Psycho-Babble Medication Thread 747867

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Fellow pharm-geeks: a question about terminology

Posted by cache-monkey on April 7, 2007, at 12:40:28

Hi all,

I mean the term geek affectionately, of course. I have been doing some reading about various changes in the dopamine d-2 receptor, and am realizing that I'm a little weak on some terminology.

Are the following more or less the same? If not, what are the differences?
* Increase in the number of receptors
* Up-regulation of receptors
* Increased expression of receptors
* Increased density of receptors
* Increased availability of receptors
[I'd also be interested in finding out which (if any) of these is implied by "sensitization".]

Your input would be greatly appreciated.

Regards,
cache-monkey

 

Re: Fellow pharm-geeks: a question about terminology cache-monkey

Posted by saturn on April 7, 2007, at 13:53:48

In reply to Fellow pharm-geeks: a question about terminology, posted by cache-monkey on April 7, 2007, at 12:40:28

>
> Are the following more or less the same? If not, what are the differences?
> * Increase in the number of receptors
> * Up-regulation of receptors
> * Increased expression of receptors
> * Increased density of receptors
> * Increased availability of receptors
> [I'd also be interested in finding out which (if any) of these is implied by "sensitization".]

I would regard all 5 of them as being equivalent.

"Sensitization" refers to the requirement of higher doses to achieve an effect once achieved at a lower dose. It is generally thought to be caused by receptor down-regulation and desensitization, which is the opposite of the changes you mentioned.

 

Re: Fellow pharm-geeks: a question about terminology cache-monkey

Posted by Larry Hoover on April 8, 2007, at 10:35:39

In reply to Fellow pharm-geeks: a question about terminology, posted by cache-monkey on April 7, 2007, at 12:40:28

> Hi all,
>
> I mean the term geek affectionately, of course. I have been doing some reading about various changes in the dopamine d-2 receptor, and am realizing that I'm a little weak on some terminology.
>
> Are the following more or less the same? If not, what are the differences?
> * Increase in the number of receptors
> * Up-regulation of receptors
> * Increased expression of receptors
> * Increased density of receptors
> * Increased availability of receptors

There are nuances within the phrasing, but unless you're analyzing a mechanism, the differences might be moot.

An increase in number of receptors would likely represent some physical counting process, which may or may not require the physical sampling of tissues.

Up-regulation of receptors was originally a functional criterion, with one or more possible mechanisms. It's often used as an umbrella term, these days.

Increased expression of receptors typically indicates some assessment of nuclear activity, via RNA concentrations, often messenger RNA (mRNA). Receptor protein concentrations might also be used, but that's a density metric.

Increased density is the same as increased number, for all intents and purposes.

Increased availability is a functional criterion, focussing on the relative concentration of inhibitors and/or receptor cofactors. I think it would be very context-driven. For example, magnesium concentration is directly proportional to GABA-A receptors lying in their receptive conformation.

> [I'd also be interested in finding out which (if any) of these is implied by "sensitization".]

Sensitization refers to changes in the charge threshold for depolarization, i.e. the amount of current available/required for a nerve cell to fire. This can be measured by patch-clamp techniques. Repetitive firing of a neuron will often result in its sensitization, one of the underpinnings of what we know as learning. Some drugs, for example, can attach to some non-binding surface of a receptor, and change its sensitivity. An increase in sensitized receptors could lead to cellular sensitizing. Or, chloride or sodium or potassium channels get messed with, affecting depolarization. It could be due to an increase in receptor density, which might influence the time required to reach depolarization, resulting in an increased rate of firing. So, once again, there's a contextual element to the meaning, but its a functional criterion.

> Your input would be greatly appreciated.
>
> Regards,
> cache-monkey

Well, that's my personal understanding of things.

Lar

 

RLS, Akathisia + Dopamine D-2 receptors?

Posted by cache-monkey on April 9, 2007, at 15:13:14

In reply to Re: Fellow pharm-geeks: a question about terminology cache-monkey, posted by Larry Hoover on April 8, 2007, at 10:35:39

Thanks Larry and Saturn for the replies.
Maybe what I'm interested in will be more clear if I give the context. What I'm really wondering about has to do with the dopamine D-2 receptors

Years ago I added Celexa on to Wellbutrin and experienced intense, but transient anxiety which might have been akathisia in retrospect. After I d/c'ed both, I gradually slid into this highly anxious state, both physically and psychically. This worsened when I attempted to quit smoking (previous attempts had only led to anxiety/OCD).

Subsequent treatment with Serzone worsened my anxiety and the addition of BuSpar led to full on chronic akathisia. This relented somewhat when I got off the BuSpar, but now any trial of an anti-psychotic at a low or moderate dose leads to acute akathisia within a week.

The common link seem to be the D-2 receptor. I recently discovered that Celexa (and also SSRIs) increases the expression of the D-2 receptor (http://tinyurl.com/2bs2ub). Further, BuSpar and neuroleptics block it, which can lead to actue and chronic akathisia when a certain percentage of receptors are blocked (e.g. http://tinyurl.com/2v2o7z).

The trouble is, I'm not sure what to make of this. Besides the null that the D-2 system is totally uninvolved, there are two hypothesis that I have:

A) My receptors are down-regulated
* This would be consistent with the acute akathisia from low concentrations of D-2 blockers. I.e. a large percentage of receptors get blocked because there are relatively few of them
* It would also be consistent with my medium term (after start-up, before discontinuation) success with Celexa: I felt better once the D-2 receptors began to proliferate

B) My receptors are up-regulated
* This tends to be the effect of mid- to long-term treatment with D-2 blockers
* This is possibly consistent with ongoing akathisia-like issues -- under the assumption that tardive akathisia is like other TD

But I'm not sure that my logic is right here. I'm also really unclear about two other things about the RLS and strong SSRI start-up akathisia? (I also had this during a brief trial with Cymbalta.) Would these be more consistent with up-regulation and low endogenous dopamine?

Anyway, I'm sorry if this is a muddle, but I'm contemplating starting another SSRI in the next few months. My main concern is whether there is reason to believe that going on something like Celexa again could possibly exacerbate some ideopathic or iatrogenic condition in my dopamine system.

If you have a few moments I could really use another brain or two to pick.

Thanks,
cache-monkey

 

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

Posted by hgi698 on April 9, 2007, at 17:51:35

In reply to RLS, Akathisia + Dopamine D-2 receptors?, posted by cache-monkey on April 9, 2007, at 15:13:14

"Dopamine receptor blockade in the mesocortical dopamine tracts appears to be involved in akathisia. PET studies have shown D2 receptor occupancy in the striatum is associated with the development of akathisia." I think that ssri's can reduce the firing of dopaminergic neurons leading to a reduction in dopamine levels and signaling via the D2 receptor. This alone would cause the akathisia. After a few weeks it would be expected that your D2 receptors would upregulate to compensate for the decreased dopamine. I think this upregulation would tend to improve the akathisia because its your brain's mechanism to maintain homeostasis. Like if you took cocaine you'd feel euphoric, but your d2 receptors would downregulate after a while to keep your mood in check.

 

Re: RLS, Akathisia + Dopamine D-2 receptors? hgi698

Posted by cache-monkey on April 9, 2007, at 18:45:28

In reply to Re: RLS, Akathisia + Dopamine D-2 receptors?, posted by hgi698 on April 9, 2007, at 17:51:35

<< I think that ssri's can reduce the firing of dopaminergic neurons leading to a reduction in dopamine levels and signaling via the D2 receptor. This alone would cause the akathisia. After a few weeks it would be expected that your D2 receptors would upregulate to compensate for the decreased dopamine. I think this upregulation would tend to improve the akathisia because its your brain's mechanism to maintain homeostasis. >>

Thanks for the input! I believe I follow what you're saying. But, I'm wondering what happens when the SSRI is removed. You have all the extra receptors and then dopamine levels go back to normal.

I would think that they then get hyper-stimulated. I would suspect that in most people there ends up being down-regulation and homeostasis is achieved once again. But, I'm wondering if in some susceptible individuals the receptors get stuck being super-sensitive, like in TD. I'm wondering if that would lead to anxiety and an alternative type of akathisia-like experience.

Thoughts?

~cache-monkey

 

sri, dopamine

Posted by med_empowered on April 9, 2007, at 23:52:53

In reply to Re: RLS, Akathisia + Dopamine D-2 receptors? hgi698, posted by cache-monkey on April 9, 2007, at 18:45:28

well, sris sometimes cause TD. Apparently its been observed in long-term prozac and I think some effexor patients. Also, just as some researchers think patients "need" neuroleptics long-term only b/c of D2 supersensitivity secondary to long-term neuroleptic use, so too it appears that some patients "need" antidepressants long-term b/c of brain changes caused by long-term, high-dose antidepressant use. I personally think the dopamine effect with sris is probably also a big part of their effects--the mild stimulant/agitation from pumped up serotonin, the dulling from reduced dopamine, plus the additional effects of either mild sedation or mild stimulation from secondary effects on other neurotransmitters...SRIs seem to me to be kind of like low-dose neuroleptics PLUS (other milder effects). Just my thoughts.

 

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

Posted by Larry Hoover on April 12, 2007, at 9:04:13

In reply to RLS, Akathisia + Dopamine D-2 receptors?, posted by cache-monkey on April 9, 2007, at 15:13:14

I've been cogitating on this for a while, and my response is pure speculation.....two of your posts together include:

> The common link seem to be the D-2 receptor. I recently discovered that Celexa (and also SSRIs) increases the expression of the D-2 receptor (http://tinyurl.com/2bs2ub). Further, BuSpar and neuroleptics block it, which can lead to actue and chronic akathisia when a certain percentage of receptors are blocked (e.g. http://tinyurl.com/2v2o7z).
>
> The trouble is, I'm not sure what to make of this. Besides the null that the D-2 system is totally uninvolved, there are two hypothesis that I have:
>
> A) My receptors are down-regulated
> * This would be consistent with the acute akathisia from low concentrations of D-2 blockers. I.e. a large percentage of receptors get blocked because there are relatively few of them
> * It would also be consistent with my medium term (after start-up, before discontinuation) success with Celexa: I felt better once the D-2 receptors began to proliferate
>
> B) My receptors are up-regulated
> * This tends to be the effect of mid- to long-term treatment with D-2 blockers
> * This is possibly consistent with ongoing akathisia-like issues -- under the assumption that tardive akathisia is like other TD

What about both occurring simultaneously? It's often little appreciated that auto-receptors (i.e. pre-synaptic receptors) also influence responsivity of the neural network. Auto-receptors are often inhibitory, serving as an internal signal feedback mechanism. There are also generally external feedback mechanisms, downstream from the neuron across the synapse. Genetic up-regulation could explain both observations, as activation of the higher receptor numbers on both sides of the synapse would lead to behavioural inhibition and excitation at the same time. Or, simply concluding that pre-synaptic and post-synaptic effects might differ, without characterizing them further.

> I would think that they then get hyper-stimulated. I would suspect that in most people there ends up being down-regulation and homeostasis is achieved once again. But, I'm wondering if in some susceptible individuals the receptors get stuck being super-sensitive, like in TD. I'm wondering if that would lead to anxiety and an alternative type of akathisia-like experience.

I think we often discount the biochemical changes that occur from experience, including that from exogenous substances. Neurons have learned responses, whatever they might be. So, prior experience can colour future opportunity. Once activated, genes are (frequently) more easily activated any time thereafter.

Lar

 

Re: sri, dopamine med_empowered

Posted by cache-monkey on April 12, 2007, at 20:33:01

In reply to sri, dopamine, posted by med_empowered on April 9, 2007, at 23:52:53

Thanks for the thoughts, med_empowered. I really think that something changed in my brain after being on Celexa/Wellbutrin. I've never been able to get the agitation to calm down since going off. My functional dx is BP NOS, but outside of a brief respite on Tegretol (before my body went allergic), I haven't gotten much relief from the mood stabilizers.

I guess I'd like to try an SSRI again, but I worry that it will make things indelibly worse...

Anyway, thanks again.

> well, sris sometimes cause TD. Apparently its been observed in long-term prozac and I think some effexor patients. Also, just as some researchers think patients "need" neuroleptics long-term only b/c of D2 supersensitivity secondary to long-term neuroleptic use, so too it appears that some patients "need" antidepressants long-term b/c of brain changes caused by long-term, high-dose antidepressant use. I personally think the dopamine effect with sris is probably also a big part of their effects--the mild stimulant/agitation from pumped up serotonin, the dulling from reduced dopamine, plus the additional effects of either mild sedation or mild stimulation from secondary effects on other neurotransmitters...SRIs seem to me to be kind of like low-dose neuroleptics PLUS (other milder effects). Just my thoughts.
>
>

 

Re: RLS, Akathisia + Dopamine D-2 receptors? Larry Hoover

Posted by cache-monkey on April 12, 2007, at 20:43:23

In reply to Re: RLS, Akathisia + Dopamine D-2 receptors? cache-monkey, posted by Larry Hoover on April 12, 2007, at 9:04:13

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.

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 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.

Thanks again,
cache-monkey

 

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.

Lar

 

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

Posted by linkadge on April 14, 2007, at 9:36:57

In reply to Re: RLS, Akathisia + Dopamine D-2 receptors? cache-monkey, posted by Larry Hoover on April 13, 2007, at 7:03:23

In one sense I agree. I have found it extremely difficult to do things off SSRI's. I just can't seem to get into the zone. It seems like my brain is expecting an SSRI to regulate things.

TD with SSRI's is a lot rarer than with APs. I got much worse apathy on AP's than with SSRI's. In addition APs also caused a lot more stiffness and movmement problems than SSRI's.

I agree with you, part of the clinical effect is probably due to lowering of limbic dopamine levels. This is probably what achieves the reduction of guilt feelings, as well as perhaps resolving certain dark moods.

Sometimes SSRI's just made me more agreeable. If the doctor asked if I was feeling better, I would be more likely to say yes even thought I may not have been. Serotonin facilitates aquisition of cues of socoal appropriatness.

I have become extrordinarily antisocial after discontinuing SSRI's. I hate people. I don't want to be around people. I just want to be left alone. It sounds to me a lot like how people describe Ecstacy withdrawl. This feels like prolonged ecstacy withdrawl.

I attain absolutely zero pleasure from the presense of others. Its not so much that I am antisocial as I have social reward deficiancy.

The permanant lack of sexual function also doesn't help the situation.

Bla Bla bla,


Linkadge

 

Re: RLS, Akathisia + Dopamine D-2 receptors? Larry Hoover

Posted by cache-monkey on April 14, 2007, at 17:14:00

In reply to Re: RLS, Akathisia + Dopamine D-2 receptors? cache-monkey, posted by Larry Hoover on April 13, 2007, at 7:03:23

Wow. Larry, thank you so much for all of the thought you put into your response. It is very much appreciated

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

You've kind of hit the nail on the head here. I guess on some level I realize that this isn't something that can be fully reasoned out. But, given the state of constant anxiety and agitation I'm in, I head toward the obsessional. And also, it's becoming really frustrating not having such non-specific symptoms (especially the physical ones that include pain flares and allergies to multiple meds). I don't have a functional diagnosis other than BP-NOS, which has become a catch-all for "well, we really don't know what's wrong with you so we'll call it BP". It's getting quite scary not to have a well-defined set of treatment options ahead of me.

<< 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. >>

Yeah, that's about right. This only adds to the frustration. I suppose this is something that I can concentrate on with my therapist.

<< 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. >>

I'm not sure that I agree with you here. One could argue that the work that he's been doing on dopamine supersensitivity (DA-SS) is that it elucidates a common mechanism in a number of psychotic/activated states. This could potentially lead to treatments for DA-SS (e.g. one paper by Seeman on reversing it through general anaesthesia). That being said, his research line right now isn't really geared toward clincal treatment.

<< 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". >>

Again, thanks for bringing this point home. It's frustrating for me to hear, but you're absolutely right in that I can't think my way out of this. In fact, trying to do so is probably ultimately unproductive. However, I think some amount of deductive reasoning is valuable in trying to narrow down the set of medications a bit.

FWIW, my current trajectory is to first switch from Klonpin to Valium, as I seem to have become mildly allergic to the former. (Or maybe I always have been and this has led to my other allerrgic responses.) And then the following meds are in the bullpen...

1) Memantine (possibly useful for agitation, might prevent further DA-SS)

2 An SSRI. I've only tried Celexa and Lexapro so far. And out of all med combinations I only felt close to stable on Celexa+Wellbutrin, and on more recently on Tegretol before I went allergic. Common mechanisms between the Celexa and Tegretol are blocking of L-type calcium channels and (probably) an increase in allopregnanolone. I'm debating between retrialing Celexa or trying Zoloft. The latter doesn't seem to have the calcium channel actions, but likely has stronger effects on allopregnanolone and hasn't been explictly been shown to increase the expression of D-2 receptors. But, with some sort of BP diagnosis, any SSRI is a little dangerous. So low and slow here regardless.

3) Dynacirc/isradipine. I actually benefitted a little bit from 120 mg / day of IR verapamil, but went allergic. L-type calcium channel blocking seems to be a common element in my few positive med experiences. So hopefully after a switch off of klonopin, I'll actually not go allergic.

Anyway, I think I'm writing this list for my own benefit. Clearly it's a bit more overthinking on my part. Hopefully with it written down somewhere (and maybe printed out to look at) I can obsess a little bit less. But, if anyone happens to want to chime in, that's fine too.

Thanks again, Larry.
~cache-monkey


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