Posted by Adam on May 25, 2000, at 1:26:24
In reply to Re:nefazodone and mCPP, posted by Noa on May 24, 2000, at 16:53:50
> I think there is a discussion in Dr. Bob's Tips about this,
(Smack on forehead) But of course! I never think to look in Dr. Bob's Tips first, since I reflexively head for NCBI now, but it would probably save me a lot of time. Thanks for the pointer.
>and a suggestion that some people are genetically predisposed to experiencing bad effects from the metabolite.
Yes, and I believe this may be due largely to deficiencies in CYP450-2D6. I've considered this, though in some ways I lean toward the more mundane drug interaction theory because, well, it's more mundane. But, I should say that it is far more likely that something like clozapine would be elevated by a 2D6-inhibiting drug than the other way around, since it is not nearly as potent at inhibition as many common antidepressants. Actually, I was able to find only one reference describing clozapine's inhibitory potential for that enzyme, while risperidone, for instance, is just a substrate but not an inhibitor. What has fed my curiosity about the genetic theory is my previous experience with tricyclics, which was horrible. On about the lowest doses of imipramine, desipramine, and clomipramine (clomipramine was really, really bad) one can reasonably take, I was flat on my butt. As one can guess, due to the structural similarities clozapine has to the tricyclic antidepressants (it's a tricyclic benzodiazepine, basically, with some interesting similarities to lorazepam and clomipramine...I really love lorazepam, by the way, though this might implicate 3A3 and 3A4), all those drugs I took are targets for 2D6. My relative lack of tolerance to the TCAs might have something to do with that. Unfortunately, I never got a blood level taken, since the longest I could stand a TCA was about two weeks. I kind of wish I had now, since that could have provided clues. Unfortunately, the only real way to know is to measure 2D6 levels. I can't imagine how I could have that done without doing experiments on myself, which, though tempting, would probably get me in big trouble at work.
>I think this could be an interesting avenue of research to pursue, not just for the question about who will respond favorably or unfavorably to this med or others, but perhaps identifying such genetic vulnerabilities can give more clues to the actual mechanisms causing the psychiatric symptoms in the first place.
I'm sure learning about genetic polymorphisms and how they contribute to almost any illness you can think of will be of immense value. I am, I guess, a genetic determinist in my thinking (and try not to stumble unwittingly into Social Darwinist territory, though I'm sure I'm not 100% successful at that). If genes aren't a big part of psychiatric disorders, I'll be amazed. In the case of mCPP hypersensitivity, I'm not sure. It seems conceivable that if there were some kind of abnormality in 5-HT2 receptors, mCPP might exert a stronger effect than normal, and even the parent compound could act more like a partial agonist (it can even under "normal" circumstances to a limited extent). I think the metabolic explanation is easier conceptually, but how that would contribute to one's mental or emotional state I haven't a clue. Interesting to ponder, though.
You know, the more I think about it, the more likely the genetic link seems. That makes the clozapine-nefazadone combo. even more scary in some ways, since I also might have had to deal with problems related to relatively high levels of a neuroleptic.
I wonder if selegiline is metabolized by 2D6...
poster:Adam
thread:33082
URL: http://www.dr-bob.org/babble/20000517/msgs/34559.html