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Poor tolerance to one NRI - success with another?

JohnBoy2000

JohnBoy2000

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May 11, 2016
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You know with SSRI's - people may try two or three, before they find one that works.
Even though they essentially share the same mechanism of action - SER transporter blockade - right?

Of course each has varying secondary characteristics - prozac - the 5HT2c blockade, zoloft - a slight DRI, the one with the cholinergic properties etc.

But - the fact remains that, someone may not tolerate an SSRI will, switch, and do better on the next - right?

Well - can the same be applied to an NRI?

If a high dose is inducing sedation/anxiety - let's say, desipramine, does it stand to pharmacological reasoning and clinical experience that, perhaps a differnt NRI, say, Reboxetine - might incite a more favorable response in said patient?
 
The difference is only caused by the things you've said:

(I) sertra's DRI effects

(II) fluox' 5-ht2c antag

(III) and so on

switching a truely selective "S"SRI (e.g maybe parox for maybe esCit) is predicted to maked no real difference (well maybe something like different CYP actions in the liver, but other than that ...)
 
Yeah I'm not convinced that some difference in association/dissociation mechanics is going to make an appreciable difference from NRI to NRI, its probably just off-target effects and PK effects that give rise to whatever differences.

As opposed to receptor association/dissociation mechanics with sodium channel antagonists and NMDA antagonists, for example see "low trapping" (memantine) vs. "high trapping" (ketamine) NMDA antagonists - depending on how the NMDA antagonist blocks the channel (Whether it gets stuck in there for very long) it can produce very different effects.
 
Cotcha Yankinov said:
Yeah I'm not convinced that some difference in association/dissociation mechanics is going to make an appreciable difference from NRI to NRI, its probably just off-target effects and PK effects that give rise to whatever differences.

As opposed to receptor association/dissociation mechanics with sodium channel antagonists and NMDA antagonists, for example see "low trapping" (memantine) vs. "high trapping" (ketamine) NMDA antagonists - depending on how the NMDA antagonist blocks the channel (Whether it gets stuck in there for very long) it can produce very different effects.
Click to expand...

Yes, even though memantine directly binds to the exact same site that mk-801 (and therefore also ketamine and PCP [which is why it's also called the PCP1-site [the PCP2-site is probably a sigma receptor {either sigma1 and/or sigma2}] binds to, but memantine is "low-trapping", which is why, even in high doses, it can never cause the same dissociation as the other, previously mentions dissos!
 
^Its interesting to note that there are some scattered reports of people holing with memantine at heroic doses lol, there was a trip report over in psychedelic drugs a few days ago about a 150mg dose that a person had a pretty good hole on. I can report some significant effects from around 100mg that got boosted to hole-ish status with some added DXM.

But the consensus seems to be that memantine is very cold and mechanical at high doses, not to mention effects linger forever 0.0

So I wonder if a high trapping NMDA antagonist is required to affect synaptic NMDA enough to lead to the particular transmitter release that produces the "warmness", while memantine can affect extrasynaptic NMDAr enough to throw off neural oscillations/regional communication and still cause dissociative experiences. I hope that makes some sense.
 
WSH said:
Yes, even though memantine directly binds to the exact same site that mk-801 (and therefore also ketamine and PCP [which is why it's also called the PCP1-site [the PCP2-site is probably a sigma receptor {either sigma1 and/or sigma2}] binds to, but memantine is "low-trapping", which is why, even in high doses, it can never cause the same dissociation as the other, previously mentions dissos!
Click to expand...
The PCP-2 site is actually on the dopamine transporter. The point of developing BTCP was to find a ligand that was selective for PCP-2.
 
Memantine doesn't produce effects that are that different from ketamine, it just has a much longer onset/metabolism time.
 
Just on a related note:

If the action of NRI's is ultimately to downregulate the postsynaptic receptors, via increase of synaptic NE - wouldn't an NE receptor blocker, kind of mimic that affect - and thusly have therapeutic effect similar to NE based AD's??
 
Some portion of the MAO of SSRIs and SNRIs is downregulation of 5-HT2A/5-HT2C and downregulation of beta-adrenoreceptors (Respectively for SSRIs and SNRIs) but this is probably a small piece of the puzzle. Things that mediate the downstream effects of NE and 5-HT receptors like cAMP and CREB are upregulated with long term antidepressant use.

The other thing is that NE increases the firing rate of 5-HT cells, and antidepressants can sensitize 5-HT1A's function and upregulate 5-HT1A. I've only read about this sensitization/upregulation of 5-HT1A with SSRIs, but I'll bet it happens with NRIs a bit too.

Mind you I'm really not sure if NRIs are actually effective antidepressants, I think in most cases what is talked about are dual action SNRIs. The effect of SNRIs vs. NRIs on depression could be very different, as is the case with dual action dopamine + NE releasing agents vs. pure NE releasing agents. NE release is probably a required part of euphoria from amphetamines, but pure NE release supposedly isn't that great.

Also you do have something like Clonidine that some people find useful, although it is a autoreceptor agonist (as opposed to mirtazapine) it also binds post-synaptically to a2a in the PFC IIRC
 
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Clonidine intrigued me given its mechanism - until I read its side effect profile.
Basically, sedation, fatigue etc - the opposite of an NRI.

NRI's are the only way to go for me.
I benefit inversely from serotonin action.

Funny how these cases differ from one person to another but, I'd bet the reboxetine trials came up so short due to just what you mention; it's more than likely only a very small percentage of the depressed population benefit from highly selective NRI.
 
And there could also just be a symptomatic benefit that would not be retained after tapering the drug, and these were endpoints that some people were looking for in the trials/approval process.

I wouldn't necessarily place NRI in the same genre of ketamine (a ketamine dose is usually effective for a few weeks but severe cases can require maintenance therapy) but if we're just thinking about symptomatic improvement then even just amphetamine comes to mind - which definitely doesn't qualify as an "antidepressant".

Another example is opiates - they can be used as a drug of last resort in severe intractable depression but they wouldn't be classified as an antidepressant.

Also, if your reasoning is that Clonidine will cause fatigue etc due to a2 agonism, then a logical conclusion would be that as Mirtazapine's a2 antagonism becomes appreciable at higher doses, you would receive the opposite effect.
 
Well - I was just basing that off SPC's and clinical information on Clonidine observations.
I had thought that being an alpha agonist it could possibly downregulate post-synaptic adrenergic receptors - reduce receptor hypersensitivity, the postulated cause of depression.
But the clinical data says that is not the outcome.

But yeah relative to remeron - I believe that is the case.
The higher the dose - the more activating many consider it to be.
 
Unfortunately I think depression and other mental illnesses are much more complicated than receptor homeostasis type issues. The goal of most depression therapies is to increase the strength of neurons and increase the number of new neurons being generated, as well as alter the function of the brain itself in a "This brain area needs to talk more to this brain area - That brain area needs to talk less to this brain area" kind of way.

Have you gone above 45mg on mirtazapine?
 
Yes - up to 60 mg - and it was horrible.
Complete regression - confined to bed, horrible IBS etc.

Hopefully switching to its analogue, Mianserin, in the next few days.

I do understand some people can do well above 45 mg of remeron though - just, I'm not one.
 
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