Remeron releases serotonin and norepinephrine?

[Dope_User]

From http://www.crazymeds.org/remeron.html

Remeron enhances the activity around the receptors for serotonin and norepinephrine, so unlike the SSRIs and SNRIs, Remeron stimulates your brain to release more of the serotonin and norepinephrine it has. It also antagonizes the H1 histamine receptor, which is a big reason why you get so tired and so hungry. At 15mg it will also make you very sleepy, yet at 30 and 45mg the sleepiness sometimes isn't so much of an issue. My guess is that at the higher dosages the extra norepinephrine regulates your sleep, trumping the sedation that often accompanies messing around with serotonin and histamine.

Two concepts in there that I'd like validated or disproved. One, does Remeron actually "stimulate your brain to release more serotonin and norepinephrine" or does it just inhibit reuptake of one or the other, or possible do both of these?
Second, 15 mg makes you sleepy due to H1 histamine receptor antagonism, but 30-45 mg sleepiness "sometimes isn't so much of an issue" due to "the extra norepinephrine regulates your sleep, trumping the sedation that often accompanies messing around with serotonin and histamine. Can anyone verify this with factual data or personal experience? Remeron worked well for me but made me excessively sleepy (at 15 mg/day). I wonder if I could try it again at 30-45 mg and have less (or no) sedating effect...or is this guy just full of it and if 15 mg knocked me out, if I took 30-45 mg would I just never wake up?

 

[MikeD]

You would most definitely wake up. But this guy could be right, I am not sure.

 

[techtech]

He's right, I find 45mg is no way near as sedating as 15mg.

 

[Dope_User]

This "guy" just doesn't seem all that reputable. He freely admits on the site that he is not a high school graduate and has no GED...not that this automatically means he doesn't know what he's talking about, but some of the stuff he writes on there, well, it just doesn't sound all that intelligent. I'd like some journal articles or something of that sort supporting the idea that for a person in which 15 mg/day Remeron is sedating, 30 or 45 mg is no longer sedating (or significantly less sedating).

 

[Dope_User]

I finally decided to check the prescribing information for Remeron.

Evidence gathered in preclinical studies suggests that mirtazapine enhances central noradrenergic and serotonergic activity. These studies have shown that mirtazapine acts as an antagonist at central presynaptic a2 adrenergic inhibitory autoreceptors and heteroreceptors, an action that is postulated to relust in an increase in central noradrenergic and serotonergic activity

I don't quite understand this fully. By "increase in central noradrenergic and serotoergic activity" do they mean that this causes release of more serotonin and noradrenaline? If not, what exactly does that mean?

It also states that it is a "potent antagonist of 5-HT2 and 5-HT3 receptors...[and] has no significant affinity for the 5-HT1A and 5-HT1B receptors." I'm not sure, but if Cymbalta were an agonist of 5-HT2 and/or 5-HT3 receptors, it seems as though taking Remeron with Cymbalta would have cancelling effects and therefore basically have no effect on 5-HT2 and/or 5-HT3 receptors (again, if Cymbalta is an agonist of5-HT2 and/or 5-HT3 receptors). Am I on the right track here? And if so, what effect would combining the two have on the antidepressant effects of both? Would they in any way "cancel" each other out or work together to provide a greater antidepressant effect than either alone?

 

[BilZ0r]

Theres a lot of questions in the thread, I'll try and cover them, but ask them specifically if I miss one...

Studies generally show that Remeron (mirtazapine) does cause increase release of dopamine, noradrenaline and serotonin... thought these studies are confounded by stress, which can cause the release, or inhibition of these neurotransmitters, and mirtazapine alters stress responses.

I couldn't comment on the dose-response sleep/wake idea... its possible, but I doubt it, sounds like an idiosyncratic response.

Activity is a naughty word, that pharmaceutical companies like to use, when they don't really know whats going on. It SHOULD mean an increase in firing rates in cell bodies, but it's often used to mean increase in release, or turn over, and even an increase in a behavioural response which can be blocked by an antagonist.

Cymbalta (Duloxetine) is a mixed NET SERT inhibitor, so it is an indirect agonist of all serotonin and adrenoreceptors. Its actions on the 5-HT2 or 5-HT3 receptor subtypes are probably not central to its antidepressant activity, so the 5-HT2A antagonistic effect of mitazapine probably would be that damaging to duloxetines clinical efficacy.