![[dr. bob]](/dr-bob-sm.gif)
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 25 of 25. This is the beginning of the thread.
Posted by King Vultan on August 22, 2004, at 23:11:12
After being off Nardil for almost two weeks now and having more or less returned to normalcy (for me, anyway), I have a few observations to offer:
1) The stuff really is very good for social phobia/anxiety. My social phobia was perhaps 90% eliminated, and I have never felt as sociable as I did while on it.
2) Nardil IMO is clearly superior to the SSRIs as far as avoiding emotional blunting and apathy, presumably because its MAO-A inhibition has a powerful effect on both serotonin and norepinephrine. My opinion is that the SSRIs seem to leave the norepinephrine system behind in the dust to atrophy--not a good thing.
3) I think that too much Nardil is not necessarily a good thing, either, as I was starting to feel some of the negative effects on emotionality and spirituality that I traditionally attribute to SSRIs at dosages of 90 and 105 mg/day of the Nardil. Perhaps part of the reason was that the enormous amount of serotonin evidently being made available was excessively depleting dopamine. Of course, the amount of dopamine available was also unusually large because of Nardil's MAO-B inhibition, but serotonin unfortunately always seems to win this battle. If I had to do it over again, I think I would have stayed at 75 mg/day.
4) Speaking of serotonin and dopamine, this drug is clearly very, very similar to the SSRIs in terms of sexual side effects. I experienced a profound loss of libido worse than any other drug I have taken, combined with delayed orgasms (for me, this is not necessarily a bad thing, though). In defense of Nardil, I made it up to the maximum recommended dose and slightly beyond, but was never able to get anywhere close to a full therapeutic dose of an SSRI such as Zoloft. If I had been able to, maybe I would have experienced the same thing.
5) This is only the second drug I can report that definitely induced weight gain, the other one being Zoloft, on which I gained perhaps 5 pounds over a period of years due to an increase in appetite. On Nardil, I gained no less than 9 pounds in two months, and once I realized this was basically able to do no better than hold my own despite dramatically increasing my exercise--I was running over 20 miles a week--and carefully considering every calorie consumed. I cannot say that the Nardil really had much of an effect on my appetite and am forced to conclude that the culprit was some weird metabolic mechanism beyond my comprehension. During the two weeks of tapering the drug and the two weeks of washout, most of the weight has magically just melted off, this despite my decreasing my running closer to what I was doing pre-Nardil. The reputation Nardil has for inducing weight gain seems to be well deserved, from what I can see.
6) I tapered off this drug starting at a level of 7 x 15 = 105 mg/day and dropping 1 pill every three days. I am reasonably tough and tolerate withdrawal symptoms fairly well but would not suggest anyone exceeding this rate of decline. Those who are sensitive to withdrawal effects would probably be advised to not taper off any faster than one pill a week.
In my case, when I got down to about 45 mg/day, I experienced this blasted REM Rebound Syndrome that I was not even aware existed. The net effect is a lot of vivid dreaming, tossing and turning, and insomnia. I had started alternating Benadryl one night and Halcion the next while on Nardil to combat the severe insomnia it induced; the effects of this REM rebound thing totally overpowered my sleeping meds and was substantially worse than the actual Nardil insomnia.
I also experienced the usual weird tinnitus and vertigo I typically get during Effexor withdrawals and also experienced an intense hunger in the first week after getting down to zero (from my body's metabolism perhaps speeding back up to normal and demanding more food?--heck if I know). However, in the last week, I've been battling some significant nausea problems. It seems like my sense of smell has improved, and I have also become significantly more squeamish. I recall a very similar thing happening to me when I first started Wellbutrin and am wondering if this is somehow dopamine related. Clearly, my dopamine levels have risen, judging from my increased--though still mediocre--libido. I know that dopamine is involved with smell, as Parkinson's patients have a tendency to lose their sense of smell, and I know that dopamine agonists also tend to cause nausea. Well, the point is probably just an academic one, anyway.
Todd
Posted by chemist on August 22, 2004, at 23:43:04
In reply to Nardil Observations, posted by King Vultan on August 22, 2004, at 23:11:12
todd, chemist here.....thank you for a very complete report. i had success with parnate a while back, and it remains (with only luvox in second place) the first choice for me. i did not expereience weight gain, although i exercise quite vigorously, and eat a largely vegan diet, so that's not a surprise. libido was not overly comprimised, although that's my opinion: my girlfriend at the time is probably a better judge, in reality :)...but i do value your posts, and this in particular, in that should my present meds need a switch in the AD department, i will take your, Ace's, Panda's, and GG's experiences with Nardil to heart.......thanks much, all the best, chemist
Posted by SLS on August 23, 2004, at 2:39:14
In reply to Re: Nardil Observations » King Vultan, posted by chemist on August 22, 2004, at 23:43:04
Hi Chemist.
Can you describe in what ways you found Luvox helpful?
Thanks.
- Scott
Posted by Sad Panda on August 23, 2004, at 6:17:01
In reply to Nardil Observations, posted by King Vultan on August 22, 2004, at 23:11:12
Hi Todd,
Nice report, just one question:
Since both MAO-A & MAO-B metabolize dopamine, while serotonin & norepinephrine are only metabolized by MAO-A, wouldn't that mean that Nardil, Marplan & Parnate all raise dopamine levels more than serotonin & norepinephrine levels?
Cheers,
Panda.
Posted by chemist on August 23, 2004, at 6:20:08
In reply to Re: Nardil Observations, posted by SLS on August 23, 2004, at 2:39:14
> Hi Chemist.
>
> Can you describe in what ways you found Luvox helpful?
>
> Thanks.
>
>
> - Scotthi scott, a pleasure of course.....a little history: about 10 years or so ago, panic attacks, GAD, insomnia, and moderate depression set in. the first psychiatriast i saw - sheer good luck - is a D.O., young guy, and into alternatives just as much as the meds, if need be. i stayed on fluvoxamine (100 mg tid), alprazolam (0.5 to 1 mg qd, prn), and ambien (just out at the time, 10 mg qhs) for roughly 3 years. there was very little therapy component, as not covered by insurance at the time. in any event, the luvox was very successful at the outset for anxiety and panic, although the xanax was undoubtedly to ``blame,'' as well. the depression lifted rather abruptly with the somewhat high dose of luvox that i titrated up to over short time: there was a short (month or so) period of reduction to 200 mg/day (divided), then a slow titration back to 300 mg/day, divided. sleep was handled well by ambien, and xanax use was constant with no escalation. side effects from luvox, which were transient, were the cholenergic variety, and libido was not a problem. i can report that the wide-dosing range (50 to 400 mg/day is common in my psychiatrist's experience) needs to be tweaked, but the 100 to 200 mg range (the latter being my current intake, and now back to same psychiatrist after many moves around the country) is fine for an (almost) 35 year old male, about 160 lbs., decent diet, lots of exercise. the issues addressed most in my experience by luvox are of the OCD variety, mainly panic/anxiety which of course led to decreased depression (or the other way around: not important, as results were achieved). my depression nowadays is more mild and of the variety associated with life events, as opposed to the ``out of the blue'' variety or that associated with physical ailments (the latter not being an issue with me, so far). the luvox is my psychiatrist's personal preference for cases such as mine - he is also a fan of xanax, as am i - and my use of parnate during some intervening years spent in a small town in Mercer County (this should ring a bell for you) was more than exceptional for moderate depression/anxiety, and coupled with therapy. in short, i have found luvox to be a more-or-less broad spectrum AD with pronounced anxiety/panic relief that does not lessen over time, and the AD effects - which i felt were more ``true'' with parnate - are in my estimation a result of the anxiety/panic reduction/management. my psychiatrist is quite proficient with pharmacology and keeps up with the literature, case reports, and new medications. he has been treating patients with luvox for almost 15 years (i have asked specifically about long-term use, success, etc.) and he does admit to having been influenced in the early years by the hype accompanying the first-generation SSRIs. that said, he uses it and xanax frequently, and his case-load is largely comprised of the 25 to 45 year-old graduate student to (i hesitate to use the word) yuppie demographic. i have no complaints, and have added therapy to the mix this time around. do feel free to shoot me an email via babblemail if there are any aspects you'd like to discuss in private (actually, please do, on an unrelated matter, if you would be so kind).....all the best, chemist
Posted by SLS on August 23, 2004, at 7:00:45
In reply to Re: Nardil Observations » SLS, posted by chemist on August 23, 2004, at 6:20:08
> do feel free to shoot me an email via babblemail if there are any aspects you'd like to discuss in private (actually, please do, on an unrelated matter, if you would be so kind).....all the best, chemist
I am not familiar with Babblemail and can't find a link to it. Maybe I should familiarize myself with it. In the meantime, you can drop me a line at:sl.schofield at att dot net
- Scott
Posted by jrbecker on August 23, 2004, at 10:11:42
In reply to Nardil Observations, posted by King Vultan on August 22, 2004, at 23:11:12
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.
> After being off Nardil for almost two weeks now and having more or less returned to normalcy (for me, anyway), I have a few observations to offer:
>
> 1) The stuff really is very good for social phobia/anxiety. My social phobia was perhaps 90% eliminated, and I have never felt as sociable as I did while on it.
>
> 2) Nardil IMO is clearly superior to the SSRIs as far as avoiding emotional blunting and apathy, presumably because its MAO-A inhibition has a powerful effect on both serotonin and norepinephrine. My opinion is that the SSRIs seem to leave the norepinephrine system behind in the dust to atrophy--not a good thing.
>
> 3) I think that too much Nardil is not necessarily a good thing, either, as I was starting to feel some of the negative effects on emotionality and spirituality that I traditionally attribute to SSRIs at dosages of 90 and 105 mg/day of the Nardil. Perhaps part of the reason was that the enormous amount of serotonin evidently being made available was excessively depleting dopamine. Of course, the amount of dopamine available was also unusually large because of Nardil's MAO-B inhibition, but serotonin unfortunately always seems to win this battle. If I had to do it over again, I think I would have stayed at 75 mg/day.
>
> 4) Speaking of serotonin and dopamine, this drug is clearly very, very similar to the SSRIs in terms of sexual side effects. I experienced a profound loss of libido worse than any other drug I have taken, combined with delayed orgasms (for me, this is not necessarily a bad thing, though). In defense of Nardil, I made it up to the maximum recommended dose and slightly beyond, but was never able to get anywhere close to a full therapeutic dose of an SSRI such as Zoloft. If I had been able to, maybe I would have experienced the same thing.
>
> 5) This is only the second drug I can report that definitely induced weight gain, the other one being Zoloft, on which I gained perhaps 5 pounds over a period of years due to an increase in appetite. On Nardil, I gained no less than 9 pounds in two months, and once I realized this was basically able to do no better than hold my own despite dramatically increasing my exercise--I was running over 20 miles a week--and carefully considering every calorie consumed. I cannot say that the Nardil really had much of an effect on my appetite and am forced to conclude that the culprit was some weird metabolic mechanism beyond my comprehension. During the two weeks of tapering the drug and the two weeks of washout, most of the weight has magically just melted off, this despite my decreasing my running closer to what I was doing pre-Nardil. The reputation Nardil has for inducing weight gain seems to be well deserved, from what I can see.
>
> 6) I tapered off this drug starting at a level of 7 x 15 = 105 mg/day and dropping 1 pill every three days. I am reasonably tough and tolerate withdrawal symptoms fairly well but would not suggest anyone exceeding this rate of decline. Those who are sensitive to withdrawal effects would probably be advised to not taper off any faster than one pill a week.
>
> In my case, when I got down to about 45 mg/day, I experienced this blasted REM Rebound Syndrome that I was not even aware existed. The net effect is a lot of vivid dreaming, tossing and turning, and insomnia. I had started alternating Benadryl one night and Halcion the next while on Nardil to combat the severe insomnia it induced; the effects of this REM rebound thing totally overpowered my sleeping meds and was substantially worse than the actual Nardil insomnia.
>
> I also experienced the usual weird tinnitus and vertigo I typically get during Effexor withdrawals and also experienced an intense hunger in the first week after getting down to zero (from my body's metabolism perhaps speeding back up to normal and demanding more food?--heck if I know). However, in the last week, I've been battling some significant nausea problems. It seems like my sense of smell has improved, and I have also become significantly more squeamish. I recall a very similar thing happening to me when I first started Wellbutrin and am wondering if this is somehow dopamine related. Clearly, my dopamine levels have risen, judging from my increased--though still mediocre--libido. I know that dopamine is involved with smell, as Parkinson's patients have a tendency to lose their sense of smell, and I know that dopamine agonists also tend to cause nausea. Well, the point is probably just an academic one, anyway.
>
> Todd
Posted by King Vultan on August 23, 2004, at 12:04:00
In reply to Re: Nardil Observations » King Vultan, posted by jrbecker on August 23, 2004, at 10:11:42
> 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.
>
>Selegiline would probably be the next thing I would ask to try if the Parnate which I will soon be starting does not work out. I can't say I really have any interest in the patch, however, and would just as soon take the drug in pill form. If I'm not mistaken, I think the patch allows freedom from the MAO dietary restrictions, but these are not a big deal to me personally, and I can easily live with them.
Todd
Posted by King Vultan on August 23, 2004, at 12:52:36
In reply to Re: Nardil Observations » King Vultan, posted by Sad Panda on August 23, 2004, at 6:17:01
> Hi Todd,
>
> Nice report, just one question:
>
> Since both MAO-A & MAO-B metabolize dopamine, while serotonin & norepinephrine are only metabolized by MAO-A, wouldn't that mean that Nardil, Marplan & Parnate all raise dopamine levels more than serotonin & norepinephrine levels?
>
> Cheers,
> Panda.
>I don't think this is a conclusion that can necessarily be reached without doing some lab studies. While it is true that MAO-A also metabolizes dopamine, some studies have indicated that selective MAO-A inhibitors have no effect on the concentration of DOPAC, a key dopamine metabolite, whereas MAO-B inhibitors and nonselective MAOIs reduce DOPAC concentrations. The implication is that the latter two types decrease the consumption of dopamine by MAO, causing the amount of resultant dopamine metabolites to fall accordingly. Specifically, it would seem to be MAO-B that is involved, as this is the only type of MAO common to both nonselective MAOIs and MAO-B inhibitors.
Beyond the MAO inhibition issues, it's clear that Parnate raises dopamine levels more than either Nardil or Marplan, judging from Parnate's relative lack of sexual side effects compared to the other two drugs. However, this has nothing to do with MAO inhibition, but rather, Parnate's amphetamine-like structure and stimulant-type effects. As for Nardil, I was frankly a little surprised as to the poor libido and sexual side effects I observed while on it, as I would have thought its MAO-B (and MAO-A) inhibition would have liberated enough dopamine to negate these effects. Such was not the case, though, at least for me.
Todd
Posted by jrbecker on August 23, 2004, at 13:04:08
In reply to Re: Nardil Observations » jrbecker, posted by King Vultan on August 23, 2004, at 12:04:00
> > 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.
> >
> >
>
> Selegiline would probably be the next thing I would ask to try if the Parnate which I will soon be starting does not work out. I can't say I really have any interest in the patch, however, and would just as soon take the drug in pill form. If I'm not mistaken, I think the patch allows freedom from the MAO dietary restrictions, but these are not a big deal to me personally, and I can easily live with them.
>
> Todd
>Todd-
yeah, the initial purpose behind developing the STS [patch form] was indeed to avoid the tyramine dietary restrictions, however, it's now been shown that this medium also limits quite a bit of the other side effects seen with oral ingestion. Most of these bothersome adverse events are due to the amphetamine-like metabolites that build up at higher dosages [see excerpt below]. The patch avoids most of this interaction because of the lack of first-pass metabolism via the transdermal route. I tried oral selegiline myself as an augmentor and found it to be way too "speedy," and actually made my depression worse at times.
I've been in contact with the researchers at Harvard/Penn on the study and they do believe it will have some utility with anergic/atypical types. Some studies have shown fairly good promise with very treatment-resistant depressive types, while some have only had modest results(it should be noted, that these studies only tested with the low dosage level of 20mg. The proposed dosage strengths will now be 20, 30 and 40 mg). Of course, if I've learned anything from all my own research in looking at study trials, it's that the methodology behind these mass-scale studies prove nothing about response for each prospective individual. So until it hits the market I remain skeptical but hopeful.
" This is the first reported clinical trial of transdermally delivered selegiline for the treatment of depression. Several studies have shown selegiline to be an effective and relatively side-effect-free antidepressant when given in high oral doses requiring restriction of dietary tyramine (13–15). We demonstrated that transdermally delivered selegiline, in a dose regimen that appears devoid of clinically significant interaction with dietary tyramine (20, 23–25), offers significantly better therapeutic benefit than placebo in major depression.Transdermal delivery of selegiline provides several pharmacological advantages over oral delivery. First, it sufficiently reduces exposure of the gastrointestinal tract to the drug to limit inhibition of intestinal MAOA activity (21). Thus, adequate gastrointestinal MAOA enzyme is left intact to metabolize dietary tyramine. Second, transdermal administration of selegiline circumvents first-pass hepatic metabolism, which results in sustained high plasma levels of the parent compound with a concomitant decrease in metabolite formation (26). This provides sufficient brain concentrations of selegiline to produce an antidepressant effect, presumably involving substantial MAOA as well as MAOB inhibition. This also may permit the expression of additional pharmacological properties of selegiline other than MAO inhibition previously observed in vitro (27). At the same time, there is less exposure to L-methamphetamine and L-amphetamine metabolites than observed with oral selegiline (26).
Because tyramine restrictions were followed in this initial trial, the risk of a "cheese reaction" could not be assessed. However, oral tyramine challenges in normal subjects after fasting (24) demonstrated that doses of 200 mg or more of oral encapsulated tyramine were required to produce a pressor response. By comparison, when similar tyramine challenges were conducted with tranylcypromine-treated subjects, pressor responses were elicited after 10 mg of oral encapsulated tyramine. The dose of oral tyramine required to produce pressor effects in selegiline patients (200 mg or more) is far in excess of typical dietary intake; a tyramine-rich meal may contain up to 40 mg. Thus, it is unlikely that the selegiline transdermal system will require dietary restrictions.
"As in previous studies of selegiline treatment of major depression, the profile of adverse events differed little between the selegiline transdermal system and placebo. This is notable, given that MAOIs, as a class, are liable to have numerous side effects. Of particular clinical importance, no differences from placebo were observed in adverse events related to cardiovascular function, such as flushing, tachycardia, headache, lightheadedness, blood pressure elevation, or orthostatic hypotension. Only skin reactions at the patch site occurred significantly more frequently with the selegiline transdermal system (36% versus 17%) (p=0.006, Fisher’s exact test). This erythematous, occasionally urticarial local reaction generally persisted for several days after each application. Application site reactions occurred in this study at rates comparable to those reported for nicotine patches (34%) (28). Lower rates have been reported with transdermal estrogen (4%–10%) (29) and nitroglycerin patches (15%) (30). It is notable, however, that only three subjects dropped out of the trial because of application site reactions, indicating this was a generally tolerable side effect.
The favorable side effect profile is likely the basis for the unusually high rate of treatment compliance observed in this study. Both treatment groups used virtually all prescribed patches. In addition, 89% of the subjects receiving active drug (79/89) completed the trial. Given the poor rate of treatment adherence generally observed in depressed patients (31, 32), the high rate seen here may reflect an important therapeutic advantage of the transdermal route of administration.
An intriguing finding was a significant difference between selegiline and placebo at week 1. Although this is not highly unusual in clinical trials of antidepressants, it raises the possibility of an accelerated therapeutic response because of the parenteral drug delivery route, as has recently been demonstrated with intravenous antidepressants (33). Because of the delayed onset of clinical response to oral antidepressant medications, further investigation of the potential for a more rapid antidepressant response to transdermal treatment is warranted.
Three methodologic limitations must be considered in interpreting these results. First, the 6-week duration of active treatment was relatively brief and may have underestimated the treatment effect of the selegiline transdermal system. Second, the fixed-dose design made it impossible to assess dose-response characteristics of the selegiline transdermal system. Finally, subjects in the present study were prescribed a tyramine-restricted diet. Accordingly, additional studies without dietary restrictions will be necessary. "
For more, see....http://www.spahs.umt.edu/DIS/pdf/TransdermalSelegiline.pdf
http://ajp.psychiatryonline.org/cgi/content/full/159/11/1869
http://www.psychiatrist.com/privatepdf/2003/v64n02/v64n0216.pdf
http://www.psychiatrist.com/privatepdf/2003/v64n02/v64n0216.pdf
Posted by linkadge on August 23, 2004, at 15:44:40
In reply to Nardil Observations, posted by King Vultan on August 22, 2004, at 23:11:12
Thats funny, because when I swiched from celexa to zoloft the only thing I noticed different was that I could smell again. I assume that this is because zoloft has some effect on dopamine.
Linkadge
Posted by King Vultan on August 23, 2004, at 16:22:31
In reply to Re: selegiline transdermally » King Vultan, posted by jrbecker on August 23, 2004, at 13:04:08
Thanks very much for the info. It does appear that this may offer some significant advantages over taking selegiline in pill form. I've read other anecdotes suggesting that selegiline taken orally does have a tendency to excessively "wire" people. If the patch method of administration can reduce that effect while simultaneously improving antidepressant efficacy and eliminating the dietary restrictions, that strikes me as a good thing. In the meantime, I am hopeful I have more success with Parnate than I did with Nardil.
Todd
Posted by KaraS on August 23, 2004, at 18:13:07
In reply to Re: selegiline transdermally » jrbecker, posted by King Vultan on August 23, 2004, at 16:22:31
> Thanks very much for the info. It does appear that this may offer some significant advantages over taking selegiline in pill form. I've read other anecdotes suggesting that selegiline taken orally does have a tendency to excessively "wire" people. If the patch method of administration can reduce that effect while simultaneously improving antidepressant efficacy and eliminating the dietary restrictions, that strikes me as a good thing. In the meantime, I am hopeful I have more success with Parnate than I did with Nardil.
>
> ToddHi Todd,
Sorry to intrude here but I had a question about selegiline. You mentioned its wiring effect. I have taken a very small amount - 5 mg. on a few different days. It actually makes me feel tired and more unfocused at first. Then many hours later I get the speedy feeling. The last time I took it was around 1:20 pm and I didn't feel speeded up until about 9:00 or 10:00 at night. I know that the amphetamine metabolites are probably responsible for the speedy feeling but should it really take that long to get to that point? I'm not sure that's a question you could answer. I'm just so confused by my paradoxical response to so many medications and supplements and I'm trying to ask as many questions as possible to try to figure this all out. (If I'm going to continue to react this way on selegiline, then I might just have to wait for the patch as well. It doesn't do me much good to start waking up about the time I need to go to sleep.)How's the Parnate for you so far? Judging from your response above, it's too early to fully tell at this point, but do you have some signs yet?
Thanks,
Kara
Posted by KaraS on August 23, 2004, at 18:17:38
In reply to Re: selegiline transdermally » jrbecker, posted by King Vultan on August 23, 2004, at 16:22:31
Forget my asking you about the Parnate. I just read your previous post which said that you haven't started it yet. You must be very slowly decreasing the Nardil. Sorry.
Posted by woolav on August 23, 2004, at 19:03:32
In reply to Re: selegiline transdermally » King Vultan, posted by KaraS on August 23, 2004, at 18:17:38
Hello, I was reading this post and now am very curious about selegiline. I went to some web sites, but its so scientific I didnt really understand. It sounds like this may be a good drug for those who dont want to take an MAOI (because your pdoc wont prescribe it) :( Is it just for depression or is it good for social phobia too?? Can anyone tell me more about it in "layman's" terms?
Thanks
S
Posted by Emme on August 23, 2004, at 19:52:43
In reply to Re: selegiline transdermally » King Vultan, posted by jrbecker on August 23, 2004, at 13:04:08
Thanks for posting that. I'm VERY happy to see that, in addition to eliminating the need for dietary restrictions, the patch would reduce the speediness. I've found selegiline hard to take consistently because the stimulation seems to just wear me out.
Posted by SLS on August 24, 2004, at 7:15:59
In reply to Re: selegiline transdermally » King Vultan, posted by jrbecker on August 23, 2004, at 13:04:08
> > 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.
Do you think the transdermal delivery of selegiline confers a more potent antidepressant performance to the drug?
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.
- Scott
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.
>
> Do you think the transdermal delivery of selegiline confers a more potent antidepressant performance to the drug?
>
> 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.
>
>
> - 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
Posted by SLS on August 24, 2004, at 14:41:16
In reply to Re: selegiline transdermally » SLS, posted by jrbecker on August 24, 2004, at 10:53:08
Hi JB.
Have I ever told you how wonderful you are? Well, I'm not about to start now... :-)
In my opinion, the most potent antidepressant in the world is clorgyline. I'm sure you know it to be a selective and irreversible MAO-A inhibitor. While it was still available for human consumption, the NIMH considered it their "ace-in-the-hole" for treating their most difficult cases of depression.
> > Do you think the transdermal delivery of selegiline confers a more potent antidepressant performance to the drug?
> wow, I could only handle 5 mg daily without totally feeling out of my mind.I hope that is an indicator of your ultimate responsiveness to a drug with the right properties.
> yes, I absolutely do believe that the transdermal medium will equate to a better antidepressant effect --
There was a poster here a few years ago named "Adam" who had participated in a transdermal selegiline trial (at McLean, I think). He had previously used the oral preparation. He said the two felt like completely different drugs, with the transdermal exerting a much more potent and "smooth" antidepressant effect. His description was compelling. I don't remember the dosage used.
> http://www.sciencedirect.com/science?_ob=ArticleURL&_aset=B-WA-A-B-AYV-MsSAYWW-UUA-AUECECCYWU-AUEBCBZZWU-CYVDVCEAC-AYV-U&_rdoc=83&_fmt=full&_udi=B6T0N-3WT2NJX-R&_coverDate=07%2F31%2F1999&_cdi=4867&_orig=search&_st=13&_sort=d&view=c&_acct=C000052790&_version=1&_urlVersion=0&_userid=1458830&md5=0fb78949bfb24159a403cf90d83254ae
>
> " 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."Wow!
> "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],"This is exactly what investigators at the NIMH concluded over ten years ago. It is not surprising how much faith they placed in clorgyline. Too bad the patent has expired on clorgyline. I would take it now and combine it with a desipramine if I had the opportunity.
> 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.
Why not! You know everything else!
:-)
- Scott
Posted by JayDee on August 24, 2004, at 15:14:22
In reply to Re: selegiline transdermally » jrbecker, posted by SLS on August 24, 2004, at 14:41:16
I just have one question: why selegine?
Why not a Nardil Patch?!?
Posted by zeugma on August 24, 2004, at 17:55:24
In reply to Re: selegiline transdermally » jrbecker, posted by SLS on August 24, 2004, at 14:41:16
It is not surprising how much faith they placed in clorgyline. Too bad the patent has expired on clorgyline. I would take it now and combine it with a desipramine if I had the opportunity.>>
That's evidence of a ridiculous state of affairs in America today. No doubt armies of chemists are clambering to come up with something as good as clorgyline but that will have the added, nonpharmacological property of lining someone's pockets for a couple of years. No wonder psychiatry is constantly reinventing the wheel- meanwhile, people are suffering from the suboptimal treatments that still have patents on them. I'm not happy about this.
-z
Posted by poop'd-out on August 25, 2004, at 0:57:20
In reply to Re: selegiline transdermally, posted by zeugma on August 24, 2004, at 17:55:24
> It is not surprising how much faith they placed in clorgyline. Too bad the patent has expired on clorgyline. I would take it now and combine it with a desipramine if I had the opportunity.>>
>
> That's evidence of a ridiculous state of affairs in America today. No doubt armies of chemists are clambering to come up with something as good as clorgyline but that will have the added, nonpharmacological property of lining someone's pockets for a couple of years. No wonder psychiatry is constantly reinventing the wheel- meanwhile, people are suffering from the suboptimal treatments that still have patents on them. I'm not happy about this.
>
> -z
>Sorry to but in but what is Clorgyline, I have never heard of this?
This thread was interesting for me since I took selegiline several years ago. I was curious that the side effects might be less trandermally than when taken orally. I personally did have SE's that I did not care for. Yet at the same time it seemed to work for me somewhat sporadically.
The SE's were dizziness, confusion, just kind of feeling blurry? Also, I had some numbness and tingling in my feet and lower legs that kind of freaked me out. It was very long ago.
Well, thanks for letting me share.
Beth
Posted by SLS on August 25, 2004, at 7:30:41
In reply to Re: selegiline transdermally, posted by poop'd-out on August 25, 2004, at 0:57:20
Hi Beth.
> Sorry to but in but what is Clorgyline, I have never heard of this?
Clorgyline is an older MAOI that is now used only in laboratory experiments. It is not available for human consumption.
- Scott
Posted by ravenstorm on August 25, 2004, at 10:25:43
In reply to Re: selegiline transdermally » poop'd-out, posted by SLS on August 25, 2004, at 7:30:41
I read somewhere that an anouncement about ensam should be coming through sometime in August.
Anybody heard anything yet??
I know they are wrangling with the FDA over whether or not the patch will be labeled as needing food restrictions or not. The company (is it Watson?) is claiming food restrictions are not needed (which makes sense to me) but the FDA is apparently requiring more proof of this.
My fear is that if the FDA only agrees to approve the drug WITH food restrictions, that Watson won't ever find a manufacturer for the drug because the perceived profit for "just another MAOI" will be too dismal.
Keeping all my fingers and toes crossed.
Posted by poop'd-out on August 25, 2004, at 15:10:31
In reply to Re: selegiline transdermally » poop'd-out, posted by SLS on August 25, 2004, at 7:30:41
> Hi Beth.
>
> > Sorry to but in but what is Clorgyline, I have never heard of this?
>
>
> Clorgyline is an older MAOI that is now used only in laboratory experiments. It is not available for human consumption.
>
>
> - ScottScott,
Thank you for the information. It sounded like people did well on this drug? Why was it discontinued?
Hope you do well with the Cymbalta, I will be watching your progress to see how you do. Glad to hear only tiredness has been a problem so far. Oh, but what a problem that can be. I think you are right though, and that eventually it will pass.
Beth
This is the end of the thread.
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