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Re: Selegiline MAOI patch rejected by FDA » Adam

Posted by Elizabeth on April 10, 2002, at 11:18:01

In reply to Re: Selegiline MAOI patch rejected by FDA, posted by Adam on April 8, 2002, at 20:25:08

> >I thought that high-dose selegiline was about as effective as the other nonselective, irreversible MAOIs...
>
> That's just the point I was making. In Bodkin's Phase II study, I think the STS looks more impressive still (http://www.mhsource.com/pt/p010525.html).

I just didn't see any reason why it'd be *less* effective. I guess that both Nardil and Parnate have some "extra" effects in addition to MAO inhibition -- Nardil a GABA effect, Parnate an amphetamine-like one -- but I don't know about other MAOIs like Marplan, Marsilid, nialamide, etc. (I'm not convinced that there's anything useful about the L-amphetamine metabolites of selegiline.)

I seldom have trouble tolerating medications, but I got a bad case of the jitters from high-dose selegiline (p.o.) so it does surprise me that so many people completed the study. OTOH, I wasn't doing too well in general when I tried selegiline (I'd recently discontinued Nardil and was experiencing protracted withdrawal), and that could have made a difference. Something to consider if I ever have to ditch the Effexor. (I hope very much that I don't; I really dislike the medication merry-go-round.)

> > Do you know what the ratio of oral dose to equivalent transdermal dose is?
> >
> All the references I have seen point to a big difference. In this study, they say it's about 1:50, for instance: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9089426&dopt=Abstract

Huh. I wonder what the ratio is for producing equivalent AD effects. If it's anywhere close to that, then oral selegiline isn't such a viable AD after all! But we know that some people do respond to oral selegiline without the pressor effects becoming a problem, so maybe the metabolites do contribute something -- other than side effects, that is. On the other hand, MAO-A and -B inhibition has to be about 100% with the 20 mg/day patch, but how high are they at various oral doses? There are lots of things going on with this -- it's pretty confusing.

> I don't have any concrete numbers. The time oft quoted to me has been as little as a week for full remission. Bodkin mentions rapid onset of effect in this hearbreakingly optimistic article: http://www.news.harvard.edu/gazette/1998/12.10/depression.html

Yeah, a week or so was what I heard, too. I wonder how long the trial lasted -- was it the usual 6-8 weeks? Hmm....

> My guess (and this is only a guess) is that active drug exclusion (maybe P-glycoprotein or some similar culprit) keeps circulating selegiline out of the gut lining. I mean, there's obviously a directionally-selective membrane somewhere in there or lots of stuff would just leak out of you by simple osmosis. Maybe at higher doses this barrier is overwhelmed.

That seems reasonable. Lots of things are like that: effects at high concentrations become very unpredictable. (Heck, at a high enough concentration, anything will bind to any receptor! So it's not hard to imagine that high enough concentrations of a drug can reach places that lower concentrations don't get to in significant amounts. Of course, I'm waving my hands here.)

> Well, that's what sucks about this. I don't think selegiline is on an even footing with other AD's though, for the reasons I mentioned.

Probably not. Still, I think that if the patch offers the capacity for much higher serum concentrations than are possible with oral selegiline, that's very significant and ought to be considered.

> >(The FDA is) also very corrupt, of course.
> >
> I'm not at all disputing this, I just wonder if you know of some specific examples of this corruption, for my own curiosity.

Not off the top of my head, no. It's basically a revolving door, though: the FDA employs people who have ties to the drug industry, and people working for the FDA often move on to work in the drug industry.

> >I'd expect (MAOIs) to have higher success rates than the other ADs.
> >
> The way some doctors talk, they do. However, when I read about them, I inevitably come across the statement "MAOIs are no more effective than other antidepressants..." yadda, yadda. I guess it's safest to be agnostic on that point.

That's how I feel too. And yet...well, you know.

> One might use the logic that since they seem to work for some people who are refractory to all other drugs, AND they are also likely to work for a good portion of the people who aren't so refractory, hence they are better overall. This line of thinking can't be completely right; however, I don't know how wrong it is.

My thought is, they work especially well (better than TCAs, at least) for "atypical" depressions; and they work for other depressions about as well as other ADs (as far as I know); therefore they should work better overall. This should work if atypical depressions constitute a significant proportion of all depressions (refractory depressions may be much rarer). Of course, there's also the possibility that MAOIs work less often in non-atypical depression, but there has been very little research on this subject. (It's certainly not consistent with my experience or impressions, although I think most people who have "classic" depression never reach the point of trying MAOIs.)

> Well, I found my own banana-peel addiction difficult to overcome, and would hate to trivialize the plight of the banana-peel addict. However, as a recovering banana-peelaholic, I can personally say giving them up made me a better man.

Hmm. Perhaps we should try and start a BPA group? Or maybe selegiline can be used to treat banana peel addiction?

> > That's not a very representative sample!
>
> I'm speculating wildly here. However, from my own experience, and from posts I've seen on this board, it's clear that some people who entered an STS study did so because they had exhausted many other options and it was time to give an MAOI a try (the STS being a relatively pain-free way to do this).

I think that's often true in clinical trials, yeah. It's a problem, although I don't really know how to solve it (without screwing up the whole system of clinical drug research, that is). The fact is that people for whom other things haven't worked are a great source of research subjects, and I'd hate to deny them access to experimental drugs. Yet a subject pool consisting mostly of refractory subjects is unlikely to do much better than placebo. Of course, the placebo arm would also consist of refractory depressives -- a group with a notoriously low placebo response rate. Also, it's true that a study of selegiline, a drug with more potential risks than numerous available ADs, might be expected to attract mainly refractory depressives. It might get a better response rate for the other indications; cocaine addiction, in particular, is something that has proven practically impossible to treat reliably, and it probably won't be hard to do better than placebo there (assuming the stuff actually works).

> I think it's generally true that a good percentage of the people who want to get into a clinical trial do so because they've not found success with the proven options and are willing to take some risks.

I don't doubt it. Of course, I've been in that situation and I was never willing to take the risk! (The risk I was worried about was the risk of being stuck in the placebo arm, not the risk of adverse effects. Also, a lot of the time, the researchers require you to be off all other medications in order to participate in a clinical trial.)

> I imagine after Phase I and Phase II studies, when good safety info. is available, and efficacy is already demonstrated, risk aversion is diminished; a wider pool of candidates presents. Perhaps this is also a less "self-selecting" pool. Plus your n is bigger, and that certainly can lead to changes in the numbers.

But these were Phase III studies, no? (I wonder how many sites there were and what the n was.)

-elizabeth


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poster:Elizabeth thread:100963
URL: http://www.dr-bob.org/babble/20020408/msgs/102621.html