Posted by SLS on May 25, 2000, at 7:19:51
In reply to Re:nefazodone and mCPP, posted by Adam on May 25, 2000, at 1:26:24
> 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.
Could the competition for enzyme sites by substrates with different binding affinities produce the same net effect?
> Unfortunately, the only real way to know is to measure 2D6 levels.
How does one go about this?
> >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.
Which? Metabolizing enzymes or synaptic structures?
> 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).
I'm too lazy to go look it up, but what is Social Darwinism (Cliff-Notes version)?
Of course, these types of investigations have been going on for a long time now. Many different polymorphisms of specific synaptic receptors and neurotransmitter transporters have been isolated.
> If genes aren't a big part of psychiatric disorders, I'll be amazed.
Big-time researchers are quite convinced of this. But they are having a hard time even isolating which chromosomes contain the genes that are involved in bipolar disorder, probably the most heritable of the affective disorders. It is most likely that there is an interplay among multiple genes. I recently spoke to Patrick J. McGrath of Columbia-Presbyterian / New York Presbyterian (or whatever they are calling themselves now). He told me that even the studies of bipolar disorder among Amish pedigrees have produced equivocal results. He said that it seemed difficult to reproduce results consistently. Psychosocial stressors are also involved in the precipitation of bipolar episodes, although not always. I suggested to him that perhaps the differences among the "heritability" of different pedigrees reflected a difference in psychosocial stresses within the different households (familial dysfunction is often passed along to subsequent generations). I was flattered by his unambiguous statement "Hmmm". Even so, concordant twins raised in the same household can be divergent in the presentation of bipolar disorder.
It seems to me that there must also be genetic variation involved in the other affective-spectrum disorders. I think the terms "genetic vulnerability" or "genetic predisposition" apply well.
> 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).
What is a "partial" agonist. I asked this question before, but was disappointed by the replies because they lacked chemical or mechanical detail.
Adam, I enjoy your posts and the wealth of accurate information they contain. Thank-you.