that only gets to you certain times. Hard to say but it sounds like this agitation has only been a real problem since starting the Avanza?? On the one hand you have depression on the other now you have agitation, your depression seems better but now you're into the other end of the spectrum??

Unfortunately I wouldn't be surprised if you came to the doc with two problems; sleep issues and depression. They would give you a shotgun pill that tries to fix both of those. However if just fixing your sleep fixes the depression but you're on something that's supposed to help both, the part of Avanza that was supposed to help your depression could be pushing you into the agitation spectrum of things since just fixing your sleep for a couple weeks might've helped your depression.

If this side effect of agitation is from the Avanza and the Avanza was started for insomnia/depression then one way to help your agitation is to find another route to treat your sleep issues/depression. I wouldn't be surprised if your sleep issues (especially if they were chronic) led to your depression issues so if I were in your shoes I would give the other insomnia treatments the old college try (enough of a try long enough off of Avanza for your brain to have withdrawn a bit and gotten closer to baseline, around 1 month or so) to see if that helps your depression by solving the sleep issues and lessens your agitation by being off of Avanza . If I were you I would think about Belsomra and the Z-class drugs for shorter term. The idea here is that some drugs are much more of a shotgun related approach and we need more of a laser. If your problems come from sleep then that's all we need to fix, if your depression is resulting from sleep issues then trying to solve both at once with something like Avanza is what I would consider a shotgun approach. Belsomra is a very interesting option. I think Belsomra (if you can get it/afford it, its extremely new so no generic yet but I might mention there are coupons for free trial of like 10 pills online) has the potential to be a great sleep aid for some people (though it doesn't work for some) with minimal side effects and likely no dependence/withdrawals long term. The other options are of course Ambien related Z-drugs/Zaleplon/Zolpidem which work well for most that don't get side effects but do have dependency issues (Zaleplon not as much).

TL;DR Solve your sleep and I don't think a shotgun approach like Avanza that could be causing agitation/side effects is necessary, nor adding another serotonergic into the mix like Lexapro. You should definitely aim to get a sleep study if you have heard that you snore, sleep apnea can cause lots of problems (Avanza is actually being investigated as a pharmacological treatment for sleep apnea). So I would try a treatment thats just tailored to your sleep issues, most importantly including some form of CBT, mindful thought clearing mediation, deep breathing and exercise, as well as making sure you're getting good melatonin production before bed. Though all of that can do wonders for depression as well as insomnia. I wouldn't convince myself that Avanza will work for sleep forever, I do believe at some point it will stop working as it did for me and a friend. CBT is the only real long term solution to try to get at whats causing your sleep issues in the first place rather than medicating through it. A note for the future, if a selective 5-HT2A antagonist is ever made available try that shit immediately, they make amazing sleep drugs but most never made it to market for suspicious reasons. We are left with ones that have some affinity though but not very selective (Avanza/Mirtazapine, Seroquel, Trazadone etc.) Good luck, hope this helps, any questions feel free to PM anyone.

 

[Flynnal]

Cotcha...Suspicious reasons? Heh, I'd love to know what those suspicious reasons were...

 

[atara]

Agomelatine's short half-life may be one of its benefits: because it is usually taken before bed, it improves sleep quality, both by agonizing M1 and M2 receptors (producing sleepiness) and antagonizing 5-ht2c (which may be associated with a reduction in anxiety and/or rumination) which helps the subject fall asleep. However since it is not present in the blood for very long, the normal mechanisms of tolerance do not completely compensate for its effects.

Sleep disruption is a major feature of depression, so by regulating this many symptoms may be alleviated as well.

 

[Cotcha Yankinov]

Sorry not trying to clutter thread but yeah flynnal..

A new sleeping pill is coming to town:
"Eplivanserin's developer, Sanofi-Aventis, is gearing up for the European launch of the drug in 2009 based upon favorable comments from the European drug agency. In addition, the company, which has funded three completed phase III clinical trials, is preparing to file for marketing approval in the United States and Canada, Pierre Gervais said at the annual American Psychiatric Association Institute on Psychiatric Services.
Eplivanserin is the furthest along in development of a new nonsedating drug class known as ASTARs, or Antagonists of Serotonin Two A Receptors. Many sleep disorder experts expect the ASTARs to take over a major chunk of the insomnia treatment market now dominated by zolpidem and other drugs acting on the GABA-A receptor, said Mr. Gervais, a pharmacist at Q&T Research of Sherbrooke, Quebec, an independent clinical research firm hired by Sanofi-Aventis to participate in an eplivanserin trial.
He reported on a trial of 351 adults with chronic insomnia who were randomized double blind to 4 weeks of either 1 mg or 5 mg of eplivanserin or placebo in the evening. The 5-mg dose, which is what will be marketed, resulted in a mean 39-minute reduction in the baseline 84-minute wake time after sleep onset. This was significantly greater than the mean 26-minute reduction with placebo.
Also, eplivanserin at 5 mg/day resulted in a 64% reduction in the number of nocturnal awakenings, compared with a 36% decrease with placebo. More eplivanserin-treated patients reported a significant improvement in the refreshing quality of sleep.
The side effect profile of eplivanserin mimicked that of placebo. The exception was dry mouth, which was reported by 1.7% of the placebo group and 5.3% of patients on 5 mg/day of eplivanserin.
The ASTAR was not associated with next-morning drowsiness or difficulty in concentration."

In some regards it might be because there was health risks related to a specific compound that one of the drugs didn't make it through but 5-HT2As are an amazing option. That we don't really actually have because they never made it to market.
A meta study can be found here if anybody is interested in these 5-HT2A antagonist/reverse agonists http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3630942/
That was written some of the people that helped with some of these newer really effective drugs (ACADIA pharm) and I swear at some points they are pointing out that its suspicious.. "It remains an enigma that 5-HT_2A receptor antagonists have such profound effects on sleep, yet so many drugs have failed in larger efficacy trials or have failed to show a sufficiently robust benefit to risk ratio in clinical trials" and "Hypnion reported that HY10275, a dual-acting H₁ receptor antagonist and 5-HT_2A receptor antagonist, improves sleep in patients with transient insomnia (Hypnion press release, January 5, 2007) before the company was acquired by Eli Lilly in April 2007. Since then, Lilly has discontinued clinical development of pruvanserin, its selective 5-HT_2A receptor antagonist"
HMMMMMM. There are mainly just drugs that hit 5-HT2A as a passerby right now and aren't selective for it, like Avanza/Mirtazapine, Seroquel/trazadone. Except Pimavanserin from ACADIA got breakthrough drug status for Parkinson's psychosis and that seems to be a wonder drug. But yeah keep an eye out for 5-HT2A related drugs. That meta study above mentions improvements in depression a lot after treatment of insomnia and its comorbidity with insomnia . Peace

 

[clubcard]

I would expect 6-F melatonin to have a much longer T1/2 but maybe just triggering the MT1 & MT2 is enough? Of course, since it's a known chemical, they couldn't use it (not patentable) BUT someone made the 6-Cl and that's now an orphan drug.