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Dr. Bob is Robert Hsiung, MD,
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Posted by SLS on January 18, 2009, at 14:33:09
In reply to Re: Atypical APs with lowest SRI - for AD augment » psychobot5000, posted by mav27 on January 18, 2009, at 11:05:25
> I've just spent the last 3 hours reading up on it (and 5ht2c)
What did you discover? I am very interested.
Thanks.
- Scott
Posted by SLS on January 18, 2009, at 14:35:14
In reply to Atypical APs with lowest SRI - for AD augment, posted by psychobot5000 on January 18, 2009, at 10:42:09
Hi.
> For my purposes (I'm looking for 5ht-2c blockade with few side-effects)
How do you think that 5-HT2c blockade would be helpful?
Thanks.
- Scott
Posted by mav27 on January 18, 2009, at 15:57:16
In reply to Re: Atypical APs with lowest SRI - for AD augment » mav27, posted by SLS on January 18, 2009, at 14:33:09
> > I've just spent the last 3 hours reading up on it (and 5ht2c)
>
> What did you discover? I am very interested.
>
> Thanks.
>
>
> - ScottGood question..lol.. i fell asleep for the last couple hours after having another dose of clonidine in a test im doing and i have the worst memory at the best of times but luckily i seemed to have bookmarked some stuff so i will have to re read through it. I think my main interest was its potency on 5ht2c compared to prozac which it turns out the ziprasidone does seem to be a lot more potent and the d2 action is Negligible under 60mg.
Posted by psychobot5000 on January 18, 2009, at 16:19:24
In reply to Re: Atypical APs with lowest SRI - for AD augment » SLS, posted by mav27 on January 18, 2009, at 15:57:16
> > > I've just spent the last 3 hours reading up on it (and 5ht2c)
> >
> > What did you discover? I am very interested.
> >
> > Thanks.
> >
> >
> > - Scott
>
> Good question..lol.. i fell asleep for the last couple hours after having another dose of clonidine in a test im doing and i have the worst memory at the best of times but luckily i seemed to have bookmarked some stuff so i will have to re read through it. I think my main interest was its potency on 5ht2c compared to prozac which it turns out the ziprasidone does seem to be a lot more potent and the d2 action is Negligible under 60mg.
>
>I also found similar things. Makes me wonder if the drug maker might have had more success combining -it- with prozac, rather than zyprexa or whichever one they use in that combination drug.
Posted by psychobot5000 on January 18, 2009, at 17:06:25
In reply to Re: Atypical APs with lowest SRI - for AD augment » psychobot5000, posted by SLS on January 18, 2009, at 14:35:14
> Hi.
>
> > For my purposes (I'm looking for 5ht-2c blockade with few side-effects)
>
> How do you think that 5-HT2c blockade would be helpful?
>
> Thanks.Hi Scott,
Let me explain: I was lead here by Agomelatine. It seems to have some considerable antidepressant efficacy, which I attribute to its 5ht2c antagonism. I've taken Rozerem/ramelteon previously, which as far as I know mimics its Melatonergic effects without the 5ht2c antagonism, and not had any such positive results--and so I figure, well, maybe the 5ht2c effects are the difference.
So that's a large part of it, right there. As for the rest, Agomelatine has a short half-life. Possibly for this reason, it causes me substantial anxiety in the middle of the day (I take it once per day at bedtime). Luckily, I've found I can correct this anxiety with another drug, nefazodone (100mg), which, not concidentally, also has substantial 5ht2c antagonism. This leads me further down the path of suspecting 5ht2c as a primary mechanism of action, though I'm aware nefazodone also has other actions that complicate the picture, particularly 5ht2a antagonism. To summarize, I strongly suspect that the anxiety relief I feel from nefazodone is at least partly due to its providing supplementary 5ht2c antagonism for me, during the point in the day when Agomelatine's blood-levels are almost nonexistent. Without this supplementary medication, I feel at unpleasant degree of anxiety during this part of the day. With it, everything works out pretty well.
This idea of mine seems to be supported also by my experience with another (messy) 5ht2c antagonist, Remeron: when on that drug my mood was lowest, and anxiety highest, during the point in the day when my blood-levels of the drug were lowest. Of course, Remeron also has lots of mechanisms of action. But it does fit in.
So that's what I'm working with, and what's gotten me interested. I think 5ht2c is probably a large part of my story, especially since I don't think my low dose of nefazodone, once a day, is adequate to act very forcefully on its other targets. It seems like a solid enough hypothesis that I can work off of it, and maybe try to fine-tune it into something that works a little better, side-effect wise, etc.
Hope that answers your question. Incidentally, so far agomelatine + nefazodone = pretty awesome antidepressant combination so far. Worth a try.
Psychbot
PS: And Philippa, yes, I do like the nefazodone, at least as a low-dose augmentor--it hasn't been too sedating for me so far.
Posted by psychobot5000 on January 18, 2009, at 17:07:38
In reply to Re: Atypical APs with lowest SRI - for AD augment » psychobot5000, posted by mav27 on January 18, 2009, at 11:05:25
Posted by SLS on January 18, 2009, at 17:34:02
In reply to Re: Atypical APs with lowest SRI - for AD augment » SLS, posted by psychobot5000 on January 18, 2009, at 17:06:25
Wow. That's some pretty nifty brainstorming. I like your observations and rationale. It is an eye-opener for me. I think I'll do a bit of reading on 5-HT2c for myself. It might be the key to many people's locked doors.
:-)
Kick butt!
- Scott
Posted by Phillipa on January 18, 2009, at 21:24:08
In reply to Re: Atypical APs with lowest SRI - for AD augment » SLS, posted by psychobot5000 on January 18, 2009, at 17:06:25
Ah thanks for remembering!!!! Love Phillipa
Posted by psychobot5000 on January 19, 2009, at 15:08:49
In reply to Re: Atypical APs with lowest SRI - for AD augment » psychobot5000, posted by SLS on January 18, 2009, at 17:34:02
I sure appreciate the complement, Scott! Some other posters, like Marty, helped lead me down this line of thought.
For what it's worth, when I read on the same subject maybe three or four years ago, there didn't seem to be all that much research interest on 5ht2c for mood disorders--even though its supposed potential, anxiolytic qualities, improved sleep, increased frontal cortex dopamine, all seemed to mark it as a potential treatment pathway. But when I read now, it seems like the interest in the field has caught up with its hypothesized potential--there's definitely more talk about it going on, from what I'm finding. Hopefully some of these new agents that target 2c and other 5ht2 receptors pan out for a substantial portion of patients.
Be well,
Psychbot
Posted by Marty on January 19, 2009, at 15:15:54
In reply to Atypical APs with lowest SRI - for AD augment, posted by psychobot5000 on January 18, 2009, at 10:42:09
Leveling Agomelatine night 5-ht2c antagonism with Geodon/Zeldox during the day is quite a good ideal Psychobot ! .. I wonder how you had this brilliant idea ;)=No credit at all ? damn.. I knew I should have put a patent on that idea ! =)
Btw, I'll report soon how effective it is.. but I can confirm the only negative point at this time: I can feel the SSRI effect on my sexuality, but ----VERY--- subtely .. and I suspect it would go away after sometime, even for me which is insanely SRI sensitive. It's worth a try if you can put your hand on some Geodon. Take 1/4 of a 40 mg capsule and you'll have an idea of what it can give you right away./\/\arty
> Hi all,
>
> Been looking up atypical antipsychotics for potential antidepressant augmentation. The best bets seem to be, based on receptor binding affinities, abilify (for its distinctive d2 effects and relatively low side-effect profile) and geodon/ziprasidone. Possibly also olanzapine.
>
> For my purposes (I'm looking for 5ht-2c blockade with few side-effects), ziprasidone/Geodon seems the obvious choice. Based on what I've read, it has the best 5ht-2c binding of atypical APs, with relatively low risks of sedation (H1 binding) and metabolic disorders. Taken at low doses (i.e. 20mg), it could hit 5ht2a and 2c without really affecting D2, they say. However, some sources claim it has a substantial SRI effect (which is anathema to me). Anyone know anything about this, specifically how its SRI effect compares to other APs--and nefazodone? I don't do well with serotonin reuptake inhibition--it gives me nasty side-effects--but I believe I need something with substantial 5ht-2c antagonism (to augment and 'balance' my night-time dose of agomelatine during the day). Anyone know what the best antipsychotic (or other med) for 5ht2c blockade--with lowest relative serotonin reuptake inhibition might be? Or even just how low-dose ziprasidone's numbers might compare with low-dose nefazodone's (i.e. which is likely to have the lowest SRI)
>
> Currently I'm trying around 100mg nefazodone per day, and while it seems to be helpful, it has some fairly unpleasant SSRI-like side-effects (i.e. sweating all night), even though nefazodone's SRI effect is relatively modest.
>
> Thanks for any input,
> Psychobot5000
>
Posted by Marty on January 19, 2009, at 15:35:22
In reply to Re: Atypical APs with lowest SRI - for AD augment » psychobot5000, posted by SLS on January 18, 2009, at 17:34:02
>It might be the key to many people's locked doors.
I can confirm it is since I'm in COMPLETE remission without side effects (exception being less hours of sleep, but much better quality). Every single symptoms I had since I'm about 13, 14 years old has vanish in less than a month. AND.. I'm not hypomanic. Just had some transient euphoria in the first 2 weeks and I'm not the only one in our group, with only me having a 'potential bipolar type 2' DX (which was officially revoked a month ago)
This is nothing short of a miracle for me. I never though I could feel that NORMAL with a drug. In fact my only hope for that type of normality was set in about 20, 30 years from now and include genetic therapy and other advancement.
I feel like the luckiest bastard on earth. The only thing keeping what's happening to me from perfection is that EVERYDAY I got at least one moment of sheer terror: What if it goes away ?
Anyway.. felt like sharing this (again?) with you Scott. I hope you're okay and I hope you're still hopeful regarding your state. Neuro/Psycho pharmacology didn't say it's last word just yet ! .. anything in the pipeline could be a miracle for you in the next few years and it may well be the one you less expect ! (ie: 5-HT2c antagonism .. I mean, come on.. this isn't a new mechanism at all.)
Later,
/\/\arty
Posted by Marty on January 19, 2009, at 15:48:38
In reply to Re: Atypical APs with lowest SRI - for AD augment » psychobot5000, posted by SLS on January 18, 2009, at 17:34:02
BTW... for anyone interested in researching about dopamine and the prefrontal cortex regions ...(5-HT2c antagonism is mainly thought to be about that by inhibiting Gaba circuitry between 5-HT2c receptors and DA neurons in this region of the brain: disinhibiting DA release.)
... here's a fascinating fact: the prefrontal cortex regions DOESN'T have any kind DA transporter! .. DA diffused itself far from its secretion site and is eventually taken cared of by NET (NorEpinephrine transporters) which possess a stronger affinity for DA than for NE itself! A consequence of this is an increase of synaptic NE since NET are occupied by more DA than usual.
Just saying.. I hope I'm not the only geek which find this fascinating :)
Side note: I had to stop my Wellbutrin for Agomelatine to work: just like with Tianeptine, Wellbutrin was somehow strangely antagonizing the effect .. Wellbutrin being a weak NET/DAT inhibitor, the fact I reported is one pretty interesting in my case !
/\/\arty
Posted by mav27 on January 19, 2009, at 16:08:25
In reply to Re: Atypical APs with lowest SRI - for AD augment » SLS, posted by Marty on January 19, 2009, at 15:48:38
http://biopsychiatry.com/5ht2c.htm
I'm thinkibg my next port of call might be mianserin, at least it doesn't have any D2 atangonistist effects and whilst the anti histamine efects are there it's less than mirtazapine whilst being more potent in every other area (plus i have to take a small amount of seroquel to sleep every night now which is just like an anti histamine at the tiny dose i take)
No annoying seratonin side effects as well hopefully.
Posted by psychobot5000 on January 19, 2009, at 16:32:56
In reply to Re: Atypical APs with lowest SRI - for AD augment » SLS, posted by Marty on January 19, 2009, at 15:48:38
Marty, thankyou--you did indeed help direct my attention to this with your helpful sharing of information and theories--it's been most helpful. And not least with your latest post about how 5ht-2c modulates dopamine in the frontal cortex. I'd wondered how/why NA is also increased, and the mechanism behind 2c's influence. That's very interesting stuff--and not something I knew before.
Well done, putting it all together--(and nice that it seems to be paying out dividends in actual treatment, eh?)
Psychbot
Posted by SLS on January 19, 2009, at 16:37:19
In reply to Re: Atypical APs with lowest SRI - for AD augment » SLS, posted by Marty on January 19, 2009, at 15:48:38
> ... here's a fascinating fact: the prefrontal cortex regions DOESN'T have any kind DA transporter! .. DA diffused itself far from its secretion site and is eventually taken cared of by NET (NorEpinephrine transporters) which possess a stronger affinity for DA than for NE itself! A consequence of this is an increase of synaptic NE since NET are occupied by more DA than usual.
Stephen Stahl?
:-)
- Scott
Posted by SLS on January 19, 2009, at 16:48:13
In reply to Re: Atypical APs with lowest SRI - for AD augment » SLS, posted by Marty on January 19, 2009, at 15:35:22
Ok, you lucky bastard...
What exactly are you taking, and at what dosages?
I am incredibly happy for you. You've brought me a moment of joy. Otherwise, not such a good day (but not bad, either).
This is all very, very exciting.
For now, I believe that the drugs I am on will get me close to where I would like to go. I just need to increase my dosage of desipramine from 200mg to 300mg. Unfortunately, I have to adhere to the pace my doctor is comfortable with. He wants me to remain at 200mg for 2 weeks and then get a blood level. How very frustrating. My only reservations involve the possibility that, even after reaching a maximal antidepressant response, I will still suffer from residual anhedonia. I believe this was the only thing that was missing last time I combined Parnate with desipramine.
There will always be agomelatine. I don't see why I couldn't add it to the other drugs I'm taking. Maybe you have some insight into this?
Currently:
Parnate 80mg
desipramine 200mg
Lamictal 200mg
Abilify 20mgThanks for everything.
- Scott
Posted by SLS on January 19, 2009, at 16:57:23
In reply to Re: Atypical APs with lowest SRI - for AD augment » SLS, posted by Marty on January 19, 2009, at 15:48:38
One more thing.
Would you please report any changes in body weight?
5-HT2c receptors help control blood leptin levels.
- Scott
Posted by Marty on January 19, 2009, at 17:19:17
In reply to Re: Atypical APs with lowest SRI - for AD augment » Marty, posted by SLS on January 19, 2009, at 16:37:19
>
> Stephen Stahl?Isn't that scientist in a special class ? I'm looking forward to follow every single paper he'll publish.. in fact I'll track every changes in the yearly re-edition of his books! lol
/\/\arty
Posted by Marty on January 19, 2009, at 17:21:05
In reply to Re: Atypical APs with lowest SRI - for AD augment » psychobot5000, posted by Marty on January 19, 2009, at 15:15:54
Oh, another quick thought sharing with anyone trying to find himself a cure:Stop thinking in terms of messengers (neurotransmitter) and think way more in terms of systems/pathways and brain regions! Drugs which increase this or decrease that often are more specific to some regions than others for some reason.. USE THAT !
'More of this or less of that' kind of thinking is just plain wrong for some of us. Ever watch some Mayo Clinic brain scan that shows how some brain regions works too hard and some too few ? We have to reinforce the expression of some brain region and weaken the expression of others.. NOT reinforce in a leveled/linear way EVERY or ANY system with more or less DA or NE or SE .. but balance the expression by favoring some over others! Brain-wide receptor NUKING versus the subtlelity of geopolitics! That's strategy is currently saving my life beyond my wildest dreams!
Neurologic engineering ... know your tools (drugs) and know yourself (reaction to tried drugs.. even side effects talks alot when you knows well your toolbox !) You can't attain a surgeon precision level .. (faaaaar from that) but I think it is possible to do a clean job of rebalancing brain regional expression. I can tell you my reinforced prefrontal cortex is quite happy to being able to shut the f*ck up to my amygdala since I'm on Agomelatine/Low dose trazodone !
For anyone not getting what I'm talking about, consider this (not too bad) analogy: It is thought your car doesn't work because of a lack of Gaz and you're trying to get the damn machine to work by filling the WHOLE car with Gazoline .. In the truck, on the windshield, IN THE TIRE.. close all the windows/door and fill the damn whole thing ! -> find where you need that gaz.. and find a way to deliver it where it counts without splashing everything else ! LOL
Does that makes sense ?
/\/\arty
Posted by psychobot5000 on January 19, 2009, at 19:30:07
In reply to Re: Atypical APs with lowest SRI - for AD augment » Marty, posted by Marty on January 19, 2009, at 17:21:05
For what it's worth, Marty, yes, I sure think that makes sense. The idea that a broad increase in levels of this or that neurochemical was -the- solution to mood disorders always rang false to me--a too simple solution to a problem in an extremely complex machine that we don't really understand yet. When you think about the problem of mood disorders in terms of the way the brain ACTUALLY SEEMS TO FUNCTION, it almost seems necessary to approach the problem through the brain's various distinct signaling and processing systems (which ones are responsible? How? can they be nudged in one direction or another in order to help?)
I'm sure your paradigm about focusing on brain-regions and pathways must be an improvement over what's come before--say, the serotonin theory of depression (which for me (as a layman) never seemed to hold the most basic level of intellectual credibility--it seemed almost...lazy).So yes! By all means let us focus on brain regions and signaling pathways!
Psychbot>
> Oh, another quick thought sharing with anyone trying to find himself a cure:
>
> Stop thinking in terms of messengers (neurotransmitter) and think way more in terms of systems/pathways and brain regions! Drugs which increase this or decrease that often are more specific to some regions than others for some reason.. USE THAT !
>
> 'More of this or less of that' kind of thinking is just plain wrong for some of us. Ever watch some Mayo Clinic brain scan that shows how some brain regions works too hard and some too few ? We have to reinforce the expression of some brain region and weaken the expression of others.. NOT reinforce in a leveled/linear way EVERY or ANY system with more or less DA or NE or SE .. but balance the expression by favoring some over others! Brain-wide receptor NUKING versus the subtlelity of geopolitics! That's strategy is currently saving my life beyond my wildest dreams!
>
> Neurologic engineering ... know your tools (drugs) and know yourself (reaction to tried drugs.. even side effects talks alot when you knows well your toolbox !) You can't attain a surgeon precision level .. (faaaaar from that) but I think it is possible to do a clean job of rebalancing brain regional expression. I can tell you my reinforced prefrontal cortex is quite happy to being able to shut the f*ck up to my amygdala since I'm on Agomelatine/Low dose trazodone !
>
> For anyone not getting what I'm talking about, consider this (not too bad) analogy: It is thought your car doesn't work because of a lack of Gaz and you're trying to get the damn machine to work by filling the WHOLE car with Gazoline .. In the truck, on the windshield, IN THE TIRE.. close all the windows/door and fill the damn whole thing ! -> find where you need that gaz.. and find a way to deliver it where it counts without splashing everything else ! LOL
>
> Does that makes sense ?
>
> /\/\arty
Posted by mav27 on January 19, 2009, at 19:31:51
In reply to Re: Atypical APs with lowest SRI - for AD augment » Marty, posted by Marty on January 19, 2009, at 17:21:05
I can't seem to find a way to the section of the brain i want so it seems easier just to fill everything up with gas as you would put it :)
Unless you have some ideas for me.. i need to target low d2 binding in the striatum section of the brain.
Posted by psychobot5000 on January 19, 2009, at 20:07:31
In reply to Re: Atypical APs with lowest SRI - for AD augment » Marty, posted by mav27 on January 19, 2009, at 19:31:51
> I can't seem to find a way to the section of the brain i want so it seems easier just to fill everything up with gas as you would put it :)
>
> Unless you have some ideas for me.. i need to target low d2 binding in the striatum section of the brain.
Tried pramipexole or ropinirole?
Posted by mav27 on January 19, 2009, at 20:30:01
In reply to Re: Atypical APs with lowest SRI - for AD augment » mav27, posted by psychobot5000 on January 19, 2009, at 20:07:31
> > I can't seem to find a way to the section of the brain i want so it seems easier just to fill everything up with gas as you would put it :)
> >
> > Unless you have some ideas for me.. i need to target low d2 binding in the striatum section of the brain.
>
>
> Tried pramipexole or ropinirole?
>Nah, docs wont prescribe dopamine agonists around here.
Posted by psychobot5000 on January 19, 2009, at 23:01:02
In reply to Re: Atypical APs with lowest SRI - for AD augment » Marty, posted by SLS on January 19, 2009, at 16:57:23
> One more thing.
>
> Would you please report any changes in body weight?
>
> 5-HT2c receptors help control blood leptin levels.
>
>
> - ScottI don't understand this side of things. Does this mean that Agomelatine might have some of the metabolic risks of atypical antipsychotics?
Psychbot
Posted by SLS on January 20, 2009, at 7:24:05
In reply to Re: Atypical APs with lowest SRI - for AD augment, posted by psychobot5000 on January 19, 2009, at 23:01:02
> > One more thing.
> >
> > Would you please report any changes in body weight?
> >
> > 5-HT2c receptors help control blood leptin levels.
> I don't understand this side of things. Does this mean that Agomelatine might have some of the metabolic risks of atypical antipsychotics?Leptin is a hormone secreted by fat cells (adipocytes). It was originally thought that its sole purpose was to decrease hunger. It is now known that leptin initiates several cascades of events, of which stimulating STAT3 transcription factor is one. When this signaling pathway is activated, the body changes the way it processes energy. The result of inhibiting this pathway is obesity and diabetes; the diabetes being a direct effect and not an effect secondary to obesity. Some people have a genetic polymorphism that make them more sensitive to this disruption.
The question is, are there other properties of atypical APs that act synergistically to amplify the 5-HT2c antagonism and its resulting reduction in circulating leptin levels.
Zyprexa is a potent 5-HT2c receptor antagonist. Risperdal is moderate. Seroquel, not so much. Even Abilify demonstrates 5-HT2c antagonsim. That's probably why I am retaining the weight I gained on nortriptyline and Nardil, which I no longer take. However, ziprasidone, a 5-HT2c antagonist as potent as olanzapine, is least liable to produce weight gain. Clearly 5-HT2c antagonism is not sufficient to produce weight gain or diabetes.
D4 receptor antagonism, maybe?
- Scott
This is the end of the thread.
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