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How potent is Mirtazapine considered to be on NorAdrenaline - vs other tetra/triC.

JohnBoy2000

JohnBoy2000

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I'm trying to figure out how I can attain the most acute effect on noradrenaline - polypharmacy being an option but, preferably limited to two drugs.

https://en.wikipedia.org/wiki/Pharmacology_of_antidepressants#Receptor_affinity

Going off this chart - the options available to me seem to be:

- Atomoxetine
- Lofepramine
- maprotiline
- mianserin
- Nortriptyline
- Reboxetine

Possibly Protriptyline - currently looking into whether or not it can be sourced.

Attempting to mitigate the effect on serotonin as much as possible, and increase the effect on NA.

Currently taking:

- Mirtazapine, 45mg
- Bupropion, 300mg (I tried 450 mg - very sedating).

Perhaps the first step would be to make the addition of a third pure noradrenergic like reboxetine or atomoxetine - to the dual combination which I am currently taking.
That was suggested in a pubmed article, referencing Stephen Stahl as the source.
Though upon reviewing the anti-depressant section of his book, I could not actually find where that was mentioned.

My other thought is, substitute mirtazapine (which I love, cause it helps me eat and puts me to sleep), for one of the aforementioned.

Possibly another tetracyclic - or third generation tricyclic like lofepramine, possibly nor/protriptyline.

Would it be possible to add in another tri/tetracyclic WITH mirtazapine and bupropion?
Or is that pushing it a little too far?
 
Well - it's intimately involved with cognitive and executive function - both of which need some tending to in my case.

I've benefited from NA in the past, have NOT benefited from SER - the opposite in fact.
It exacerbates my chronic fatigue (main condition), and impairs further my concentration.

Bupropion - best med so far.
That being said - it's still falling short of the mark.
Need more, to regain functionality enough to, say, get a part time job.
 
Fair enough perhaps alpha 2a adrenic Antagonism it indirectly increases noradrenaline by presynaptic autoreceptors. Actually I think mitrazapine might have some affinity here. Also what about caffeine that has clears on attention and executive functions. Also there is the alpha 1 adrenic receptor. And there might be a difference between how drugs increase norepinephrine I wonder of tricyclic and tetracyclic vind directly to the net transporter like say strattera
 
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d1nach said:
Fair enough perhaps alpha 2a adrenic Antagonism it indirectly increases noradrenaline by presynaptic autoreceptors. Actually I think mitrazapine might have some affinity here. Also what about caffeine that has clears on attention and executive functions. Also there is the alpha 1 adrenic receptor. And there might be a difference between how drugs increase norepinephrine I wonder of tricyclic and tetracyclic vind directly to the net transporter like say strattera
Click to expand...

I
I dunno, I'm kind of going on the assumption here that you guys are the experts...

Alpha 2 antagonism does disinhibit NE releaese.
Alpha 1 - from what I understand, antagonism here would be preferably avoided - I vaguely recall stahls book outlining this implicates sertonine more so.

Mianserin does impact NET, as well as maprotiline, though the later much more potently, seemingly.

Going on it's binding profile, mianserin seems to be a more potent version of mirtazapine, in terms of 5ht2a/c blockade and resulting NE effects.

Maprotaline appears to function more so as an NE reuptake inhibitor.


So - that's loosely the information regarding their mechanics I'm aware of.

http://www.dr-bob.org/babble/20140419/msgs/1064802.html

I came across this post, the poster seemingly quite well informed regarding the pharmaco-mechanics - though it is just anecdotal, seemed to feel mianserin implicated NE much more potently the mirtazapine.
 
Caffeine doesn't implicate NE.

Ritalin had only a minimal impact, I doubt a cup of coffee is gonna do a whole lot more.
 
Im no expert haha im just some twenty year old. But it seems like affinity for the norepinephrine transporter is hands down highest for atomoxetine and reboxetine which makes sense because chemically they look very similar with affinities of 5 and 16 ki nM which is much much higher than mianserin at 71 ki nm and with much less other binding sites. (The lower the number the higher the binding )

As for alpha adrenic 1 I meant agonism. *although I forget how yohimbine works but I think thanks a antagonist at one of the alpha adrenic receptors and I dont think its type 2 because it increases not decreases bp. So im not positive

Alpha type 2 adrenic receptors antagonizing them would be expected to lower noradrenaline but the brain has these weird autoreceptors on presynaptic neurons so blocking those paradoxically increases noradrenaline
 
Hold on here now I have a headache ok I think both alpha adrenic 2 activation and deactivation increase adrenic signaling beca use both are simply occupying a auto/hetero receptors that is how both mitrazapine and yohimbine could antagonism a2a and tenex agonize a2a but both increase noradrenaline signaling in the brain.
 
Mirtazapine can also cause release of serotonin because the presynaptic autoreceptors it blocks are located on terminals that release serotonin as well.

Anyways, it's important to seperate the acute effects of serotonin from the chronic effects.
 
^agreed. you really got to give the seritonin targets of antidepressants a few weeks before you can tell of they work
 
http://www.dr-bob.org/babble/20140419/msgs/1064802.html

I came across this post, the poster seemingly quite well informed regarding the pharmaco-mechanics - though it is just anecdotal, seemed to feel mianserin implicated NE much more potently the mirtazapine.
Click to expand...


Anyone have an opinion on the information in that link?

In terms of increasing focus on NE, my options are, replacing mirtazapine with either:
- Maprotiline
- mianserin
- lofepramine
- nortriptyline

Again, with a preference to exclude SER implications, and anticholinergic implications.

I also like the somnolence inducing properties of the tetracyclics, as well as their appetite stimulation, so personally, I feel maprotiline or mianserin would be good next steps.

Though given binding profiles, it's difficult to differentiate as to which has the more potent NE effects.

Maprotiline has the higher NE reuptake inhibition binding value, slight implication on 5HT2a, negligible 5HT2c, and negligible effects on alpha 2 antagonism.

mianserin has a much weaker NE reuptake inhibition value, but much tighter binding to 2a/2c receptor subtypes, as with alpha 1.

So it seems a little like mirtazapine, except with the addition of higher NET.
I suspect it's more sedating also, given is tighter H1 binding, relative to the binding values on the other subtypes; an opinion shared anecdotally by the poster in the above link.
 
I see no reason why Mianserin's a2a antagonism wouldn't function the same exact way as mirtazapine's and affect the release of many different neurotransmitters. If Mianserin has specificity for increasing NE over mirtazapine, that effect must be coming from elsewhere (other than presynaptic a2a antagonism).

I think it's an NRI.
 
[TABLE="class: sortable wikitable jquery-tablesorter"]
[TR]
[TH="class: headerSort, bgcolor: #F2F2F2, align: center"]Compound[/TH]
[TH="class: headerSort, bgcolor: #F2F2F2, align: center"]SERT[/TH]
[TH="class: headerSort, bgcolor: #F2F2F2, align: center"]NET[/TH]
[TH="class: headerSort, bgcolor: #F2F2F2, align: center"]DAT[/TH]
[TH="class: headerSort, bgcolor: #F2F2F2, align: center"]H1[/TH]
[TH="class: headerSort, bgcolor: #F2F2F2, align: center"]M1-5[/TH]
[TH="class: headerSort, bgcolor: #F2F2F2, align: center"]α1[/TH]
[TH="class: headerSort, bgcolor: #F2F2F2, align: center"]α2[/TH]
[TH="class: headerSort, bgcolor: #F2F2F2, align: center"]5-HT1A[/TH]
[TH="class: headerSort, bgcolor: #F2F2F2, align: center"]5-HT2A[/TH]
[TH="class: headerSort, bgcolor: #F2F2F2, align: center"]5-HT2C[/TH]
[TH="class: headerSort, bgcolor: #F2F2F2, align: center"]D2[/TH]
[TH="class: headerSort, bgcolor: #F2F2F2, align: center"]MT1A[/TH]
[TH="class: headerSort, bgcolor: #F2F2F2, align: center"]MT1B[/TH]
[/TR]
[/TABLE]
[TABLE="class: sortable wikitable jquery-tablesorter"]
[TR]
[TD]Mianserin[/TD]
[TD]4000[/TD]
[TD]71[/TD]
[TD]9400[/TD]
[TD]1.0[/TD]
[TD]500[/TD]
[TD]74[/TD]
[TD]31.5[/TD]
[TD]1495[/TD]
[TD]3.21[/TD]
[TD]2.59[/TD]
[TD]2052[/TD]
[TD]?[/TD]
[TD]?[/TD]
[/TR]
[/TABLE]
[TABLE="class: sortable wikitable jquery-tablesorter"]
[TR]
[TD]Maprotiline[/TD]
[TD]5800[/TD]
[TD]11.1[/TD]
[TD]1000[/TD]
[TD]1.7[/TD]
[TD]560[/TD]
[TD]91[/TD]
[TD]9400[/TD]
[TD]?[/TD]
[TD]51[/TD]
[TD]122[/TD]
[TD]665[/TD]
[TD]?[/TD]
[TD]?[/TD]
[/TR]
[/TABLE]
[TABLE="class: sortable wikitable jquery-tablesorter"]
[TR]
[TD]Mirtazapine[/TD]
[TD]>10000[/TD]
[TD]4600[/TD]
[TD]>10000[/TD]
[TD]1.6[/TD]
[TD]794[/TD]
[TD]608[/TD]
[TD]20[/TD]
[TD]18[/TD]
[TD]69[/TD]
[TD]39[/TD]
[TD]5454[/TD]
[TD]?[/TD]
[TD]?[/TD]
[/TR]
[/TABLE]

That's a little hard to read but, it's alpha 2 binding is slightly weaker the remeron, but, how potent 71nM is considered terms of NET, relative to it's other values and thus its potential concentration - not really a crazy strong inhibitor - but certainly significant compared to remeron.

Maprotiline seems to act solely in NET.
That would be the alternative.

Anecdotal run down I linked above claims greater activation with mianserin - much greater.
 
I tried to access some website which had the functional activity ic50 values for greater clarity but, need an academic password or some shit.
 
The 5-HT2C blockade is significantly stronger indeed. Generally these sorts of mechanisms that lead to higher neurotransmitter levels synergize well with disabling homeostatic mechanisms. For example, blocking autoreceptors and blocking reuptake inhibition - the autoreceptors can normally respond to the increased neurotransmitter concentrations by shutting off the pre-synaptic neuron, but not if they're blocked.
 
Alright, riddle me this.

Mirtazapine exerts a blockade on several 5ht receptor subtypes.

This seemingly incites a release of NE.
It antagonizes alphalfa-2 - same deal - implicates NE.

Has a hefty enough 5ht-1a blockade - I have no idea how that implicates serotonin levels; apparently its agonism raises dopamine levels.

So - it appears to downregulate serotonin, no?

How is that useful to someone who has low serotonin levels?

It claims to be a noradrenergic and specific serotonin antidepressant.
But, given its binding profile, is it not more, just a noadrenergic AD?

As well as the fact that it's co-prescribed with SSRI's all the time - with no fear of serotonin syndrome.

So again - where along the line does it positively influence serotonin?

It does not act as a reuptake inhibitor.

Where along the line does it implicate serotonin exactly?
 
Cotcha Yankinov said:
The a2 autoreceptors are located presynaptically on serotonergic cells (among other cell types)

But see this study for comparisons between Mianserin and mirtazapine https://www.ncbi.nlm.nih.gov/m/pubmed/8627567/
Click to expand...

Pfff
The abstract there at least seemed to claim mirtazapins more potent effect on noradrenaline - using, "DOPAC", as a marker of this - seemingly.

Have I interpreted that correctly?

I just used scihub, or such - to successfully unlock the full text.
Oorah!

Just out of curiosity - did you get that article by typing "mirtazapine mianserin comparison" into pubmed?
Or come across it through another means?
 
I just took strattera 80 mg and it seems pretty strong at noradrenaline nose was congested all clear now no euphoria pupil dialation to be honest it feels like adderall without the euphoria I dislike I feel anxious though
 
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