Posted by Shawn. T. on August 8, 2002, at 22:42:03
In reply to Re: Tremendous strides with ondansetron » Shawn. T., posted by Stan on August 7, 2002, at 7:44:30
> "hi shawn - i haven't tried any of the 5-HT3 antagonists alone or in combination but i'm certainly going to research those links you posted to see if one might be appropriate for experimentaion without costing a fortune like ondanestron. i recall you mentioned that blocking this receptor may inhibit the release of substance P which in turn may result in a reduction in psychic pain as well as physical pain. for some reason i seem to remember hearing some second-hand reports that merck's "substance P" drug trials weren't going very well and perhaps their investigational drug wasn't proving very effective at alleviating depression & anxiety.....but that info could be flawed."
I believe that they should look into using that drug for pain relief instead of the treatment of depression. Substance P acts at neurokinin-1 (NK-1) receptors. There are two other NK receptors, and NK-2 antagonism may turn out to be more effective than NK-1 antagonism (a drug or combination of drugs acting at both of these receptors would be very effective at relieving inflammation). Neurokinin A acts at NK-2 receptors, and neurokinin B acts at NK-3 receptors. I'm fairly positive that your information wasn't flawed.
>
> <<<<I disagree with
the kitchen sink statement about Remeron; I find that it is a well thought out drug.>>>>>
>
> i was the one that made that statement, but i didn't mean it in a derogatory sense -- in fact it may be the next antidepressant that i try. i think antagonism of 5-HT2A, 5-HT2B, 5-HT2C, and 5HT3 (all of which remeron accomplishes) is capable of producing positive improvements in depressives whose symptoms include anxiety, insomnia, agitation, restlessness, etc. i'm taking serzone, which only antagonizes 5-HT2A, and i'm still highly anxious and wondering if blocking those additional sub-receptor groups with remeron would be more beneficial for me.
>Serzone increases activation of 5-HT2c & 5-HT3 receptors via its serotonin reuptake inhibition property. That could cause anxiety.
"however, as far as remeron's effects at adregenic and histamine sites go, i'm not so sure that that the drug scores high marks for minimizing side effects with its various manipulations in those places. it is an alpha-2 antagonist, which is good in the sense that this allows more serotonin to be released (and "directed" towards the 5HT1A receptor) but perhaps not so good from the standpoint of releasing too much NE and perhaps being over-stimulative and actually having an anxiogenic effect for some sensitive patients who are bothered by over-activation."
You're exactly right; alpha-2 antagonism is not a desirable property to have in an antidepressant drug. Alpha-2 receptors can decrease inflammatory cytokine levels and noradrenaline levels, which are definitely desirable properties to have in an antidepressant (NA reuptake inhibitors increase alpha-2 activation, which interestingly can cause anxiolytic effects). High noradrenaline levels can cause alpha-1 NA receptor activation; that results in increased CRF (corticotropin release factor) release. This is offset, however, by the inhibitory effects of beta adrenoceptors on CRF release (it probably be unwise to combine a beta blocker with Remeron). High NA levels are generally undesirable; that is why I am not crazy about high doses of Remeron.
"it seems that a VERY potent antihistamine effect (blocking H-1) was thrown in to counterbalance this excess NE release.....and there's the rub."
I would guess that they would have left the H1 effects out if they could have. I think that 7.5mg is better than 15mg because the H1 effects aren't quite as severe (people generally aren't as drowsy while taking the smaller dose). I would like to know how strongly the smaller dose affects 5-HT2a/c receptors.
"no drug is perfect, of course, but it seems to me that this is where this drug falls down.....it's common for antihistamines to produce sedation and weight gain, and many people become more depressed when they are tired much of the time and if they're already above their ideal weight (very common for americans), additional gains can be equally depressing. histamine blockers can be somewhat anxiolytic and promote sleep, but it appears that remeron's antihistamine effects are just too potent for the average individual. higher doses (45-60 mg) are supposed to activate the NE-releasing effect to such a degree that the antihistamine consequences become less noticable and sedation less pronounced.....but i wonder why the alpha-2 and H-1 antagonism wasn't left out altogether (hence my "kitchen-sink" comment about affecting multiple receptors). but since i've never taken it and because i assume that it's very difficult to "design" these newer drugs to an optimal degree, then i guess we just have to give remeron the benefit of the doubt. i look forward to trying it this fall sometime."
I sort of consider Remeron to be the handwashing sink (just a smaller sink) of antidepressant drugs; it is certainly not perfect, just better than most. The higher dose/ lower side effect theory is interesting, but in the end, not exactly true. I like the idea of lowering those dose below 15mg to decrease histamine relate side effects rather than increasing it. I'm going to discuss with my psychiatrist how the lower dose has worked in other patients; he may have suggested the lower dose because I was already taking Wellbutrin, however.
>
>
> "i'd be very interested in reading your comments pursuant to that topic, shawn, if you get a chance to post them."I'm still researching the topic; there isn't exactly a wealth of data out there, but just enough for me to get by.
"also, here's a link to an article that covers certain aspects of remeron which may be of interest to you -- if you scroll down aways you'll see that the author suggests that at low doses, remeron's potent antihistamine properties essentially override its other effects, which he claims kick-in only after doses considered therapeutic for depression are administered (15 mg and higher). by the way, what do you think of serzone? if you haven't tried it, perhaps you'll have comments on a purely theoretical basis. here's that link:
>
>
> Column - Imipramine, Mirtazapine, and Nefazodone: Multiple Targets:
> http://www.preskorn.com/columns/0003.html
>
> Stan
>
>
I'd read that a while ago; I sort of skimmed over it then, however. Dr. Preskorn has a good article on why in vitro data is usually not a good predictor of in vivo pharmacology. I usually dismiss most of the in vitro studies that I see, unless the specific situation seemed to make such an approach valid.
Shawn
poster:Shawn. T.
thread:115356
URL: http://www.dr-bob.org/babble/20020807/msgs/115748.html