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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 21 of 21. This is the beginning of the thread.
Posted by Peter S. on December 31, 2002, at 21:25:29
I'm waiting with baited breath for Cymbalta to be released. Apparently Lily just received an approvability letter from the FDA. Anybody know what this means and how long it might take to get to market?Thanks!
Posted by ross c on January 1, 2003, at 8:54:18
In reply to Cymbalta/Duloxetine news?, posted by Peter S. on December 31, 2002, at 21:25:29
hi
dual will be released spring of 2003. if not sooner. the FDA inspected eli lillys plants and alot of them needed some fixing or we would have cymbalta out already. hang in there. the letter just means it got final approval to market and release the med as a safe med.
ross
Posted by linkadge on January 1, 2003, at 9:48:04
In reply to Re: Cymbalta/Duloxetine news?, posted by ross c on January 1, 2003, at 8:54:18
I really do believe that norep + serotoin meds offer a better responce, I remember feeling wholy better on Effexor. Norepinephrine at the wrong sites can cause tachycardia which was what I got. I couldn't stay on it for long. I will try duloxotine when available. I just hope it doesn't cause insommnia.
Linkadge
Posted by Dinah on January 1, 2003, at 11:33:43
In reply to I do believe in norepinephrine, posted by linkadge on January 1, 2003, at 9:48:04
My only two really bad med experiences were Wellbutrin and Effexor. Their common denominator is NE, right? In which case NE appears to bring on suicidal agitated depressions in me.
Wouldn't it be nice if they could do a test so that disastrous med trials could be averted? I don't suppose depression that is helped by NE looks any different from depression that is exacerbated by NE.
Posted by linkadge on January 1, 2003, at 14:31:49
In reply to Re: I am scared silly of norepinephrine, posted by Dinah on January 1, 2003, at 11:33:43
The problem is the proportions. For some, just a smidge of norepinephrine would counteract some of the apathy brought on by ssri's, but you're right,
when in the wrong proportions it can exasperate anxiety, and suicidal tendancies. By itself, it only energieses and creates mental turmoil, it creates no peace, and no comfort. It is a strange chemical. The problem is that it probably acts totally different at different sites.Linkadge
Posted by johnj on January 1, 2003, at 17:26:49
In reply to Re: I am scared silly of norepinephrine, posted by linkadge on January 1, 2003, at 14:31:49
the mechanism by which TCA's work?
Posted by linkadge on January 1, 2003, at 19:08:05
In reply to Isn't NE and serotonin , posted by johnj on January 1, 2003, at 17:26:49
Thats right, the different TCA's
work on these two in different
proportions.Linkadge
Posted by johnj on January 2, 2003, at 8:20:33
In reply to Re: Isn't NE and serotonin , posted by linkadge on January 1, 2003, at 19:08:05
Thanks, I need to give it a try when it comes out the TCA side effects aer killing me.
Posted by Noa on January 2, 2003, at 12:44:39
In reply to Re: Isn't NE and serotonin » linkadge, posted by johnj on January 2, 2003, at 8:20:33
are these newer meds (eg duloxetine) more selective than the TCAs in terms of which receptors they target?
Posted by Peter S. on January 2, 2003, at 14:53:26
In reply to Cymbalta/Duloxetine news?, posted by Peter S. on December 31, 2002, at 21:25:29
These drugs seem to have exactly the same mechanism (nor. and ser. reuptake inhibition), so since I don't respond to Effexor it seems that there is less of a chance of responding to Cymbalta. But then again, who knows?
They say studies have shown people responding to Cym WITHIN ONE WEEK so maybe they are different in some way.
Posted by highanxiety on January 2, 2003, at 15:32:22
In reply to Cymbalta vs Effexor, posted by Peter S. on January 2, 2003, at 14:53:26
Will there be a weight gain issue with these new ads? does anyone know yet?
Posted by Shawn. T. on January 2, 2003, at 22:08:16
In reply to I do believe in norepinephrine, posted by linkadge on January 1, 2003, at 9:48:04
I made a web page for this post rather than list all of the references in the message: http://www.neurotransmitter.net/nedepression.html ... I'm not sure how difficult my arguments might be to understand, but they're a general overview of what I know about the connections between unipolar depression and norepinephrine. Note that Cymbalta/duloxetine is much more selective than TCA's for the norepinephrine and serotonin transporters. The question that I pose is whether or not that is selective enough.
I find the fact that norepinephrine reuptake inhibitors are effective antidepressants to be intriguing given the fact that people with unipolar depression typically exhibit unusually high measures of norepinephrine activity. In responders, antidepressants in general tend to decrease the levels of a norepinephrine metabolite called MHPG, which is a general indicator of overall norepinephrine turnover. I looked into this, and the common denominator when it comes to antidepressant drugs seems to be their ability to reduce the responsivity of CRF neurons to stress (see Stout et al., 2002). They do not decrease the expression of CRF under normal conditions, so the effects are specific to conditions where the CRF neurons would be activated in response to stress. The fact that drugs that inhibit the reuptake of norepinephrine exhibit this activity seems to be a result of their ability to down-regulate beta-adrenoceptors. I say this because beta-adrenoceptors are located on CRF neurons and cause CRF secretion when activated. Apparently, the unusually high levels of norepinephrine seen in depression are not significant enough to cause the down-regulation of beta-adrenoceptors, but the artificially high levels caused by norepinephrine reuptake inhibiting drugs are significant enough. The cause of the high noradrenergic tone in unipolar depression seems to be, at least in part, due to the excitation of norepinephrine neurons by CRF. The decrease in MHPG, the primary metabolite of norepinephrine, that is often apparent in responders to antidepressants is therefore likely due to a normalization of the activity of CRF neurons. For anyone familiar with CRF, it also indirectly causes the release of the "stress hormone" cortisol among other functions.How do serotonin reuptake inhibitors fit into this scheme of CRF primacy in unipolar depression? SSRI's like Prozac do inhibit the stress sensitivity of CRF neurons, so they are similar to selective norepinephrine reuptake inhibitors in this sense. 5-HT2A receptors are the most likely candidates for serotonin receptors involved in the stimulation of CRF neurons. Increased activation of 5-HT2A receptors as one would expected from increased extracellular serotonin levels will either desensitize of down-regulate them. So SSRI's desensitize 5-HT2A receptors, blocking their ability to cause the secretion of CRF when activated under stressful conditions by serotonin. SSRI's often decrease MHPG with successful treatment, which is, in my opinion, likely secondary to their effects on CRF neurons.
So when you consider the increased efficacy of drugs that inhibit the reuptake of both norepinephrine and serotonin, you are correct in assuming that the combination of mechanisms could enhance the positive neurobiological effects. This is assuming, however, that the cause of depression being treated with this type of drug is due to CRF hyperactivity. Bipolar depression and some types of unipolar depression seem to involve other factors much moreso than CRF and norepinephrine. The real implication of all of this is that CRF antagonists are an ideal choice of antidepressant for people with unipolar depression that involves CRF dysfunction. The CRF theory of unipolar depression seems to hold much more weight than theories involving serotonin or norepinephrine. Note that speaking of HPA axis dysfunction doesn't necessarily imply CRF dysregulation, so those who make their case for CRF- centered theories (Nemeroff seems to be the researcher most convinced) are providing a more specific argument.
As a side note, the subsensitivity of norepinephrine alpha-2 receptors in depression may be a result of CRF's stimulatory effects on norepinephrine release. In other words, persistent activity due to CRF at alpha-2 receptors could decrease their responsiveness to norepinephrine. The significance of this subsensitivity is more evident if you consider the fact that the activation of alpha-2 receptors has a generally inhibitory effect on the HPA axis (but not CRF). So the desensitization of alpha-2 receptors decreases the brain's ability to counteract some of the effects of stress. Cortisol seems to cause both the down- and up- regulation of alpha-2 receptors depending on how long levels remain abnormally high, which would probably explain why people with unipolar depression can exhibit either extreme.
Shawn
Posted by Ritch on January 3, 2003, at 10:16:35
In reply to Re: I do believe in norepinephrine (and CRF), posted by Shawn. T. on January 2, 2003, at 22:08:16
> As a side note, the subsensitivity of norepinephrine alpha-2 receptors in depression may be a result of CRF's stimulatory effects on norepinephrine release. In other words, persistent activity due to CRF at alpha-2 receptors could decrease their responsiveness to norepinephrine. The significance of this subsensitivity is more evident if you consider the fact that the activation of alpha-2 receptors has a generally inhibitory effect on the HPA axis (but not CRF). So the desensitization of alpha-2 receptors decreases the brain's ability to counteract some of the effects of stress. Cortisol seems to cause both the down- and up- regulation of alpha-2 receptors depending on how long levels remain abnormally high, which would probably explain why people with unipolar depression can exhibit either extreme.
>
> ShawnShawn, thanks for that information. For some reason, I get rage reactions from meds (or their metabolites) that antagonize the alpha-2 adrenoreceptors. Is there a mechanism that involves the a2 receptors/CRF, etc. to explain that?
thanks in advance, Mitch
Posted by Shawn. T. on January 3, 2003, at 17:33:45
In reply to Re: I do believe in norepinephrine (and CRF) » Shawn. T., posted by Ritch on January 3, 2003, at 10:16:35
You're welcome. I believe that several studies have linked increased levels of MHPG to agressivity. Alpha-2 antagonists increase MHPG, or general rates of norepinephrine turnover. The activation of alpha-1 adrenoceptors has been linked to heightened aggression. I believe that the increased norepinephrine tone secondary to alpha-2 antagonism leads to activation of alpha-1 receptors. Unlike beta-2 adrenoceptors, the responsiveness of alpha-1 receptors increases after treatment with drugs that increase levels of extracellular norepinephrine. I don't believe that alpha-1 induced aggression involves involves CRF. It's tough to speculate on how alpha-1 activation might lead to aggression/rage; I suspect that they may have excitatory actions on hypothalamic neurons mediating the control of aggressive behavior.
Posted by Noa on January 3, 2003, at 18:36:00
In reply to Re: I do believe in norepinephrine (and CRF) » Ritch, posted by Shawn. T. on January 3, 2003, at 17:33:45
Boy, I wish I understood this stuff!!
Posted by Ritch on January 3, 2003, at 18:36:33
In reply to Re: I do believe in norepinephrine (and CRF) » Ritch, posted by Shawn. T. on January 3, 2003, at 17:33:45
Thanks for the response. The ones that have caused the worst rages have been Remeron, Buspar's metabolite (without an SSRI) and Wellbutrin (although a2 antagonism isn't noted with it). Psychostimulants haven't triggered any rages. Diazepam and higher dose doxepin have in the past as well.
Posted by johnj on January 5, 2003, at 16:48:29
In reply to Re: I do believe in norepinephrine (and CRF) » Ritch, posted by Shawn. T. on January 3, 2003, at 17:33:45
HI Shawn:
Thanks for the information. Eventhough I have a biology undergrad degree it is hard to follow. I had a point/question for you. I take a TCA and even when I felt the most recovered I had quick temper. I had a temper like this before the illness, but after practicing martial arts I became very mellow. After not practicing for 3 years and then having a panic attack followed by depression I notice this temper when my AD is working well. When I am feeling down or nervous I become more closed. I was hoping to switch to Cymbalta due to my TCA not allowing me to work out.
Do you think a TCA could use something to calm the temper/aggressive aspect? I have not had an aggression problem on remeron(just too spaced so I quit). I am wondering if buspar would do anything at all? Thanks
johnj
Posted by Shawn. T. on January 5, 2003, at 23:28:08
In reply to Re: I do believe in norepinephrine (and CRF) » Shawn. T., posted by johnj on January 5, 2003, at 16:48:29
I'm sure that there exist certain susceptibility factors that could make a person more likely to experience antidepressant- induced aggression. I really have no idea about what the best method to counteract the problem might be, but I can give you some suggestions. Serotonin reuptake inhibitors desensitize the 5-HT1A receptors that Buspar exerts its primary mechanism of action at, so combining Buspar with a TCA or duloxetine would likely provide side effects without relief. I wouldn't advise that you try a benzodiazepine because of their side effects (effects on memory, addiction, etc.), but they would probably do the job. You could try alternative medicine; I know that ginseng has been shown to reduce aggressive behavior in mice (do a medline search for verification). Ginseng generally doesn't have any side effects, so it would probably be a good place to start. A standardized extract of Korean or American ginseng would probably be your best bet. One study found that gingko reduced aggression in MAO-A deficient mice, but it's difficult to say how that effect could translate to treating aggression in humans with drug- induced increases in extracellular serotonin and norepinephrine. Gingko may interact with drugs that thin the blood, but it's relatively side effect free otherwise. Another plus from taking ginseng or gingko that you might find with TCA's is a reversal of the potential adverse memory effects from their anticholinergic effects. You mention that you were 'spaced' on Remeron; I didn't have that problem when taking it with Wellbutrin, but I did experience it a bit on Remeron alone. Taking extracts of ginseng and gingko seems to prevent those effects in my case at least. Hope that helps,
Shawn
Posted by Dr Tara on February 25, 2003, at 19:43:26
In reply to Cymbalta vs Effexor, posted by Peter S. on January 2, 2003, at 14:53:26
Though Effexor and Cymbalta are both "dual action" in that they both affect the serotonin and the norepinephrine systems, they are not identical in action. Effexor, at lower doses, only affects the serotonin system; the norepinephrine effect occurs only at higher doses. Cymbalta (duloxetine) has a more balanced effect on the two systems. There is also some evidence that Cymbalta does a better job of treating those who have both chronic pain and depression.
Posted by Jack Smith on February 26, 2003, at 0:22:50
In reply to Re: Cymbalta vs Effexor, posted by Dr Tara on February 25, 2003, at 19:43:26
Posted by SLS on February 26, 2003, at 19:56:10
In reply to If Cymbalta is so good, why isnt it out yet? (nm), posted by Jack Smith on February 26, 2003, at 0:22:50
Hi jack.
The FDA issued Eli Lilly what is called an "approvable letter". I think this means that the drug has met the requirements for safety and efficacy for the indication it was applied for. It is usually the intent of the FDA to approve it pending issues involving the wording of the label "package insert" and manufacturing.
I spoke to a customer service representative and a clinical investigator at Lilly about the release of Cymbalta. Neither was able to fix a date, only that it should be this year. I bet it becomes available within the next 3 months. I hope so. It's the drug I would like to try next.
- Scott
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