![[dr. bob]](/dr-bob-sm.gif)
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 9 to 33 of 33. Go back in thread:
Posted by SLS on August 5, 2004, at 9:01:08
In reply to Re: CYMBALTA - With Drug Approval, Lilly Sighs Relief, posted by bob on August 5, 2004, at 2:14:19
> I'm really not sure what this drug is bringing to the party that Effexor XR isn't already doing. Surely it will have astounding sexual side effects, delayed weight gain, withdrawl syndrome, urinary hesitancy, and so on, and so on. I guess you never know until you try, but my body can't take these "trials" very well anymore. Is there anything novel about this drug, other than the ratio of reuptake being more towards norepinephrine than Effexor?
Hi Bob.I apologize for the tone of my previous post. It probably sounded angry. I don't have much patience for people who would want to take potentially life-saving pills out of my mouth.
One thing to take into consideration is the possibility that Cymbalta might do the same thing as Effexor, but in different parts of the brain.
- Scott
Posted by bob on August 5, 2004, at 12:48:27
In reply to Re: CYMBALTA - With Drug Approval, Lilly Sighs Relief, posted by SLS on August 5, 2004, at 7:04:28
> > Is there anything novel about this drug, other than the ratio of reuptake being more towards norepinephrine than Effexor?
>
>
> For those people who respond to Cymbalta and not to other drugs, that should be novel enough. And there always are people who find a newly approved antidepressant better for them than any that had been previously available. Scientists don't know why these drugs affect different people differently. They just do.
>
> Bring on more new drugs! - at least until one comes out that works for me. You don't have to take them if you don't want. Let me worry about the side effects and withdrawal syndrome.
>
> I'll let you know how things turn out.
>
> :-)
>
>
> - Scott
>
>
>
>Well, if I haven't found a suitable drug, then I pretty much have to try it, right? Either that, or stay on the unsuitable I'm on. How is that I can just sit back and let you worry about the side effects?
I am not saying they shouldn't come out with new drugs. It just would be nice to have something slightly novel, one of these days. The more drugs out there, the better, but hopefully one day they will understand something about what's going on, so that they don't make "me too" drugs forever and ever.
Just like you, I will probably try this drug too, so I won't need to hear what it does for you. Thanks anyway.
Posted by caraher on August 5, 2004, at 13:01:04
In reply to Re: CYMBALTA - With Drug Approval, Lilly Sighs Relief, posted by bob on August 5, 2004, at 2:14:19
> I'm really not sure what this drug is bringing to the party that Effexor XR isn't already doing. Surely it will have astounding sexual side effects, delayed weight gain, withdrawl syndrome, urinary hesitancy, and so on, and so on. I guess you never know until you try, but my body can't take these "trials" very well anymore. Is there anything novel about this drug, other than the ratio of reuptake being more towards norepinephrine than Effexor?
I did some reading about trials completed to date and got the impression that sexual side effects weren't as bad. Nothing about withdrawal syndrome but my understanding is that it has a half-life of something like 14 hours, which my amateur grasp of such things suggests might make withdrawal a problem.
The trouble is that based on what we know about the systems it works on, kinetics, etc. I totally sympathize with saying it's not a whole lot different from Effexor. But you can also make exactly the same argument to the effect SSRIs are all basically the same, so why should there be more than one available? But it's pretty clear that not all SSRIs are created equal, which makes me inclined to think that there's plenty of room for another option like Cymbalta alongside Effexor.
Posted by bob on August 5, 2004, at 13:06:05
In reply to Re: CYMBALTA - With Drug Approval, Lilly Sighs Relief » bob, posted by SLS on August 5, 2004, at 9:01:08
> > I'm really not sure what this drug is bringing to the party that Effexor XR isn't already doing. Surely it will have astounding sexual side effects, delayed weight gain, withdrawl syndrome, urinary hesitancy, and so on, and so on. I guess you never know until you try, but my body can't take these "trials" very well anymore. Is there anything novel about this drug, other than the ratio of reuptake being more towards norepinephrine than Effexor?
>
>
> Hi Bob.
>
> I apologize for the tone of my previous post. It probably sounded angry. I don't have much patience for people who would want to take potentially life-saving pills out of my mouth.
>
> One thing to take into consideration is the possibility that Cymbalta might do the same thing as Effexor, but in different parts of the brain.
>
>
> - ScottScott:
No problem - don't beat yourself up over it. Both of us are dealing with a lot of frustration related to these issues and our problems. I will not ever tell anyone to take, or not take, any of these meds (although I may come across thiat way). I've been on literally over 30 of these things, with not much happiness. I personally have a whole lot of trouble getting on and off meds, so it's not easy to just drop what I'm taking and try another.
As for Cymbalta acting on different parts of the brain, I have no doubt that will be true. Like you said, science just doesn't understand how these things work, despite the bouncing-egg Zoloft commercials you see on tv that would have you believe otherwise.
Posted by bob on August 5, 2004, at 13:19:22
In reply to Re: Cymbalta/Duloxetine--Something's Up, posted by caraher on August 5, 2004, at 13:01:04
Again, I am not advocating that any drugs not be allowed to come to market just because there are other drugs like it there already. I'm sure the drug companies won't let that happen anyway, since most of their money comes from making approximate copies of someone else's idea anyway. Like was mentioned before, we understand almost nothing about the mechanisms at work in the brain, so the more the merrior in terms of pharmacological compounds. By the way, what are you talking about with the "kinetics"? I don't think I've heard of that before in this context.
As for all the SSRI me too drugs, I think it's a similar situation. For me they were all quite similar in the end, with the exception of prozac, which has a very long half-life. They do have subtle differences, though, so I guess that's why we need many variations of them. One thing I don't understand is, why don't companies make slight tweaks to their drug compounds in order to make it "patentable" and then bring it to market. Heck, make 10 different variations. This was done with Celexa and Lexapro, so why not do it more?
Lastly, I had heinous problems with Effexor withdrawl. I can guarantee that people who have withdrawl with SSRIs will not enjoy coming off of Cymbalta. Effexor half life is under 10 hrs. I just came off Celexa a month ago, and had some problems (although they paled in comparison to what I went through with Effexor). Celexa's half-life is something like 32 hours. I think Cymbalta is 14? That's not out of problem territory. Sustain release formulas doesn't really help the problem all that much in my mind, since it's the elimination rate that is the culprit, not the introduction rate. You can affect the former by changing the latter, but only to a certain extent.
Posted by linkadge on August 5, 2004, at 17:07:57
In reply to Re: Cymbalta/Duloxetine--Something's Up » caraher, posted by bob on August 5, 2004, at 13:19:22
I wouldn't really believe it when they say that cymbalta has reduced sexual dysfunction.
They have to say this. Seeing as it is another me too drug, people want to think that it is an improvement on previous drugs.
As far as side effects go, sexual dysfunction is the biggest one in terms of patient compliance so it only stands to reason that the drugs companies would over-emphasize the drug's supposed lack of side effects in this area.
Lexapro was supposed to have considerably fewer sexual side effects than celexa, is this the case? not really.
But I think it is pure bull gepirone was considered 'unaprovable' for anxiety/depression, and this drugs slips through the cracks. Gepirone was really a step forward.
Linkadge
Posted by bob on August 5, 2004, at 17:11:09
In reply to Re: Cymbalta/Duloxetine--Something's Up, posted by linkadge on August 5, 2004, at 17:07:57
Also beware of the reduced appetite thing. Plenty of drugs depress appetite in the short, stunted trial lengths they use (12 weeks). Check back in a year or two when true long term data exists.
Posted by nmk on August 5, 2004, at 18:12:58
In reply to Re: CYMBALTA - With Drug Approval, Lilly Sighs Relief, posted by bob on August 5, 2004, at 2:14:19
My pdoc can't wait for this drug to be released and has been talking it up for months. He thinks I may benefit from it but I am very frightened due to my horrible experience with Effexor. I was on Effexor for approx. 3 months and all it did for me was increase the depression, anxiety, and agitation. I won't even go into the withdrawal experience.
Help me out here please. I have been on this med merry-go-round for 2 1/2 years and am tired of all the med trials. Is it worth a shot or should I go with plan B which is to try Parnate? I am so confused.
Thanks,
Nicole
Posted by nmk on August 5, 2004, at 18:24:31
In reply to Re: CYMBALTA - I am VERY afraid!, posted by nmk on August 5, 2004, at 18:12:58
Sorry to post again....I forgot to hit the "notify follow-up thread" box the first time.
Posted by KaraS on August 5, 2004, at 22:25:21
In reply to Re: CYMBALTA - I am VERY afraid!, posted by nmk on August 5, 2004, at 18:12:58
> My pdoc can't wait for this drug to be released and has been talking it up for months. He thinks I may benefit from it but I am very frightened due to my horrible experience with Effexor. I was on Effexor for approx. 3 months and all it did for me was increase the depression, anxiety, and agitation. I won't even go into the withdrawal experience.
>
> Help me out here please. I have been on this med merry-go-round for 2 1/2 years and am tired of all the med trials. Is it worth a shot or should I go with plan B which is to try Parnate? I am so confused.
>
> Thanks,
>
> NicoleWhy not start on the Parnate and see how that goes? Keep checking these boards to see if those who reacted like you did to Effexor have similar
experiences with Cymbalta for your future reference. You may not need to know about the Cymbalta if the Parnate works out well for you. If the Parnate doesn't work out adequately, you may have a better sense of whether you want to try it from reading about others experiences. Of course, you can't predict with certainty how you're going to react by reading about others but it can give you more info in making your decision.
-K
Posted by bob on August 6, 2004, at 0:27:39
In reply to Re: CYMBALTA - I am VERY afraid!, posted by nmk on August 5, 2004, at 18:12:58
> My pdoc can't wait for this drug to be released and has been talking it up for months. He thinks I may benefit from it but I am very frightened due to my horrible experience with Effexor. I was on Effexor for approx. 3 months and all it did for me was increase the depression, anxiety, and agitation. I won't even go into the withdrawal experience.
>
> Help me out here please. I have been on this med merry-go-round for 2 1/2 years and am tired of all the med trials. Is it worth a shot or should I go with plan B which is to try Parnate? I am so confused.
>
> Thanks,
>
> NicoleI think I would agree with KaraS. Maybe Parnate should be tried first, since it is more different from Effexor than Cymbalta, at least on paper. You can always go and try the Cymbalta. It is a very unfortunate fact, that there is really no way to predict any particular person's reaction to any particular drug. There is very little science to that aspect of taking these meds.
Posted by Cecilia on August 6, 2004, at 4:51:19
In reply to Re: CYMBALTA - I am VERY afraid!, posted by bob on August 6, 2004, at 0:27:39
Anyone know what the main difference between these three drugs is? They all supposedly work on both serotonin and norepinephrine. I couldn`t tolerate Effexor at all-the smallest dose made me sick as a dog. Having tried pretty much every antidepressant available in the U.S., (as well as going to Canada for TMS) I started trying overseas drugs (with my doctor`s permission-and don`t worry, Dr. Bob, I won`t say from where). First I tried moclobemide-did nothing but make me grind my teeth. Now I`m trying tianeptine-no effects so far (one month) side or otherwise. My plan was to try milnacipran next, but now that duloxetine has actually been approved (I never thought it would) I suppose I should go for that 1st. Except, like others have mentioned, I am very afraid. Of the side effects-Effexor was like poison for me, and of the side efeects we don`t know about yet. The article on Cymbalta made a big deal about how it has been studied in 6000 people. Six thousand-that`s nothing!!!. They`re talking about taking Serzone off the market for liver failure that affects one in 250,000. I actually feel safer with non FDA approved drugs that have been around for years in other countries. Milnacipran has been around for years as an AD, but is only being studied in the U.S. for fibromyalgia. Is there any rhyme nor reason about any of these drugs, which ones get studied and for what indications, which ones get approved or not? When I asked my doctor about tianeptine, which supposedly works exactly opposite to the SSRI`s, decreasing serotonin instead of increasing it, all he could say was, well, nobody knows how any of these drugs work. Very reassuring. Can they really all just be placebos? I`m sure, like the rest of us, I`ll end up being a guinea pig for Cymbalta, because you can`t stand to live without hope. But I just can`t believe that after all these years we`ve been waiting for it they`ve only tried it on 6000 people. Cecilia
Posted by linkadge on August 6, 2004, at 7:31:44
In reply to Effexor, Duloxetine, Milnacipran, posted by Cecilia on August 6, 2004, at 4:51:19
I thought that effexor would be better than celexa because I would get more energy and perhaps a better AD effect.
Quite the opposite. It made me very depressed and melancholic, something like what some people report with reboxetine. Effexor made me ANGRY, something that the SSRI's never did. Some people mistakenly think that they need a noradrenic boost, when in reality they are like me very highly motivated to begin with, and need something to push the pause button.
Linkadge
Posted by bob on August 6, 2004, at 9:54:29
In reply to some people just don't do well with norepinephrine, posted by linkadge on August 6, 2004, at 7:31:44
> I thought that effexor would be better than celexa because I would get more energy and perhaps a better AD effect.
>
> Quite the opposite. It made me very depressed and melancholic, something like what some people report with reboxetine. Effexor made me ANGRY, something that the SSRI's never did. Some people mistakenly think that they need a noradrenic boost, when in reality they are like me very highly motivated to begin with, and need something to push the pause button.
>
> LinkadgeEffexor caused anger in me also, at higher doses.
Posted by Cecilia on August 7, 2004, at 2:09:25
In reply to Re: some people just don't do well with norepinephrine, posted by bob on August 6, 2004, at 9:54:29
I definitely don`t do well with anything stimulating. I can`t say any AD has ever made me feel better, but plenty have made me feel worse. And yet I keep trying-sometimes I think it`s not because I have any real expectation of anything working, but more to punish myself for being depressed. I`m annoyed that duloxetine is only going to be available in enteric coated capsules, not tablets, as I`ve learned over the years (through the school of bitter experience) to start any med on the smallest possible dose. And weaning off-people have no choice but to go from 20 mg to zero-a recipe for disaster. Cecilia
Posted by SLS on August 7, 2004, at 7:19:44
In reply to some people just don't do well with norepinephrine, posted by linkadge on August 6, 2004, at 7:31:44
Hi Linkadge.
> I thought that effexor would be better than celexa because I would get more energy and perhaps a better AD effect.
>
> Quite the opposite. It made me very depressed and melancholic, something like what some people report with reboxetine. Effexor made me ANGRY, something that the SSRI's never did. Some people mistakenly think that they need a noradrenic boost, when in reality they are like me very highly motivated to begin with, and need something to push the pause button.I would like to offer the suggestion that things are not always that simple when it comes to psychobiology. For instance, one of the few medications that have helped me is desipramine. By contrast, reboxetine exacerbated my depression and pushed me into an anxious suicidal state. Both of these drugs are considered to be selective NE reuptake inhibitors, yet, for me, they affected me in opposite ways. On the other hand, as you have noted, there are often trends in someone's history of drug reactions that can serve to guide treatment selection. I would just hate to see anyone try to guess their way out of a potentially successful treatment by using an overly simple and often unreliable model of psychopharmacology to errantly exclude effective alternatives. (This is not a commentary on your post so much as it is an observation of mine that this approach has been pervasive among publishing investigators for years).
Someone here posted something quite provocative the other day that has stuck in his mind. His doctor described the differences between the NE actions of nortriptyline and atomoxetine in the following manner:
nortriptyline - NE - brainstem = antidepressant
atomoxetine - NE - cortex = anti ADD/ADHDI'm not sure of the accuracy of these statements, but they do serve to illustrate the importance of determining not only WHAT a drug does, but also WHERE it does it. Location, location, location. You have a good grasp of the division of brain functions among circuits and anatomical structures. When you read the data offered by investigations in psychobiology, take note of where in the brain ligands accumulate or measures of functional change occur. You should be able to do a great deal with this kind of information.
- Scott
Posted by linkadge on August 7, 2004, at 8:07:03
In reply to Re: some people just don't do well with norepinephrine » linkadge, posted by SLS on August 7, 2004, at 7:19:44
That sounds kind of fishy to me. If a drugs is a reputake inhibitor it works at the uptake sites equally. I don't know how it could not.
It is just like ritalin, the ADD effect is presumably by dopamine action in the frontal cortex, but it is certainly not selective to the frontal cortex. It can cause psychosis by lower brainstem activation as well.
I think that perhaps some of the *secondary properties* of the drug can control its actions. All TCAs have affinity for the 2a receptors, although for desipramine this is very small it could be involved in mood regulation.
I don't think there is anything wrong with using the drugs properties to predict a theraputic responce, the problem is that there are virtually no drugs for which we know all the properties :)
Linkadge
Posted by Bob on August 7, 2004, at 9:03:12
In reply to Re: some people just don't do well with norepinephrine, posted by Cecilia on August 7, 2004, at 2:09:25
> I definitely don`t do well with anything stimulating. I can`t say any AD has ever made me feel better, but plenty have made me feel worse. And yet I keep trying-sometimes I think it`s not because I have any real expectation of anything working, but more to punish myself for being depressed. I`m annoyed that duloxetine is only going to be available in enteric coated capsules, not tablets, as I`ve learned over the years (through the school of bitter experience) to start any med on the smallest possible dose. And weaning off-people have no choice but to go from 20 mg to zero-a recipe for disaster. Cecilia
Thanks for the heads up! That is something VERY important to know, and I couldn't agree with you more. I don't think drug makers have any ideal how hard it is to discontinue some of these meds. I'm taking Welbutrin XL right now, and they only offer it in 150mg and 300mg doses, that are not splittable. For me, that's a fiasco waiting to happen. You know, if they haven't fully acknowledged the withdrawal by now, I'm not sure it's ever going to happen.
Posted by SLS on August 7, 2004, at 11:43:31
In reply to Re: some people just don't do well with norepinephrine, posted by linkadge on August 7, 2004, at 8:07:03
> That sounds kind of fishy to me. If a drugs is a reputake inhibitor it works at the uptake sites equally. I don't know how it could not.What sounds fishy? That drugs accumulate in tissues with varying distributions? That these various tissues (circuits) are responsible for different brain functions? That two drugs with the same pharmocodynamic properties would yield different results because they exert them in different pathways?
> I don't think there is anything wrong with using the drugs properties to predict a theraputic responce, the problem is that there are virtually no drugs for which we know all the properties :)Theoretically, of course there's nothing wrong with this concept. However, one would have to account for the myriad of biological variables that enter into an equation of a drug reaction for each drug for each individual.
1. The differential distribution into specific tissues within an individual different drugs.
2. Interindividual differential distribution into specific tissues the same drug.
These things are determined by multiple variables, some of which would include: regional vascularization and blood flow and perfusion rates, variable permeability and active transport across BB barrier, transport through anatomic different ventricles and CSF canals, distribution by varying densities of glial cells, etc. I'm just making up stuff as I go along here. :-) Again, look at the medical literature. You will see that different drugs can exert similar effects in different parts of the brain.
I can think of dozens of biological differences that can occur between any two individuals at one point in time or the same individual at any two points in time that allow for endless permutations of variables that confound the ability of one to predict the outcome of a drug trial, even if every single property of that drug were identified.
I think it is an important thing to admit to ourselves, not only our lack of understanding of the untold biological mechanisms that are incorporated into brain function, but also our lack of computational power to resolve them so as to predict output based upon input.
I'm sorry for how short and sloppily worded this is.
- Scott
Posted by Bob on August 7, 2004, at 12:07:55
In reply to Re: some people just don't do well with norepinephrine » linkadge, posted by SLS on August 7, 2004, at 11:43:31
"I think it is an important thing to admit to ourselves, not only our lack of understanding of the untold biological mechanisms that are incorporated into brain function, but also our lack of computational power to resolve them so as to predict output based upon input."
Amen! Well put. Not only do we have almost no understanding about these things, but we have almost no ability to realize how little we know.
Posted by linkadge on August 7, 2004, at 12:30:04
In reply to Re: some people just don't do well with norepinephrine » linkadge, posted by SLS on August 7, 2004, at 11:43:31
I agree with what you are saying. In theory we should be able to predict a drug responce by using its properties, but the varibles are often out of the realm of hypothesis.
What I am saying is that (you being the exception) it is more often than not the case that some degree of responce can oftentimes be predicted based on the proposed workings of the drug.
I have responded to most SSRI's similarily (exception of dirty prozac) and have responded to most dopaminergics similarly. I have also found I respond to most noradrenic enhancing meds similarly. By no means is my experience inclusive, but I think it can *sometimes* be a good place to start.For the most basic example, you may not want to give a depressed schitzoprenic wellbutrin as an antidepressant (because of dopaminergic interactions) while celexa might be more suitable.
Linkadge
Posted by SLS on August 7, 2004, at 13:26:44
In reply to Re: some people just don't do well with norepinephrine, posted by linkadge on August 7, 2004, at 12:30:04
> some degree of responce can oftentimes be predicted based on the proposed workings of the drug.
> I have responded to most SSRI's similarily (exception of dirty prozac) and have responded to most dopaminergics similarly. I have also found I respond to most noradrenic enhancing meds similarly. By no means is my experience inclusive, but I think it can *sometimes* be a good place to start.Yup. I agree.
- Scott
Posted by zeugma on August 8, 2004, at 10:01:05
In reply to Re: some people just don't do well with norepinephrine, posted by SLS on August 7, 2004, at 13:26:44
I was the poster who brought up the atomoxetine-nortriptyline contrast. Atomoxetine's major metabobolite, 4-hydroxyatomoxetine, is a kappa-opiate partial agonist:
1: Bioorg Med Chem Lett. 2004 Aug 2;14(15):4083-5. Related Articles, Links
Synthesis and biological evaluation of the major metabolite of atomoxetine: elucidation of a partial kappa-opioid agonist effect.Creighton CJ, Ramabadran K, Ciccone PE, Liu J, Orsini MJ, Reitz AB.
Drug Discovery, Johnson and Johnson Pharmaceutical, Research and Development, Spring House, PA 19477-0776, USA. ccreight@prdus.jnj.com
The major human metabolite of atomoxetine (4-hydroxyatomoxetine) was tested against a panel of receptors and enzymes, and was found to interact with the mu, delta, and kappa-opioid receptors based upon studies involving both binding and functional assays. 4-hydroxyatomoxetine was determined to be a partial agonist of the kappa-opioid receptor.
Dysphoria is a frequent response to kappa partial agonists. This metabolite could be responsible for the fatigue, and potential induction of depression, by atomoxetine.
Posted by SLS on August 8, 2004, at 10:20:39
In reply to this just in on atomoxetine » SLS, posted by zeugma on August 8, 2004, at 10:01:05
> I was the poster who brought up the atomoxetine-nortriptyline contrast. Atomoxetine's major metabobolite, 4-hydroxyatomoxetine, is a kappa-opiate partial agonist:
Hi Z.
It never ceases to amaze me how much biological activity these drugs and their metabolites have. On the one hand, it is upsetting to have to continually rework one's models and hypotheses to keep up with the overwhelming number discoveries made in neuroscience. On the other hand, it is settling to contemplate that the diverse and often unpredictable clinical effects of these drugs are that much closer to being elucidated. I wish I could keep up with all of it.
Thanks for posting this.
- Scott
Posted by zeugma on August 8, 2004, at 11:14:47
In reply to Re: this just in on atomoxetine » zeugma, posted by SLS on August 8, 2004, at 10:20:39
> > I was the poster who brought up the atomoxetine-nortriptyline contrast. Atomoxetine's major metabobolite, 4-hydroxyatomoxetine, is a kappa-opiate partial agonist:
>
> Hi Z.
>
> It never ceases to amaze me how much biological activity these drugs and their metabolites have. On the one hand, it is upsetting to have to continually rework one's models and hypotheses to keep up with the overwhelming number discoveries made in neuroscience. On the other hand, it is settling to contemplate that the diverse and often unpredictable clinical effects of these drugs are that much closer to being elucidated. I wish I could keep up with all of it.
>
> Thanks for posting this.
>
> - ScottHi Scott.
I agree that it is a mixed blessing about the complexity of these drugs' actions. In the case of atomoxetine I cannot help thinking that a degree of suspicion must have attached to atomoxetine, since its billing as a relatively pure NE reuptake inhibitor should not have caused the degree of sedation/fatigue that postmarketing reports have elicited.
Certainly the models we have for drug development and the rationales for mechanisms of efficacy are far too simple. We have to trust our own responses to these drugs and trust that the neuroscientists will be following in our wake sooner or later :)
-z
This is the end of the thread.
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