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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 25 of 29. This is the beginning of the thread.
Posted by Agomelatinehope on April 5, 2011, at 7:07:48
Hi. This is my first message. I'm from Spain and I've been suffering
from insomnia and depression for quite a long time (6 years or so).Over the years I've tried practically every single AD but I haven't
found one whose effect lasted long. The AD I've been more time on is
Cymbalta (until it stopped working and I felt like I was deprived of
my feelings, a very creepy and sad feeling). My insomnia is right now
my main concern since it has affected my life in every field.Agomelatine
There is something really strange about this AD.
I've been able to feel its positive effects and it was simply amazing:
I could slept greatly, I got energy all day long, I felt braver and
more confident. I felt like doing things all the time. I started to
listen to music again and resumed my forgotten hobbies. The drug I had
all been all my life looking for. It started working from the first
day.I have to point out that I only felt this effect when switching from
fluoxetine (Prozac) to Agomelatine.So I thought that maybe Fluoxetine + Prozac was the right combination
for me and started taking both. But... It just didn't work. I couldn't
feel those amazing positive effects.Then I tried to take agomelatine alone but i didn't feel any positive
effects (maybe it needed more time to work)Last week I changed from Prozac to Agomelatine and I felt again those
wondrous effects but it didn't last long, just three days.Kind of strange, isn't it?
The Prozac dose I was taking was 10mg (half pill).
From what I recall reading is that
it only had 5HT2-C antagonistic qualities at lower doses so...
Maybe that great feeling was the mixture of the 5HT2-C antagonistic
qualities of Prozac (since it has such long life and I had stopped
taking just before taking ago) + Ago itself.So, do you think it might be a good idea to take for instance, 5mg
Prozac (1/4 pill) + Ago ? Would I get then that estimulating feeling
on a daily basis?Thank you so much!
Posted by Brainbeard on April 5, 2011, at 16:30:44
In reply to It seems Ago + Prozac is the perfect match BUT..., posted by Agomelatinehope on April 5, 2011, at 7:07:48
> So, do you think it might be a good idea to take for instance, 5mg
> Prozac (1/4 pill) + Ago ? Would I get then that estimulating feeling
> on a daily basis?You very well may! You did the math, brother. 5mg a day, perhaps even less - I would give it a shot.
Posted by mtdewcmu on April 5, 2011, at 20:16:04
In reply to It seems Ago + Prozac is the perfect match BUT..., posted by Agomelatinehope on April 5, 2011, at 7:07:48
> I have to point out that I only felt this effect when switching from
> fluoxetine (Prozac) to Agomelatine.I had a similar experience. I took Paxil for about a month and had horrendous side effects. Then I suddenly switched from Paxil to Remeron and a low dose of Zoloft, and I felt amazing for about a week. Remeron is a 5-ht2c antagonist just like Agomelatine. I don't think the positive feelings had anything to do with the low dose of Zoloft. I think it was stopping Paxil, possibly enhanced by Remeron.
I have not been able to reproduce that feeling on any combination of meds. My feeling is that it had more to do with getting off an SSRI than the meds I switched to, although Remeron may have enhanced it somehow. I also felt pretty good one time after abruptly stopping Prozac and going med-free.
Sad to say, my friend, that I think if you try to recreate that experience permanently, you will be disappointed. My best guess is that it is related to the sudden relief of SSRI side effects, possibly amplified by the blocking of 5-ht2c that the other drug provides.
Posted by desolationrower on April 5, 2011, at 21:28:16
In reply to It seems Ago + Prozac is the perfect match BUT..., posted by Agomelatinehope on April 5, 2011, at 7:07:48
> The Prozac dose I was taking was 10mg (half pill).
>
> From what I recall reading is that
> it only had 5HT2-C antagonistic qualities at lower doses so...not sure which of the two drugs. But you need a highish dose of prozac/fluoxetine for the 5ht2c to be significant. The more of a drug you take, the more receptors/pumps it can interact with. And higher doses start to interact with receptors/pumps that it has less affinity for.
> Maybe that great feeling was the mixture of the 5HT2-C antagonistic
> qualities of Prozac (since it has such long life and I had stopped
> taking just before taking ago) + Ago itself.this seems more likely.
> So, do you think it might be a good idea to take for instance, 5mg
> Prozac (1/4 pill) + Ago ? Would I get then that estimulating feeling
> on a daily basis?
>
> Thank you so much!Maybe the benefit was taking the sri along with the agomelatine, which was significant enough of a 5ht2c antagonist. I think combining these drugs could work well. though you might want an sri with more hypnotic effect like fluvoxamine.
-d/r
Posted by Phillipa on April 5, 2011, at 23:07:02
In reply to Re: It seems Ago + Prozac is the perfect match BUT..., posted by desolationrower on April 5, 2011, at 21:28:16
Since prozac has such a long life maybe it was like taking both from the beginning as takes what is it five weeks for prozac after being on it for a while the totally leave the body? Phillipa
Posted by Brainbeard on April 6, 2011, at 2:26:19
In reply to Re: It seems Ago + Prozac is the perfect match BUT..., posted by desolationrower on April 5, 2011, at 21:28:16
> not sure which of the two drugs. But you need a highish dose of prozac/fluoxetine for the 5ht2c to be significant.
The very opposite is true in this case! You need a low dose of Prozac for the 5ht2C-antagonism to be significant.
This is why: serotonin receptors have to be (nearly) saturated by a reuptake blocking molecule for SRI to reach clinical significance. 5HT2C receptors, on the other hand, only need a little antagonism to result in significant effects (boosted dopamine and noradrenaline, basically). On top of that, 5ht2C-antagonism and SRI are opposing mechanisms. At normal and higher doses of Prozac, the 5ht2C-antagonism is lost since it is flushed away by all the serotonin that begins to agonize 5ht2c-receptors (as well as all other serotonin subtype receptors). This is borne out by the fact that Prozac, in high doses, can be used as an agent against bulimia since it suppresses - which is an effect of 5ht2C-agonism.
For reference/evidence, see http://www.pnas.org/content/94/5/2036.full.pdf. I've written about this before in this post: http://www.dr-bob.org/babble/neuro/20091104/msgs/931609.html
Posted by Brainbeard on April 6, 2011, at 2:27:40
In reply to For serious 5ht2C-antagonism, LOW doses are needed, posted by Brainbeard on April 6, 2011, at 2:26:19
since it suppresses .... APPETITE. (This word was missing in the above post.)
Posted by Agomelatinehope on April 6, 2011, at 4:38:19
In reply to Re: For serious 5ht2C-antagonism, LOW doses are needed, posted by Brainbeard on April 6, 2011, at 2:27:40
Last night I took half pill of agomelatine and I have just taken 5mg of prozac.
I'll keep you informed
PS. I'm taking just half agomelatine pill because if I start with the whole pill I experience a strange side effect: My penis hurts when urinating (which I think may be related to the fact that ago is quite toxic and is eliminated in the urine)
PS2. I'm taking also Xanax 1mg at night, do you think this may interfere with my "experiment"?
Posted by desolationrower on April 6, 2011, at 16:35:59
In reply to For serious 5ht2C-antagonism, LOW doses are needed, posted by Brainbeard on April 6, 2011, at 2:26:19
> > not sure which of the two drugs. But you need a highish dose of prozac/fluoxetine for the 5ht2c to be significant.
>
> The very opposite is true in this case! You need a low dose of Prozac for the 5ht2C-antagonism to be significant.
>
> This is why: serotonin receptors have to be (nearly) saturated by a reuptake blocking molecule for SRI to reach clinical significance. 5HT2C receptors, on the other hand, only need a little antagonism to result in significant effects (boosted dopamine and noradrenaline, basically). On top of that, 5ht2C-antagonism and SRI are opposing mechanisms. At normal and higher doses of Prozac, the 5ht2C-antagonism is lost since it is flushed away by all the serotonin that begins to agonize 5ht2c-receptors (as well as all other serotonin subtype receptors). This is borne out by the fact that Prozac, in high doses, can be used as an agent against bulimia since it suppresses - which is an effect of 5ht2C-agonism.
>
> For reference/evidence, see http://www.pnas.org/content/94/5/2036.full.pdf. I've written about this before in this post: http://www.dr-bob.org/babble/neuro/20091104/msgs/931609.html
>hm, i guess it is plausible to have a nonlinear quasi cubic function effect between the two. i think this is generally true, not something unique about fluoxetine. its why polypharmacy with selective drugs is a good idea. I'm not convinced about the 'only need a little antagonism for a significant effect'.
the average binding is 1-2 orders of magnitude greater for teh transports than the 5ht2c receptor, so i think they are being optimistic, and you are being optimistic in interpreting that study. I couldn't find any citing studying confirming your posited function.
also, antagonists aren't the same as inverse agonists. afaik, fluoxetine is an antagonist, which means it has the same effect at a 5ht2c receptor that [null] binding to it would. So don't think in terms of (percent of 5ht2c occupied by 5ht)/(percent of 5ht2c occupied by fluoxetine); think of (percent of 5ht2c occupied by 5ht)/(total). also, the part of the study that shows significant effect of a small amount of fluoxetine at 5ht2c is on cloned oocytes, not actually in a brain.
there is a problem in that higher doses will marginally increase reuptake pump blockage, doing little to increase 5ht levels, but greatly increasing the number of fluoxetine molecules which can block 5ht from 5ht receptors. i don't see anything in the linked study that shows different. It is not true that very high sri gives you super 5ht which could displace the antagonist, though you do get higher levels than lower dose.
reuptake pumps are not like on/off switches, but they do have a sigmoid curve (flattening off from reduced effect and increasing action on autoreceptors). I think it a matter of the grainyness of the data (same reason you can't get one AD to show efficacy advantage over another) that it looks like reuptake inhibitors are all or nothing: it is based on clinical eg HAM-D data.
in this case, the addition of agomelatine is going to act as another competitor for the 5ht2c, resulting in less fluoxetine there, and more fluoxetine elsewhere. If you want 5ht2c antagonism, the agomelatine is much cleaner. targeting a slip in the function of fluoxetine is going to be tricky if possible at all. which is why choosing are more selective drug is better. and the OP has the option of a 5ht2c antagonist in agomelatine.
-d/r
Posted by SLS on April 6, 2011, at 17:34:33
In reply to Re: For serious 5ht2C-antagonism, LOW doses are needed, posted by desolationrower on April 6, 2011, at 16:35:59
> polypharmacy with selective drugs is a good idea.
Amen.
- Scott
Posted by SLS on April 6, 2011, at 17:39:50
In reply to Re: It seems Ago + Prozac is the perfect match BUT..., posted by Brainbeard on April 5, 2011, at 16:30:44
>
> > So, do you think it might be a good idea to take for instance, 5mg
> > Prozac (1/4 pill) + Ago ? Would I get then that estimulating feeling
> > on a daily basis?
>
> You very well may! You did the math, brother. 5mg a day, perhaps even less - I would give it a shot.
What about combining Prozac and Remeron? If circadian cycles are disturbed, perhaps low dosages of Rozerem would be helpful. I am treating these drugs as if they were selective, which they are not. Who knows what else is important in the actions of these non-selective drugs?
- Scott
Posted by Agomelatinehope on April 7, 2011, at 8:15:08
In reply to Re: It seems Ago + Prozac is the perfect match BUT... » Brainbeard, posted by SLS on April 6, 2011, at 17:39:50
Ok people. Good news!
I'm feeling GREAT today , anhedonia seems to have vanished. I'm feelin optimistic and feeling like doing a lot of stuff :)
Last night I took a pill of agomelatine 25mg.
I do not know if this feeling is due only to the agomelatine or to the 5mg of Prozac that I took yesterdar morning but what I'm sure is that I'm getting closer :)
Posted by Brainbeard on April 7, 2011, at 15:06:16
In reply to Re: For serious 5ht2C-antagonism, LOW doses are needed, posted by desolationrower on April 6, 2011, at 16:35:59
>I'm not convinced about the 'only need a little antagonism for a significant effect'.
I'm not convinced of your counter-arguments either, mostly because I don't understand them. :)
Agomelatine is an effective 5HT2C-antagonist, right? Interestingly, the Ki value for agomelatine's binding affinity to the 5HT2C receptor is way higher than Prozac's: it's 710nM! (http://www.medicographia.com/html/static/html/issues/article_latest.asp?page=issues/99/art_10/p_2) This means that agomelatine's binding affinity for the 5HT2C-receptor is WWWWWWAAAYYYYYYYYYYY lower than fluoxetine's. It'd better be true that only a little antagonism of 5HT2C-receptors yields significant effects, or agomelatine's supposed 5HT2C-antagonism is a scam.
Posted by desolationrower on April 7, 2011, at 17:28:14
In reply to Re: For serious 5ht2C-antagonism, LOW doses are needed, posted by Brainbeard on April 7, 2011, at 15:06:16
> >I'm not convinced about the 'only need a little antagonism for a significant effect'.
>
> I'm not convinced of your counter-arguments either, mostly because I don't understand them. :)
>
> Agomelatine is an effective 5HT2C-antagonist, right? Interestingly, the Ki value for agomelatine's binding affinity to the 5HT2C receptor is way higher than Prozac's: it's 710nM! (http://www.medicographia.com/html/static/html/issues/article_latest.asp?page=issues/99/art_10/p_2) This means that agomelatine's binding affinity for the 5HT2C-receptor is WWWWWWAAAYYYYYYYYYYY lower than fluoxetine's. It'd better be true that only a little antagonism of 5HT2C-receptors yields significant effects, or agomelatine's supposed 5HT2C-antagonism is a scam.i hadn't seen those values before.
its more likely that the regular dose of agomelatine is just acting to induce deep sleep
-d/r
Posted by mtdewcmu on April 7, 2011, at 20:48:20
In reply to Re: For serious 5ht2C-antagonism, LOW doses are needed, posted by desolationrower on April 7, 2011, at 17:28:14
> > Agomelatine is an effective 5HT2C-antagonist, right? Interestingly, the Ki value for agomelatine's binding affinity to the 5HT2C receptor is way higher than Prozac's: it's 710nM! (http://www.medicographia.com/html/static/html/issues/article_latest.asp?page=issues/99/art_10/p_2) This means that agomelatine's binding affinity for the 5HT2C-receptor is WWWWWWAAAYYYYYYYYYYY lower than fluoxetine's. It'd better be true that only a little antagonism of 5HT2C-receptors yields significant effects, or agomelatine's supposed 5HT2C-antagonism is a scam.
The absolute value for Ki doesn't matter. It only matters what the Ki is relative to the Ki for the other receptors. You can compensate for a low binding affinity by increasing the dose, unless side effects or toxicity become significant.
Posted by mtdewcmu on April 7, 2011, at 20:49:01
In reply to Re: For serious 5ht2C-antagonism, LOW doses are needed, posted by Brainbeard on April 7, 2011, at 15:06:16
By the way, that link doesn't work for me.
Posted by agomelatinehope on April 8, 2011, at 4:48:07
In reply to It seems Ago + Prozac is the perfect match BUT..., posted by Agomelatinehope on April 5, 2011, at 7:07:48
I woke up several times last night but every time I did I could easily get back to sleep directly to dreaming (REM?) I'm having a lot of weird dreams, not scary, but just very meaningful for me...
I'm sure Ago is doing sth to me but what I don't really know is to what extent Fluoxetine is contributing.
BTW, I have just taken about 5mg of Prozac.
Posted by SLS on April 8, 2011, at 5:11:33
In reply to Re: For serious 5ht2C-antagonism, LOW doses are needed, posted by mtdewcmu on April 7, 2011, at 20:48:20
> The absolute value for Ki doesn't matter.
I think it might. One example would be the tendency for Abilify to reduce the effectiveness of Seroquel and perhaps other APs with a low affinity for D2 receptors. D2 binding is quite a bit higher for Abilify, which then would act as a D2 partial agonist. Abilify competes with Seroquel and wins.
> It only matters what the Ki is relative to the Ki for the other receptors. You can compensate for a low binding affinity by increasing the dose, unless side effects or toxicity become significant.
I see what you are saying. Using my example above, I have seen Abilify necessitate an increase in the dosage of Seroquel from 200 mg to 900mg. Discontinuing Abilify allowed for a return to a lower dosage of Seroquel.
- Scott
Posted by desolationrower on April 8, 2011, at 13:09:13
In reply to Re: For serious 5ht2C-antagonism, LOW doses are needed, posted by mtdewcmu on April 7, 2011, at 20:48:20
> > > Agomelatine is an effective 5HT2C-antagonist, right? Interestingly, the Ki value for agomelatine's binding affinity to the 5HT2C receptor is way higher than Prozac's: it's 710nM! (http://www.medicographia.com/html/static/html/issues/article_latest.asp?page=issues/99/art_10/p_2) This means that agomelatine's binding affinity for the 5HT2C-receptor is WWWWWWAAAYYYYYYYYYYY lower than fluoxetine's. It'd better be true that only a little antagonism of 5HT2C-receptors yields significant effects, or agomelatine's supposed 5HT2C-antagonism is a scam.
>
> The absolute value for Ki doesn't matter. It only matters what the Ki is relative to the Ki for the other receptors. You can compensate for a low binding affinity by increasing the dose, unless side effects or toxicity become significant.i think it does. The drug doesn't have to bind to a receptor, it can also just float around in your plasma.
I was just guessing based on the dose and bioavalibility and halflife values compared to other drugs. I think you can calculate it somehow, although i don't know if that is too reliable.
-d/r
Posted by poser938 on April 11, 2011, at 1:24:01
In reply to It seems Ago + Prozac is the perfect match BUT..., posted by Agomelatinehope on April 5, 2011, at 7:07:48
what about cyproheptadine? it's an antagonist and 5HT2a and 5ht2c receptors. ive taken it before for for anhedonia caused by mirapex and it helped alot!
Posted by desolationrower on April 11, 2011, at 6:24:35
In reply to Re: It seems Ago + Prozac is the perfect match BUT..., posted by poser938 on April 11, 2011, at 1:24:01
> what about cyproheptadine? it's an antagonist and 5HT2a and 5ht2c receptors. ive taken it before for for anhedonia caused by mirapex and it helped alot!
I like it; the short half life means for anhedonia you'd probably want to dose a could times a day, although once before bed it useful if you just want the improved sleep quality & resulting benefits.
Did you notice dosing issues? i've only used it for sleep.
-d/r
Posted by Franz on May 31, 2011, at 23:42:17
In reply to For serious 5ht2C-antagonism, LOW doses are needed, posted by Brainbeard on April 6, 2011, at 2:26:19
> The very opposite is true in this case! You need a low dose of Prozac for the 5ht2C-antagonism to be significant.How low?. The usual dose is 20 mg. Would you say 10 , 5mg?
Thanks
Posted by Brainbeard on June 1, 2011, at 2:45:54
In reply to Re: For serious 5ht2C-antagonism, LOW doses are needed » Brainbeard, posted by Franz on May 31, 2011, at 23:42:17
10 would be the absolute maximum. Think rather of 2.5-5mg.
>
> > The very opposite is true in this case! You need a low dose of Prozac for the 5ht2C-antagonism to be significant.
>
> How low?. The usual dose is 20 mg. Would you say 10 , 5mg?
>
> Thanks
Posted by Phillipa on June 1, 2011, at 19:27:54
In reply to Re: For serious 5ht2C-antagonism, LOW doses are needed, posted by Brainbeard on June 1, 2011, at 2:45:54
Brainbeard can you explain in layman's terms what this means? Thanks Phillipa
Posted by Franz on June 1, 2011, at 19:52:21
In reply to Re: For serious 5ht2C-antagonism, LOW doses are needed, posted by Brainbeard on June 1, 2011, at 2:45:54
Thanks. The problem is my Dr considers less than 20 mg not therapeutic. Have you find a Dr that uses low doses?.
> 10 would be the absolute maximum. Think rather of 2.5-5mg.
>
> >
> > > The very opposite is true in this case! You need a low dose of Prozac for the 5ht2C-antagonism to be significant.
> >
> > How low?. The usual dose is 20 mg. Would you say 10 , 5mg?
> >
> > Thanks
>
>
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