Posted by Rick on August 28, 2001, at 20:37:13
In reply to Re:SP Cocktail/Mechanisms of Action/Memory Culprit, posted by PaulB on August 24, 2001, at 15:55:55
Paul:
Once again, you’ve provided some interesting reading and insightful thoughts, although I have a different perspective on some of the subtopics.
>When I said I was less enthusiastic about Provigil I meant in reference to its use to eliminate or reduce the cognitive side-effects of Klonopin which is what, in this instance it was being suggested for and not as a concomitant medication for SP. I know there has been a lot written here at PB about the possibility that Provigil and its older analogue Adrafinil may be effective for SP. There was a really long list of postings not long ago debating whether dopamine was disfunctional in SP. Outside of PB I have yet to come across evidence or opinion that medicines that enhance dopamine are helpful for SP. There was one example though, in reference to Parnate, whose added 'noradrenergic and dopaminergic effects' make it superior to Nardil for SP. I know people will disagree here because there is no question that Nardil has similar effect and Nardil is often considered superior to Parnate?
If anyone can vouch for the fact that dopaminergic agents can be problematic in social phobia rather than helpful, it’s me! My experiences with with dopamine-based treatments and augmentors have ranged from bad to awful (the latter represented by solo seligiline at 10-15 mg – yikes!) No one really has a solid handle on Provigil’s pharmacology. The manufacturer flatly states that it posseses little in the way of either dopaminergic OR adrenergic activity. That may be overstated. I’ve seen conflicting studies. But one thing that does NOT seem to be controversial is the conclusion that Provigil’s effects appear to be mediated in very limited areas of the brain -- quite unlike Ritalin or amphetamines, which have widespread activity. This assertion, plus the related positioning as a "more gentle" kind of stimulant, drove my interest in trying Provigil as an augmentor after other stimulating meds made me nervous. And – at least combined with Serzone and 1 mg Klonopin – I got the non-wired stimulation effect I was looking for...plus wonderful and unanticipated psychic benefits (further reduction in anxiety – as long as the dose is optimized -- plus enhanced confidence, enthusiasm, and sociability).
> >It's well known that Klonopin can cause episodic amnesia, though not necessarily in everyone. And it's well known that Serzone and other AD's can cause this too, although some of that might be attributable to unresolved depression or inaccurate subjective assessment of memory. Sorry about jumping back and forth here...but since it's unlikely I have more Klonopin in my bloodstream than pre-Serzone (remember, I was taking more K then), wouldn't the amelioration of memory loss upon temporary Serzone discontinuation implicate Serzone as the source of my memory impairment, rather than Klonopin?
>I wouldnt think so. Discontinuing Serzone means stopping the inhibition of the CYP3A4 enzyme. This means Klonopin can be metabolised again and levels would decrease to much lower than combined Serzone-Klonopin. Even if you were taking more K before Serzone theres no way it would reach plasma levels that would be obtained by K+ Serzone at even high dosages because its extensively metabolised and INCREASINGLY metabolised dont forget.
Interestingly, I found some information indicating that Provigil/modafinil is an inducer of CYP3A4, which should reverse at least some of Serzone’s CYP3A4 inhibition, shouldn’t it? Wouldn’t this mean that Serzone’s potentiation of Klonopin is then reduced as well? On a side note, Provigil is actually metabolized in part by CYP3A4, which means it can induce its own metabolism to some degree. Even though this supposedly happens only at higher doses, I sometimes wonder if that’s why every so often Provigil seems to lose it’s “oomph”, which is quickly remedied by a day or two at double-dose. Now, to complicate things even more, if Serzone is a stronger inhibitor of CYP3A4 than Provigil is as an inducer, does this mean that Serzone could potentiate Provigil, too? This is all very circular and confusing to me, but whatever interactions are going on seem to be beneficial for my Social Phobia treatment...although there could still be some negative impact cognitively, I suppose. Regardless, it works for me, and my liver enzymes remain right where they should be. (I wonder if the same would be true of adrafinil, whose manufacturer recommends quarterly hepatic function tests even when used as monotherapy?)
> >Related to that question, here's one thing I've long wondered. Perhaps that sole Klonopin user who has managed to get to this point in my rambling might be able to offer up some thoughts: Specifically, assuming X amount of Klonopin can lead to amnesic effects in someone, can it take a full year or more for this effect to surface? I had minimal memory deficit (it's still not huge, just inconvenient) for the full year that I took 2-3 mg Klonopin minus any AD.
>I am not sure. But you mention that you took Klonopin for a full year at 2-3mgs with minimal memory deficits. If the releif in SP symptoms was satisfactory then wouldnt it be okay without further augmentation with another drug, esp one that causes drug-drug interaction with K?
I’m not inclined to head back to the Klonopin monotherapy that gave me a (completely subjective ) 65-70% improvement, when the current cocktail gives me 90% with a more multidimensional effect. And for whatever reasons, my vital physical signs like blood pressure and fasting glucose have gone from adequate to excellent since I started the combo – while, as I mentioned, hepatic function remains unaffected by the putative drug interactions.
Now, if the memory effects were to go from moderately bothersome to worse, I could reconsider. I do understand your reasoning on this topic, but I have a strong sense that, for me, the Serzone in and of itself is *at least* as much a culprit as the low-dose Klonopin (even if the K IS extensively potentiated). Maybe I have an attention bias towards anecdotal reports that talk about meds I personally use, but Serzone seems to receive a lot more than its fair share of cognitive-impairment complaints.
Thanks again for the helpful and interesting thoughts.
Rick
poster:Rick
thread:36517
URL: http://www.dr-bob.org/babble/20010828/msgs/76760.html