Posted by jrbecker on August 24, 2004, at 10:53:08
In reply to Re: selegiline transdermally » jrbecker, posted by SLS on August 24, 2004, at 7:15:59
> > > perhaps the selegiline patch (more MAO-B, less MAO-A inhibition) might be a better fit for you if and when it comes out in early 2005.
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> Do you think the transdermal delivery of selegiline confers a more potent antidepressant performance to the drug?
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> I tried the oral form, but only up to a dosage of 30mg. I found it to be without any effect, positive or negative. Historically, selegiline has not been considered very effective as an antidepressant. I am a bit disbelieving to here that it is so for so many treatment-resistant cases. But then again, look at Seroquel. It was first thought to be a crappy AP, but it is being used more and more with success, especially at higher dosages.
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> - Scott
wow, I could only handle 5 mg daily without totally feeling out of my mind. tolerance is completely individual i guess.yes, I absolutely do believe that the transdermal medium will equate to a better antidepressant effect -- if by what you mean by this is that MAO inhibition [both A & B] in the brain is much more efficient by dosage level. This is for two reasons: 1) liver metabolism is limited and thus, metabolite conversion is decreased, and 2) more steady-state plasma levels offered by the more consistent medium of transdermal administration.
Some used to debate whether the true antidepressant effects came from the amphetamine-like metabolites themselves. And indeed individuals who take low oral doses and report positive effects from it are probably benefiting from the metabolite effects and MAO-B inhibition alone (more the former). On the flip side, most of its negative psychiatric side effects (e.g., speediness, insomnia, irritability, etc) comes from these metabolite effects as well. The good news is that most of the robust antidepressant effect is demonstrated by MAO-A itself. This was confirmed in this study of oral vs. transdermal selegiline in rats...
" Results demonstrate that (a) selegiline is effective as an antidepressant in the forced-swim test after both oral and transdermal delivery; (b) the antidepressant-like effect of selegiline requires greater than 70% inhibition of MAO-A activity, and inhibition of MAO-B in the absence of MAO-A inhibition was ineffective; and (c) the transdermal delivery of selegiline is 10–20 times more potent (on a mg/kg basis) than oral selegiline in producing both its antidepressant-like effect and inhibiting cortical MAO-A compared to the oral administration of selegiline.It is now widely accepted that MAO-A inhibition is required for clinical improvement in depressed patients following the administration of selegiline [3, 14, 15, 16, 27 and 30], but the contribution of metabolites to this effect is equivocal. First-pass metabolism of selegiline is substantial, is mediated by the hepatic cytochrome P450 system, and does not result in racemization; major metabolites include desmethylselegiline, methamphetamine, and amphetamine [11]. In addition, MAO-B inhibition leads to a decreased metabolism and increased accumulation of phenylethylamine (PEA), an amphetamine-like compound [4, 6, 10, 22, 24, 28 and 30]. Several reports suggest that oral, intraperitoneal, and subcutaneous administration of selegiline can result in sufficient circulating levels of amphetamine and PEA to influence general locomotor activity in open-field tests and cognition in the water maze. Engberg et al. [7] demonstrated that general locomotion increased significantly in a dose-dependent manner by selegiline, an effect that was completely blocked by prior administration of proadifen hydrochloride, an inhibitor of microsomal liver enzymes. Similarly, Okuda et al. [21] demonstrated that the effects of selegiline on both locomotor activity and brain dopamine levels resembled those of amphetamine, and could not be attributed to MAO-A inhibition, while Head and Milgram [10] attributed the effects of selegiline on stereotypic and exploratory behavior to the production of amphetamines or accumulation of PEA. In addition, Gelowitz et al. [9] demonstrated that both selegiline and amphetamine enhanced learning the Morris water maze, and that the improvement in cognitive performance was unrelated to MAO inhibition.
Although evidence suggests that the locomotor and cognitive effects of selegiline may be attributed to its metabolites or to the accumulation of PEA, few studies have investigated the relationship among selegiline metabolism, MAO inhibition, and the antidepressant-like effects of this compound. Both amphetamine and PEA have been shown to produce mood elevation, although it is unlikely that the latter reaches sufficiently high levels to produce this effect following MAO-B inhibition [3 and 22]. Fozard et al. [8] compared the effects of selegiline with another MAO-B inhibitor [(E)-2-(3,4-dimethoxy-phenyl)-3-fluoroallylamine HCl, MDL 72145] in the forced-swim test and demonstrated that although both compounds produced equivalent inhibition of MAO-B, only selegiline decreased immobilization times. In addition, this behavioral effect was manifest following a dose of selegiline that did not alter MAO-A activity, suggesting that the antidepressant-like action of selegiline was unrelated to enzyme inhibition. Interestingly, based on the ability of selegiline, but not the other MAO-B inhibitor, to reverse reserpine hypothermia and stimulate blood pressure and heart rate, effects that could be mimicked by the administration of amphetamine, these authors suggested that the antidepressant-like effects of selegiline may be attributed to its sympathomimetic metabolites [8]. Results from the present experiments do not support this idea. Rather, results suggest that the antidepressant-like effects of selegiline are a consequence of MAO-A inhibition and do not involve actions of the metabolites. Studies have shown that the STS provides consistent plasma levels of selegiline (minimal peak-trough fluctuations), increases the amount of drug in plasma delivered to the brain, and decreases metabolite production compared to oral administration [2 and 25]. Indeed, plasma levels of amphetamine and methamphetamine, determined 24 h following a single oral dose of 30 mg/kg selegiline to rats, were 15.4 ± 3.87 and 12.2 ± 2.72 ng/ml (mean ± SEM, n = 3), respectively, whereas there were undetectable levels of amphetamine and methamphetamine in plasma from rats who had received a single patch application, even at doses twice that used in the present study (unpublished results). Thus, transdermal application of selegiline bypassed first-pass metabolism. "
Now the second interpretation to your question of whether transdermal selegiline will be a potent antidepressant is if you're asking simply how this drug stacks up against other MAO-Is (e.g., the gold standard: Nardil) or even SNRIs like Effexor or Cymbalta. For this I have no answer, I remain somewhat skeptical as I mentioned before. This is because in one big study trial, the selegiline patch was seen as pretty good in comparison to placebo for treatment-resistant depressive (TRD) types. However, a slightly larger follow-up study showed only modest benefits. So who knows what to conclude. But here are some positive caveats to keep in mind...1) these trials only studied a 20mg dose of transdermal selegiline. 20mg is now considered the low-end of the dosage window. The company is expected to offer dosage levels of 20-40 mg.
2) the subjects in the trials were the very worst-off of depressive sufferers. In terms of admission criteria, subjects had to have a HAM-D rating of 20 pts or higher (in one study the avg was about 23 pts). Now, compare this with most drug trials (such as for cymbalta, effexor, or past SSRI trials), and the admission criteria of a HAM-D rating score is only greater than 15, so the avg overall rating score is much lower than 20 pts for these drug trial subject pools.
So the point is, in a trial like this, where the drug is specifically for treatment-resistant depression, the results have to tempered with the fact that the subject pool is much more worse-off.
3) Drug trial methodology has with it some serious limitations. I can go off on a rant about this forever, but I thought I'd give one good example. Take the HAM-D 17 point checklist scale, the most frequently used depression scale in drug trials. Now, if you look at the symptom measures in the scale itself, most of the questions are related to melancholic depressive symptoms (an updated scale has recently accomodated a couple measures for atypical symptoms regarded to sleep and appetite). And overall, the scale is an assessment of functionality, not affect. OK, so then take this scale and test it against the experimental drug (selegiline), which might cause insomnia, loss of appetite, or perhaps a slight anxiety increase.... all this despite the fact that it has good antidepressant utility. So the scale sometimes does not speak directly to antidepressant effect itself. Other scales are a little better at this and are being used a little more, such as the Montgomery-Abel. This scale was also used in the trial. The Beck inventory is more cognitive in its questionining and gets more to the psychological functioning of the subject.
Anyways, I'm ranting, but hopefully you see my point.
Bottom line, will it be the next Nardil? No, definitely not. Will a subset of the atypical depression population see this as a better option, not only in terms of antidepressant effect, but also in terms of side effect profile when in comparison to the trycyclics and other modern classes? Yes. Will you and I be in that subset where the tradeoff of antidepressant effect and side effect tolerance is to our favor over other current options? Don't know.JB
see also:http://ajp.psychiatryonline.org/cgi/content/full/159/11/1869
http://www.psychiatrist.com/privatepdf/2003/v64n02/v64n0216.pdf
poster:jrbecker
thread:381095
URL: http://www.dr-bob.org/babble/20040821/msgs/381683.html