Posted by Tomatheus on December 24, 2005, at 3:51:45
In reply to Re: Selegiline, posted by RobertDavid on December 24, 2005, at 0:06:20
> He claims that with the patch delivery not only are the side affects and food restrictions significantly reduced, but it works much better for both anxiety and depression. I've wonered why it the same drug would be so different with patch delivery vs oral, but that's what he says and what I have heard from others. We'll see.
RobertDavid,
I'm definitely no expert in psychopharmacology, so please keep in mind that my thoughts on this topic should be taken with a grain of salt. But if I were a researcher or a doctor, I would hypothesize that the Emsam patch will likely be both more effective and more tolerable (in terms of side effects) than oral selegiline because it has been shown to be much more consistent in its inhibition of MAO (types A and B) than the pill form. According to a graph on page 5 of Dr. Gregory M. Dubitsky's (2005) PowerPoint presentation on Emsam's tyramine safety, the selegiline blood concentration reaches 2000 pg/mL within an hour after 10mg of the drug is administered in its pill form, and then the concentration appears to sharply drop off until it reaches 0 pg/mL after six hours. With 20mg x 20 sq cm of Emsam, however, the selegiline blood concentration only varies slightly; it remains relatively close to 1000 pg/mL from the moment it is administered until the patch is due to be removed 24 hours later (Dubitsky, 2005).
I don't have any hard data to support what I am about to say next, but I am beginning to suspect that the brain's serotogenic, noradregenic, and dopaminergic systems actually adjust the production rates of their respective neurotransmitters to compensate for changes in MAO-A and MAO-B activity. So, if my suspicion is correct, inhibiting MAO-B for example, would allow more dopamine to be *released* (since MAO-B is located *inside* dopaminergic neurons). Then, as more dopamine accumulates in the synapses at the times when it is *released*, it triggers the feedback mechanisms that control the *production* of dopamine, and less is produced as a result. So, in my view, MAO inhibition allows the brain to release more neurotransmitters at the times when it is supposed to (e.g., when environmental stimuli prompt it to) instead of relying more heavily on constantly creating more neurotransmitters. With every MAOI that I have tried (moclobemide, Parnate, and Nardil), I've always noticed mood elevations immediately after starting the drugs and after dose increases. Based on messages posted on this board, it appears that others have had similar experiences with MAOIs. What I suspect happens during these periods of mood elevation is that the drugs inhibit MAO at a relatively fast rate while the neurotransmitters are still being produced as quickly as they were before the MAO inhibition took place. So, with new, higher levels of neurotransmitter *release* and non-adjusted levels of neurotransmitter *production*, synaptic neurotransmitter levels are high, and mood elevation takes place. Eventually, though, the neurotransmitter feedback systems kick in, and neurotransmitter production levels adjust themselves to compensate for the higher level of neurotransmitter release triggered by MAO inhibition. If more MAO is inhibited each day over a period of several weeks as it is with Nardil and Parnate, neurotransmitter production levels keep adjusting themselves until the level of MAO inhibition begins to flatten out. It is often around this time that the "true" effects of MAOIs begin to be felt (at least at the given dose).
Now, keep in mind that everything I described in the previous paragraph is highly speculative. So, the viability of my hypothesis depends on the validity of the ideas that I just described above, which very well may not hold much water. But if there is some truth to what I described in the previous paragraph, inhibiting MAO-A and MAO-B at a consistent level would be critical to the effectiveness of MAO-inhibiting drugs. If the level of MAO inhibition varies considerably over a 24-hour period, then it is doubtful that neurotransmitter production levels would ever be able to properly adjust themselves. Although moclobemide, a reversible inhibitor of MAO-A, has been found to be as effective as SSRIs in comparative research studies, real-world reports from doctors and patients (including here on this board) suggest that the drug is relatively ineffective in practice. Even in the comparative research studies, it has been found to be less effective than both Nardil and Parnate (Lotufo-Neto et al., 1999). There are obviously a lot of factors that could be used to explain moclobemide's relative lack of effectiveness, but I have suspected for some time that the drug's inconsistency in its MAO-A inhibition is a big part of the reason why it tends not to be very effective. Moclobemide is rapidly absorbed after it is taken, and the drug reaches its maximum plasma concentration within an hour (Nair et al., 1993). The drug is also rapidly eliminated from the body, and its inhibition of MAO-A typically lasts no longer than eight to 10 hours (Nair et al., 1993). On the other hand, MAO-A and MAO-B levels typically take about two weeks to return to 100 percent after the administration of a single dose of Nardil or Parnate. Even with Nardil, one of the complaints about the "new" Pfizer formulation has been the bioequivalency test only demonstrated that Pfizer reached the bloodstream in a timely fashion. It did not demonstrate whether or not plasma levels of the "new" Nardil were just as consistent (over time) as those of the "old Nardil."
So, we know that moclobemide tends to be less effective than the irreversible MAOIs (Nardil and Parnate), and we also know that it does not inhibit MAO-A as consistently as the irreversible drugs. From what I've read, there also seems to be a consensus that the "new" Pfizer formulation of Nardil is generally less effective than the "old" formulation. Of those who have taken both formulations, some have said that the "old" formulation was clearly more effective than the "new" one, and others have said that there is little to no difference. I have yet to read a report from someone who actually found the "new" Nardil to be superior to the "old" Nardil. So, in addition to knowing that some individuals have found the "old" Nardil to be superior to the "new" Nardil (but not vice versa), we are now also aware of the possibility that the inactive ingredients of the "new" Nardil may not allow phenelzine to inhibit MAO-A and MAO-B as consistently as the "old" Nardil did (of course, this needs to be confirmed). Finally, we know that some doctors have said that the Emsam patch is supposed to be more effective at treating depression and anxiety than oral selegiline, and we also know that the plasma concentration of selegiline is much more consistent when the drug is taken in patch form than in pill form. So, what I'm beginning to see is a positive correlation between consistency of MAO inhibition and effectiveness. Does this mean that consistent MAO inhibition actually *causes* a drug to be more effective? Of course not. My hypothesis obviously needs some hard data to support it, but I think it's something to consider.
Before I finish (I know, it seems like this message will never end), I would like to point out that I am somewhat skeptical of Emsam's potential as an antidepressant. Even though I like the idea of delivering an MAO-inhibiting drug to the bloodstream via a transdermal patch (because of the fact that it allows for greater consistency of MAO inhibition than pill form), selegiline is still primarily an MAO-B inhibitor. It is believed to lose some of its selectivity for MAO-B at higher doses, but the fact remains that it still inhibits MAO-B more than it does MAO-A. Even though some individuals may benefit from Emsam's relative preferentiality to MAO-B, the results of research studies support the idea that MAO-A is more central to antidepressant activity than MAO-B (Thase et al., 1995). Should this dissuade a treatment-resistent depressive from trying Emsam? Of course not. It does hold a lot of promise. I may even try it myself, depending on how I ultimately respond to Nardil. But I have my doubts.
Tomatheus
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REFERENCES
Dubitsky, G. M. (2005). Tyramine safety with Emsam. Retrieved Dec. 9, 2005, from http://www.fda.gov/ohrms/dockets/ac/05/slides/2005-4186S2_02_FDA-Dubitsky.ppt
Lotufo-Neto, F., Trivedi, M., & Thase, M. E. (1999). Meta-analysis of the reversible inhibitors of monoamine oxidase type A moclobemide and brofaromine for the treatment of depression. Neuropsychopharmacology, 20, 226-47.
Nair, N. P. V., Ahmed, S. K, & Ng Ying Kin, N. M. K. (1993). Biochemistry and pharmacology of reversible inhibitors of MAO-A agents: Focus on moclobemide. Journal of Psychiatric Neuroscience, 18, 214-25.
Thase, M. E., Trivedi, M. H., & Rush, A. J. (1995). MAOIs in the contemporary treatment of depression. Neuropsychopharmacology, 12, 185-219.
poster:Tomatheus
thread:588813
URL: http://www.dr-bob.org/babble/20051221/msgs/591806.html