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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 23 of 23. This is the beginning of the thread.
Posted by overtheedge on April 1, 2009, at 13:30:51
have there been any new AD that have come out in the last yr or so? i have not heard of any, maybe you all have.
Thanks
Posted by chris87 on April 1, 2009, at 13:50:22
In reply to are there any new AD out there?, posted by overtheedge on April 1, 2009, at 13:30:51
I think that Pristiq is fairly new. It's an SNRI, and I believe the manufacturer is claiming it to be like an improved version of Effexor. In reality, it's introduction probably had more to do with Effexor's patent expiring.
Posted by overtheedge on April 1, 2009, at 18:06:06
In reply to Re: are there any new AD out there?, posted by chris87 on April 1, 2009, at 13:50:22
Has anyone tried it, from what i read it has mixed reviews but then doesn't all of them?
Posted by desolationrower on April 1, 2009, at 20:01:07
In reply to Re: are there any new AD out there?, posted by overtheedge on April 1, 2009, at 18:06:06
well, i guess tramadol extended release and milnacipran and ropinirole xr and i think some MPH formulas, lysine bonded AMP, maybe some other stuff. if you mean things actually approved for depression, ANOTHER bupropion formulation,oh and i think 'symbyax' (fluoxetine+olanzapine) but thats not worth taking AND its a patent extender...
-d/r
Posted by Phillipa on April 1, 2009, at 21:20:45
In reply to Re: are there any new AD out there?, posted by desolationrower on April 1, 2009, at 20:01:07
Further up the board should be some threads on pristiq. Some give good reviews. Phillipa
Posted by JayBTV2 on April 2, 2009, at 10:51:33
In reply to are there any new AD out there?, posted by overtheedge on April 1, 2009, at 13:30:51
Agomelatine (Valdoxan) was just approved for use in Europe. It's a novel AD acting on Melatonin receptors. Supposed to work really well and not cause a lot of the SSRI side effects (Re: Libido).
Probably won't be available in the US until 2010 or 2011 but it's the most interesting of the new batch IMO.
Check http://www.neurotransmitter.net/newdrugs.html for other drugs in the pipeline....
Posted by bleauberry on April 2, 2009, at 15:49:34
In reply to are there any new AD out there?, posted by overtheedge on April 1, 2009, at 13:30:51
Keep an eye on Milnacipran (Ixel overseas, Savella in USA), scheduled to be released in USA pharmacies some time in May. It was approved for Fibromyalgia in USA, but has been a strong performing antidepressant in the rest of the world for years. I suspect they chose the Fibro route with FDA to avoid the treacherous political/economic environment of antidepressants in the USA. Once doctors get wind of it being a good antidepressant, I suspect it will be prescribed off label regularly. Weird. It is specifically an antidepressant elsewhere in the world, but will have to be off label in USA.
It is an SNRI with a potency of approximately 3 parts norepinephrine to 1 part serotonin. Fairly equally balanced, in contrast to Cymbalta which is 9:1 serotonin:norepinephrine or Effexor which is 30:1 serotonin:norepinephrine.
I saw at a forum where patients rate their meds that one person who failed all meds and also failed ECT, found Milnacipran to work very well.
It is a number one antidepressant in Japan.
It was already supposed to have been released, but the company at the last minute decided to change the colors of the pills in the starter pack.
Posted by TriedEveryDrug on April 2, 2009, at 21:58:35
In reply to Re: are there any new AD out there?, posted by chris87 on April 1, 2009, at 13:50:22
I've taken effexor and pristiq. To me, pristiq seems like it has fewer side effects.
Maybe because there is 1 fewer metabolism step.
Posted by TriedEveryDrug on April 2, 2009, at 22:00:14
In reply to Re: are there any new AD out there?, posted by desolationrower on April 1, 2009, at 20:01:07
what is this lysine bonded to AMP thing?
I searched and could not find anything.
Posted by TriedEveryDrug on April 2, 2009, at 22:14:27
In reply to Re: are there any new AD out there?, posted by bleauberry on April 2, 2009, at 15:49:34
I think you have reversed the ratios for 5HT:NE reuptake?
according to this article http://www.nature.com/npp/journal/v25/n6/abs/1395741a.htmlit appears that cymbalta is 1:9 serotonin:norepinephrine and effexor is 1:30...
Posted by desolationrower on April 2, 2009, at 23:04:55
In reply to Re: are there any new AD out there?, posted by bleauberry on April 2, 2009, at 15:49:34
vyvanse is the brand name, maybe that will be easier to search for.
The confusing thing with binding affinities is the "ki" value is something, i forget the equation and units, but the lower it is, the more potently the compound binds to the target, or the less you need. So if one drugs has a ki of 10 it is weaker than a drug that has a binding of 2.
-d/r
Posted by bleauberry on April 3, 2009, at 16:20:56
In reply to Re: cymbalta / effexor 5HT/NE reuptake ratios » bleauberry, posted by TriedEveryDrug on April 2, 2009, at 22:14:27
You interpreted it backwards. Both meds are predominantly serotonin meds with a scant bit of norepinehprine.
> I think you have reversed the ratios for 5HT:NE reuptake?
>
>
> according to this article http://www.nature.com/npp/journal/v25/n6/abs/1395741a.html
>
> it appears that cymbalta is 1:9 serotonin:norepinephrine and effexor is 1:30...
Posted by overtheedge on April 3, 2009, at 16:27:31
In reply to Re: cymbalta / effexor 5HT/NE reuptake ratios » TriedEveryDrug, posted by bleauberry on April 3, 2009, at 16:20:56
thanks, i did my reading on this too, seems fairly diffrent from the other ssris, but right now i just went back to my starting dose of zoloft and came off the abilify and seem to be ok at the moment and do not want to ruin anything.... but if this does not work thats the next drug i will try.
Posted by Bob on April 4, 2009, at 11:39:49
In reply to Re: are there any new AD out there?, posted by bleauberry on April 2, 2009, at 15:49:34
> Keep an eye on Milnacipran (Ixel overseas, Savella in USA), scheduled to be released in USA pharmacies some time in May. It was approved for Fibromyalgia in USA, but has been a strong performing antidepressant in the rest of the world for years. I suspect they chose the Fibro route with FDA to avoid the treacherous political/economic environment of antidepressants in the USA. Once doctors get wind of it being a good antidepressant, I suspect it will be prescribed off label regularly. Weird. It is specifically an antidepressant elsewhere in the world, but will have to be off label in USA.
>
> It is an SNRI with a potency of approximately 3 parts norepinephrine to 1 part serotonin. Fairly equally balanced, in contrast to Cymbalta which is 9:1 serotonin:norepinephrine or Effexor which is 30:1 serotonin:norepinephrine.
>
> I saw at a forum where patients rate their meds that one person who failed all meds and also failed ECT, found Milnacipran to work very well.
>
> It is a number one antidepressant in Japan.
>
> It was already supposed to have been released, but the company at the last minute decided to change the colors of the pills in the starter pack.
________________________________________________And I believe it will be called 'Savella.'
Posted by sowhysosad on April 4, 2009, at 19:13:38
In reply to Re: cymbalta / effexor 5HT/NE reuptake ratios » bleauberry, posted by TriedEveryDrug on April 2, 2009, at 22:14:27
> I think you have reversed the ratios for 5HT:NE reuptake?
>
>
> according to this article http://www.nature.com/npp/journal/v25/n6/abs/1395741a.html
>
> it appears that cymbalta is 1:9 serotonin:norepinephrine and effexor is 1:30...According to this one http://www.psychotropical.com/dual_action_ads.shtml it's 1:10 for cymbalta so pretty similar, but 1:200 for effexor!
Maybe that would explain why a friend and my wife both suffered extreme agitation on effexor!
Posted by bleauberry on April 5, 2009, at 6:46:54
In reply to Re: cymbalta / effexor 5HT/NE reuptake ratios, posted by sowhysosad on April 4, 2009, at 19:13:38
> > I think you have reversed the ratios for 5HT:NE reuptake?
> >
> >
> > according to this article http://www.nature.com/npp/journal/v25/n6/abs/1395741a.html
> >
> > it appears that cymbalta is 1:9 serotonin:norepinephrine and effexor is 1:30...
>
> According to this one http://www.psychotropical.com/dual_action_ads.shtml it's 1:10 for cymbalta so pretty similar, but 1:200 for effexor!
>
> Maybe that would explain why a friend and my wife both suffered extreme agitation on effexor!
>Effexor has changing ratios as the dose changes...increased affinity for NE at higher doses. But no matter how you look at it, 1:30 or 1:200, yeah, it is basically a glorifed SSRI with not much effect on NE. I believe when they measure brain increases of NE and DA, Prozac actually does more of that than Effexor.
Exteme agitation. Yeah, that stinks. I don't know what causes that. Some would say that is a sign of bipolar. I think it could be any number of things. In any case, it basically tells me that whatever that med is, it is probably an offensive one for that person's particular biochemistry. Sometimes slow lengthened titration allows adaptation to be smoother so the agitation isn't severe and eventually is nonexistent. I've never had the strength to endure a med that felt that bad. My instincts just say..."poison!"
Posted by sowhysosad on April 5, 2009, at 22:14:47
In reply to Re: cymbalta / effexor 5HT/NE reuptake ratios » sowhysosad, posted by bleauberry on April 5, 2009, at 6:46:54
> Effexor has changing ratios as the dose changes...increased affinity for NE at higher doses. But no matter how you look at it, 1:30 or 1:200, yeah, it is basically a glorifed SSRI with not much effect on NE. I believe when they measure brain increases of NE and DA, Prozac actually does more of that than Effexor.
>
> Exteme agitation. Yeah, that stinks. I don't know what causes that. Some would say that is a sign of bipolar. I think it could be any number of things. In any case, it basically tells me that whatever that med is, it is probably an offensive one for that person's particular biochemistry. Sometimes slow lengthened titration allows adaptation to be smoother so the agitation isn't severe and eventually is nonexistent. I've never had the strength to endure a med that felt that bad. My instincts just say..."poison!"
>Am I misunderstanding how reuptake ratios are interpreted? I'd always assumed that 1:200 5HT:NE would mean that blockade of the NE transporter was 200x greater, yielding a more noradrenergic effect.
With regard to the agitation from Effexor, I'd assumed it was because of the norepinephrine boost.
However, if I'm misinterpreting the ratios, it's gotta be the same phenomenon as SSRI startup anxiety. As I understand it, it's over stimulation of one of the 5HT2 receptor groups (A or C I believe), which normally subsides when the receptors downregulate.
Posted by sowhysosad on April 5, 2009, at 22:24:12
In reply to How are reuptake ratios expressed?, posted by sowhysosad on April 5, 2009, at 22:14:47
> > Effexor has changing ratios as the dose changes...increased affinity for NE at higher doses. But no matter how you look at it, 1:30 or 1:200, yeah, it is basically a glorifed SSRI with not much effect on NE. I believe when they measure brain increases of NE and DA, Prozac actually does more of that than Effexor.
> >
> > Exteme agitation. Yeah, that stinks. I don't know what causes that. Some would say that is a sign of bipolar. I think it could be any number of things. In any case, it basically tells me that whatever that med is, it is probably an offensive one for that person's particular biochemistry. Sometimes slow lengthened titration allows adaptation to be smoother so the agitation isn't severe and eventually is nonexistent. I've never had the strength to endure a med that felt that bad. My instincts just say..."poison!"
> >
>
> Am I misunderstanding how reuptake ratios are interpreted? I'd always assumed that 1:200 5HT:NE would mean that blockade of the NE transporter was 200x greater, yielding a more noradrenergic effect.
>
> With regard to the agitation from Effexor, I'd assumed it was because of the norepinephrine boost.
>
> However, if I'm misinterpreting the ratios, it's gotta be the same phenomenon as SSRI startup anxiety. As I understand it, it's over stimulation of one of the 5HT2 receptor groups (A or C I believe), which normally subsides when the receptors downregulate.
>I think I've sussed it: the ratios relate to inhibitor affinities expressed in Ki nM.
In Ki nM a LOWER number is BETTER, so the normal logic of a ratio is reversed, ie. the lower value in the ratio represents the higher affinity.
Am I right boffins?
If so, that would explain why I've found imipramine to be so unpleasantly noradrenergic. I'd assumed its 2:1 5HT:NA ratio to mean it favoured serotonin, which is why I asked the doc for it instead of clomipramine which is 1:2!
Posted by Larry Hoover on April 6, 2009, at 8:29:39
In reply to Re: How are reuptake ratios expressed?, posted by sowhysosad on April 5, 2009, at 22:24:12
> I think I've sussed it: the ratios relate to inhibitor affinities expressed in Ki nM.
>
> In Ki nM a LOWER number is BETTER, so the normal logic of a ratio is reversed, ie. the lower value in the ratio represents the higher affinity.You have to be careful about how you interpret Ki. The unit is nanoMolar, which is a concentration term. It's the concentration at which a substance occupies 50% of the available active sites. It's a dynamic measurement, as molecules are constantly binding to, and departing from, the active site. You're quite right; the lower the value, the higher the affinity.
In the case of transporters, binding to the active site can reasonably be interpreted as inhibition. Just as you can't park two cars in the same parking spot, if the transporter is occupied by an antidepressant, it can't transport its normal payload.
It's a little different when you start talking about receptors, because binding is only part of the picture. The receptor response to that binding is the other part. The substance binding there, the ligand, can activate the receptor (i.e. it is an agonist), it can partly activate it (partial agonist), it can just sit there and do nothing (competitive inhibitor), it can produce a negative response (reverse agonist), or other effects. These are all acute effects. Then you have to consider the downstream processes initiated by binding. Much more complicated than transporter binding effects.
You can look up Ki values in this database:
http://pdsp.med.unc.edu/pdsp.phpIn the opening page, what you want to do is put the chemical name of the drug (e.g. venlafaxine, not Effexor) into the test ligand box, and hit enter. You'll get a page with (hopefully) an array of data to consider.
Towards the left, you have the specific receptor identified. You'll need to know that serotonin is call 5-HT. I think all the others are straight forward. The Ki is in the middle column. But you'll also need to consider the "Hot ligand", the substance being displaced, and the species from which the receptor is drawn. The former criterion is very important when considering transporter binding, as the displaced substance should e.g. be serotonin when you're looking at serotonin transporter binding affinity, not some other drug. And the species matters, because we're not rats or whatever.
But even this information is just a starting point in assessing a drug. Individuals differ in their receptor density (regulation), receptor structure (genetics), parent drug to metabolite ratios (both regulatory and genetic), presence/absence of co-factors (receptor sensitivity modifiers of many types), and so on.
In the end, what matters is can you tolerate the drug, and does it help. Typical binding affinities help us to predict what will happen, but in the end, you have to do the experiment itself to know what happens in your body.
Lar
Posted by desolationrower on April 6, 2009, at 8:55:41
In reply to Re: How are reuptake ratios expressed? » sowhysosad, posted by Larry Hoover on April 6, 2009, at 8:29:39
larry explained that well, the only thing i'd add is that the binding is http://en.wikipedia.org/wiki/Sigmoid_function sigmoidal. this is relevant when the drug binds to two different receptors, like velafaxine. that rapid increase in the middle of the curve means that the first receptor gets almost full before the other one really gets going, which is why you only start to get a little bit of NA effect at a high dose of venlafaxine, especially since the binding is quite different. i think there is a article on this on preskorn's site, if you search there.
-d/r
Posted by Larry Hoover on April 6, 2009, at 9:41:56
In reply to Re: How are reuptake ratios expressed?, posted by desolationrower on April 6, 2009, at 8:55:41
Excellent point about the sigmoid function, d/r.
An excellent example of that is the pain-reduction vs. psychoactive response to opiates. In treating my pain, I could take substantial doses of oxycodone and have no psychoactive effect whatsoever. My pain wouldn't go to zero, but it became tolerable. If I tried to obtain zero pain, I would be hugely high. Sometimes, in hindsight, I did take too much, but I assessed that via the psychoactive effect. If I got a buzz, I took too much drug. The pain receptors have a higher affinity for the opiates than do the buzz ones, and I wanted to keep the latter unoccupied. That helped me titrate my dose over time. In fact, the first indication that my baseline pain was diminishing was that my dose was dropping. I was still facing severe pain, but I had an objective measure of the need for treatment.
Lar
Posted by sowhysosad on April 6, 2009, at 14:20:45
In reply to Re: How are reuptake ratios expressed? » desolationrower, posted by Larry Hoover on April 6, 2009, at 9:41:56
Fascinating stuff guys. Thanks for that.
Posted by sowhysosad on April 6, 2009, at 14:41:18
In reply to Re: How are reuptake ratios expressed?, posted by desolationrower on April 6, 2009, at 8:55:41
> larry explained that well, the only thing i'd add is that the binding is http://en.wikipedia.org/wiki/Sigmoid_function sigmoidal. this is relevant when the drug binds to two different receptors, like velafaxine. that rapid increase in the middle of the curve means that the first receptor gets almost full before the other one really gets going, which is why you only start to get a little bit of NA effect at a high dose of venlafaxine, especially since the binding is quite different. i think there is a article on this on preskorn's site, if you search there.
>
> -d/rSo, with that in mind, it could explain why I get such a strong noradrenergic effect from imipramine but no discernible serotonergic effect.
Perhaps I didn't push the dose high enough to reach "saturation point" at the norepinephrine transporter.
The concept of sigmoid function also lends further weight to Ken Gillman's idea that an SRI+NRI combo like sertraline + nortriptyline is better than a dual action drug,
This is the end of the thread.
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