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

Cotcha Yankinov said:
How high up on dose with mirtazapine have you gone?
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Mostly
45 mg.

When I was concurrently taking 225mg of effexor, I went up to 60mg - but the effect was reversed and it exacerbated all the symptoms.
Whether that was a product of the combination, or just going above the licensed dose of 45 mg - I don't know.

If I were to do 60 mg with bupropion now being the combination - perhaps the effect would be different?
 
I suspect blockade of autoreceptors strongly modulated the response to Effexor

Mirtazapine is a fairly different drug at higher doses, but is probably (in terms of synaptic neurotransmitter concentrations) very synergetic with reuptake inhibitors

And yes I would be wary of seizures.

Have you thought about nootropics such as noopept? I would very wary of trying that whilist on other drugs however.
 
Cotcha Yankinov said:
I suspect blockade of autoreceptors strongly modulated the response to Effexor

Mirtazapine is a fairly different drug at higher doses, but is probably (in terms of synaptic neurotransmitter concentrations) very synergetic with reuptake inhibitors

And yes I would be wary of seizures.

Have you thought about nootropics such as noopept? I would very wary of trying that whilist on other drugs however.
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When you say different at higher doses - different how?

I know at 15 mg it's apparently considered more so just a strong anti-histamine, and up to 45 mg, implicates the alpha 2 blockade, noradrenaline release, serotonergic blockades etc.

Up at 60 mg, alright so, it does more of the same?
But a variation in its actual neuromechanics?
 
Mitrazapine does not bind to the noradrenaline transporter. The NET regulates influx of noradrenaline in back into the presynaptic neuron. Inhibiting noradrenaline transporters increase noradrenaline in the synaptic cleft increasing the probability it will bind to a receptor as a ligand. Mitrazapine acts directly as a ligand at alpha adrenic receptors by acting as an antagonist/inverse agonist thereby bllcking noradrenalines ability to bind to alpha 2 adrenic receptors on the presynaptic neuron it increases free noradrenaline in the synaptic cleft increasing the probability it can bind to post synaptic receptors and by clogging the presynaptic alpha 2 adrenic receptors it prevents the megative feedback loop of norepinephrine binding as a ligand to presynaptic a2a receptors triggering Gi gcpr signaling which decreases çAMP signaling resulting in a reduction of your brains ability to sense noradrenaline in the cleft reduced ability to accept noradrenane onto inhibitory autoreceptors and reduced downregulation of noradrenline release in response to elevated noradrenaline in the synapse.
 
The dose response curve is such that you're going to see less histaminergic type effects (those receptors will saturate) above 60mg. The histamine receptors will also desensitize.

In addition to blocking a2 autoreceptors, elevated serotonin concentrations will eventually desensitize serotonergic auto receptors, allowing serotonin concentrations to vastly increase and give rise to different effects over different time periods.

I wouldn't count out serotonergics just because they make you fatigued in the short run.
 
I agree the brains very complex and its likely optimal effects would involve multiple chemicals
 
Cotcha Yankinov said:
The dose response curve is such that you're going to see less histaminergic type effects (those receptors will saturate) above 60mg. The histamine receptors will also desensitize.

In addition to blocking a2 autoreceptors, elevated serotonin concentrations will eventually desensitize serotonergic auto receptors, allowing serotonin concentrations to vastly increase and give rise to different effects over different time periods.

I wouldn't count out serotonergics just because they make you fatigued in the short run.
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Okay that actually leads me on to another important question.

Mirtazapine is antagonizing a lot of the 5ht receptor subtypes.

You mention also that it increases serotonin activity though.

I assume, as I'm not clear on it, that this is also done through alpha 2 blockade?
Cause according to its binding profile, that appears to be the only other implication of mirtazipine outside of its 5HT blockades - ignoring its antihistamine action of course - cause that don't mean squat anyways.

So - is mirtazapine considered a potent activator of serotonin, based purely on its alpha 2 blockade?

If we were to somehow speculate on it's effect ratio of serotonin to noradrenalines, as in, effexor is 30 to 1.
Cymbalta is 10 to 1 (favoring serotonin).

Would it be possible to speculate on mirtazapines?
I'm aware in not effecting the neurochemical transport mechanisms, so not comparing from that point of view of course.

Would it be considered primarily a serontonin agent?
Or a noradrenaline agent?

By example - bupropion is a NA and DA agent - but primarily a NA agent.
 
Mirtazapine is an indirect agonist of 5-HT1A which is largely responsible for antidepressant response, the other receptors like 5-HT2A are actually desensitized (they are atypically regulated) with continued blockade, but seeing as excess 5-HT2 receptor activation could be contributing to depression in some cases the antagonism/inverse agonism is certainly not a bad thing.

I was under the impression mirtazapine was probably around 50/50 serotonin/NE but there could be actual data somewhere, it's just probably expensive to do that measurement of respective metabolites in vivo and it could vary from species to species. But I was under the impression that 5-HT1A activation was thought to be regarded as most responsible for mirtazapine's antidepressant efficacy, because if I recall correctly blockade of 5-HT1A blocked mirtazapine's beneficial effects in behavioral models.

And yes the a2 receptors are located on presynaptic serotonergic terminals as well as NE terminals, and many terminals do release more than one neurotransmitter anyways (co-release). Normally when adrenaline binds to a2 autoreceptors it shuts off the presynaptic neuron and stops it from releasing neurotransmitters into the synaptic cleft - blockade of autoreceptors blocks this homeostatic inhibition.

See for example pindolol, a (far from selective) 5-HT1B/5-HT1D autoreceptor antagonist that was very mildly effective as an adjunct with SSRIs.
 
^ i agree fully with cotcha on mitrazapines interactions at5 ht1 and 5 ht2

Im not sure if you know this so i figured i mine well say it 5 ht stands for seritonin both seritonin and 5 ht stands for 5 hydroxytryptamine i remember it by trypamines like dimethyltryptamines are psychadelics because they interact with 5 hydroxy tryptamine receptors
 
Cotcha Yankinov said:
Mirtazapine is an indirect agonist of 5-HT1A which is largely responsible for antidepressant response, the other receptors like 5-HT2A are actually desensitized (they are atypically regulated) with continued blockade, but seeing as excess 5-HT2 receptor activation could be contributing to depression in some cases the antagonism/inverse agonism is certainly not a bad thing.

I was under the impression mirtazapine was probably around 50/50 serotonin/NE but there could be actual data somewhere, it's just probably expensive to do that measurement of respective metabolites in vivo and it could vary from species to species. But I was under the impression that 5-HT1A activation was thought to be regarded as most responsible for mirtazapine's antidepressant efficacy, because if I recall correctly blockade of 5-HT1A blocked mirtazapine's beneficial effects in behavioral models.
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[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 headerSortUp, 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]
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[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]
[/TR]
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[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]
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From that PMC article I linked above, that would make sense, regarding your assertion that 5HT1a is responsible for mirtazapines serotonergic effects - as mianserin lacks serotonergic activity, and its binding value is very weak/negligible on 5HT1a.
Much tighter on 2a and 2c, as well as its NET binding, which isn't super strong, but significant.

My doc recommended I introduce lofepramine.
I mentioned mianserin, to which he didn't really have a response.

My doc is from a neuroscience background (masters), so seems to focus quite a bit on downstream drug implications and cell biology - and for that reason, doesn't really put any stock into the "pharmacodynamic theory" - i.e. examining the binding on receptor subtypes and using that as a means to predict the outcome or effect of the drug.
In other words, he doesn't base his recommendations off pretty much exactly what we're doing here - and discredits that approach, pretty much entirely.

For that reason, I'd have to put his recommendation in perspective of his background and overall treatment approach.

I personally think replacing mirtazapine with mianserin, instead of lofepramine - seems like the more logical thing to do, seems as mirtazapines "side effects" - appetite increase and somnolance - are its most valuable properties for me.
Lofepramine doesn't carry these properties - Mianserin, being a tetracyclics, does.
As well as the latters lack of anti-cholinergic effects - which of course sound nasty, and which I'd rather avoid.

Desipramine would really be the ideal drug but - like I said, no way no how under the NHS.
It can't even be sourced, for whatever reason.
 
d1nach said:
What do you mean by downstream targets cell biology????
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Good
question.

He started rambling about the implications of the different drugs, despite their binding profiles, ultimately functioned in very different ways giving their chemical structure, and how something to do with binding on the surface of cells, of surface of proteins - and mouthfuls of other jargon and he was basically using as a means to say, "I'm not gonna prescribe you something, just cause you're showing me a sheet with a list of binding profiles, the tightest ones that implicate noradrenaline, being the drug you want.

I had a look at some neuroscience books - and they seemed to have a lot of information on them topics, cell biology etc.
Markedly different from neuropharmacology books, which is where i feel the information most pertinent to me determining what potentially the most effective drug for me is, lies.

So - what do I mean by it?
I'm just vaguely repeating information thrown at me by a psychiatrist with a masters in neuroscience.

On that note - what qualification does a psychiatrist get, to become a psychiatrist??

I know they start as a medical doctor - but after that - what then?

Pharmacology, neuroscience - does it differ for different doctors?
 
Just to clarify I wasn't really implying mirtazapine's efficacy was coming from mirtazapine directly binding to 5-HT1A - the effects could be downstream of autoreceptor blockade resulting in an increase in synaptic serotonin.

And what your psychiatrist is probably trying to say is that binding affinity assays (these in vitro assays only examine affinity and ignore intrinsic efficacy/functional selectivity for receptor signaling cascades) don't have much to say about how much a specific drug will help with a specific disease. That would be better investigated with in vivo studies in animals and clinical trials in humans.
 
Cotcha Yankinov said:
Just to clarify I wasn't really implying mirtazapine's efficacy was coming from mirtazapine directly binding to 5-HT1A - the effects could be downstream of autoreceptor blockade resulting in an increase in synaptic serotonin.

And what your psychiatrist is probably trying to say is that binding affinity assays (these in vitro assays only examine affinity and ignore intrinsic efficacy/functional selectivity for receptor signaling cascades) don't have much to say about how much a specific drug will help with a specific disease. That would be better investigated with in vivo studies in animals and clinical trials in humans.
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Yeah that sounds about right.

Though, the binding profile list on wiki - aren't them values taken from in vivo studies?

And isn't mirtazapine effect on 5HT1a receptor, actually an agonist one?
In contrast to its antagonist effects on the other 5H subtypes.
Thus the former in creases serotoninergic response, not downregulating it, right?

Again - that being the cause - given the properties of serotonin increase - diarrhea, somnolance - not constipation and induction of energy, as is the case with noradrenaline; again it's something I'd rather exclude relative to my own symptoms.
 
In vivo refers to studies that examine behavior etc. in the intact animal. In vitro would be in the spectrum of examining tiny bits of neurons to somewhat intact brain slices.

I haven't even seen the affinity of mirtazapine of 5-HT1A reported, I think its pretty negligible. But yes, mirtazapine ultimately appears to decrease 5-HT2 activation and increase 5-HT1A activation.

https://www.ncbi.nlm.nih.gov/pubmed/9361334
https://www.ncbi.nlm.nih.gov/pubmed/15145142
 
Are you sure hes a neuroscientist? Psych doctors go to medical school. They can habe a masters in neurosciencebut not necessarily. My doctor rants that clinical experience is more important than binding profiles maybe that could be what he is tlking about. I have a doctor who is a phd in neuroscience and he doesnt prescribe medicine he does testing for brain damage from concussions and stuff
 
To answer the original question, a psychiatrist could have to do their residence in a psychiatric facility and they would certainly gain a lot of hands on training there, but they might have to be board certified on a psychiatry board and they could also be board certified for neurology, whereas a neurologist might only be the latter.

Their class repertoire and personal interests could result in a focus on mental illness rather than stroke etc like you might see with a neurologist.

PhD neuros could be very different. No medical degree or even medical school maybe, no residency, no MCATs for US/Canada, but that's just my guess. I would expect them to have expanded knowledge of neurobiology, biochemistry, and of course neuroscience itself compared to a psychiatrist, but it could be the case in some instances that psychiatrists are better suited to prescribing medications and interviewing/counseling patients, including CBT etc.. Psychiatrists could also have a much better understanding of the DSM, while a PhD Neuro is probably going to know more about fMRI and histology etc, and actually designing/interpreting studies.

But I suppose it all depends on your degrees and classes. I have heard of psychiatrists that have a doctorate in medicinal chemistry for example. I'm sure there are PhD neuros that have a speciality in mental illness, or neurodegenerative disease, and then PhD neuros that are ion channel physiologists or whatever and aren't necessarily looking at an entire disease but just looking at the fundamental components of the brain.
 
d1nach said:
Are you sure hes a neuroscientist? Psych doctors go to medical school. They can habe a masters in neurosciencebut not necessarily. My doctor rants that clinical experience is more important than binding profiles maybe that could be what he is tlking about. I have a doctor who is a phd in neuroscience and he doesnt prescribe medicine he does testing for brain damage from concussions and stuff
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Oh
yeah - the dude is a psychiatrist.

He did a masters in neuroscience but, as to whether he ever practiced in that field?
I don't know.
 
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