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Re: RLS, Akathisia + Dopamine D-2 receptors? cache-monkey

Posted by Larry Hoover on April 13, 2007, at 7:03:23

In reply to Re: RLS, Akathisia + Dopamine D-2 receptors? Larry Hoover, posted by cache-monkey on April 12, 2007, at 20:43:23

> Larry,
> Thanks for your input, although I must admit I'm not sure what to make of it. I mean, I get what you're saying, but the functional import of it is not so clear. If you have a little more time to amplify, I would appreciate it.

The important thing to conclude is that you do not have a definitive answer, IMHO. Your bodily response, from an observational perspective, is ambiguous. Your desire to have it understood may not be satisfied.

The functional import part I think you're fully prepared for: management. Above all, for you, med trials should include very slow dose titration, starting well below normal therapeutic doses. You are especially sensitive. "Normal" dosing is a statistical concept. A plot of clinical response vs. dose would likely yield a normal curve, the bell curve. Most individuals would lie near the centre of that plot, and their dose would be the "normal" dose. Yet, most clinicians, and their vulnerable patients, forget that some actual individuals lie towards the extremes of that plot. We do see some people getting and using doses well above the normal value, but what of those who lie well below the normal? I seldom see *any* consideration of those folk, the med-sensitive. Those beyond two standard deviations below the norm still represent one in forty people, and their "clinical" dose might be a tiny fraction of the norm. The normal starting dose might be in their toxic range, or merely in the intolerable zone. Drug intolerances are seldom assigned to mismanagement, but that's what I would call it.

> I guess what I'm concerned about is dopamine supersensitivity, which is thought to be the basis of tardive phenomena. Philip Seeman's been doing a lot of work showing that the conversion of D-2 receptors to a supersensitized high-affinity state happens with chronic D-2 blockade, ethanol withdrawal, and a whole variety of brain injuries.

I'm an empiricist. Seeman is seeking a mechanistic "proof" of a fully-observed phenomenon, the empirical evidence. What isn't known, and can't be proven from his work, is the time course of that conversion reaction. Does it remit? Who knows. That doesn't make it unmanageable, in any case. Doing management experiments (including slow/low dose titrations) will obtain further empirical evidence. No amount of thinking will provide similar "proof".

> I suppose a simple, although non-specific, test would be to see how I respond to a dose of ritalin or adderall. Increased agitation would be an inicator of supersensitization.

Exactly the sort of experiment that could be helpful/informative, but be cautious about presuming that agitation is really about sensitization. If the experience is unpleasant, I might judge it to simply be inappropriate for you at this time. You cannot differentiate between state responses and trait responses from a single exposure. What do I mean by that? Trait responses, as I intend them, are the immediate acute physical effects of a drug, but only those which are transient. Transient side effects are state responses. Trait responses include immediate effects that do not remit (i.e. non-transient), but also those that appear over time as the body adapts (which you could further differentiate as tardive trait responses). From one exposure, you cannot determine the critical criterion, transiency, which differentiates state from trait. Hindsight is required, to assign this distinction, but if and only if you have a continued exposure and further observations. And I do acknowledge that state, and especially trait responses, are subject to confounding influences.

My definitions are arbitrary. You may perhaps find them nowhere else, I don't know, but they serve me well.

> Thanks again,
> cache-monkey

My pleasure. I just hope my thinking is of some benefit to you.





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