Why is Mirtazapine Activating After A Certain Point?

[Mermaid16]

I have tried to increase over 30mg as Mirt does seem to lift my depression very quickly, but anything over 30mg is too activating and my anxiety is through the roof, so then I have to reduce back down. Why is this?

[MyNameIsTerry]

I think this post is like shining the bat torch into the sky and Ian will be along soon to give you a far better answer :biggrin:

But I think it's because the antidepressant effects kick in above the dose where the body adjusts to the antihistamine effects. This means more Serotonin which causes blocking to Norepinephrine receptors, which means more Noepinephrine gets produced & released to compensate.

I think...

[panic_down_under]

I think this post is like shining the bat torch into the sky and Ian will be along soon to give you a far better answer :biggrin

:roflmao: I did used to fly mainly at night, so Batman and I had that in common. But I moved a lot faster and packed a much bigger punch.


But I think it's because the antidepressant effects kick in above the dose where the body adjusts to the antihistamine effects. This means more Serotonin which causes blocking to Norepinephrine receptors, which means more Noepinephrine gets produced & released to compensate.

Yep, mostly this ^^. At the lower half of the dose range mirtazapine pretty much just clogs up the histamine receptors, i.e. is an antihistamine, which calms by sedation, but as the dose increases the med begins affecting other receptors systems, with 5-HT2a the next to fall setting in train pretty much that scenario.

After mirtazapine became available all the other drug companies began developing 5-HT2a receptor antagonists for depression and anxiety. None made it onto pharmacy shelves, at least not for psych disorders. They didn't work. Quite a few antihistamines, for example cyproheptadine (Periactin) which is also used to treat serotonin syndrome, are even more 5-HT2a antagonists. Excitation/nervousness/restlessness are common side-effects.

Most atypical antipsychotics are are also potent 5-HT2a antagonists, but they have other things going for them which tend to moderate the activation at higher doses, though at the expense of potentially some very unpleasant side-effects.

[hanshan]

Mirtazapine affects a number of neuroreceptors, mostly as an antagonist (blocker), but with a variety of effects.

Its most potent initial effect is as an antihistamine, hence the sedative effect, although tolerance to this effect quickly develops.

What has not been mentioned above is that mirtazapine is an antagonist of alpha 2 receptors. Alpha 2 receptors limit the release of both serotonin and noradrenaline. Hence, if these receptors are blocked, more serotonin and noradrenaline are released. The extra noradrenaline can account for the activating effect.

Conversely, mirtazapine also blocks some serotonin (5-HT) receptors. Blocking the 5-HT3 receptor has an anti-nausea effect. Blocking the 5-HT2A and 5-HT2C receptors is still a subject of discussion. Stimulating the 5-HT2A receptor can cause hallucinations, so blocking may reverse that. There is also a belief that some people with depression have an oversupply of 5-HT2A receptors, and if so, blocking may help relieve depression.

[Mermaid16]

Thanks guys for your replies. I dropped the dose back down and the anxiety dropped back down as well. I don't really understand the how these drugs work, but am praying that the clomipramine doesn't cause any activation. I hate med changes and am already anxious about dropping the Nortriptyline and starting the Clomipramine this week. Fingers crossed it goes okay. I'm prepared to be a little uncomfortable but hoping it won't be too bad.

[panic_down_under]

What has not been mentioned above is that mirtazapine is an antagonist of alpha 2 receptors. Alpha 2 receptors limit the release of both serotonin and noradrenaline. Hence, if these receptors are blocked, more serotonin and noradrenaline are released.

If a2 receptor antagonism triggered a clinically significant release of serotonin then taking mirtazapine with SSRIs and especially MAOIs would trigger serotonin toxicity, but such combinations are not uncommon and have proven to be risk free. To quote one of the leading ST authorities (and of serotonin neurotransmission generally), Dr Ken Gillman (http://scholar.google.com.au/citations?user=ea6KeD0AAAAJ&hl=en):

As I have pointed out before, drugs like bupropion and mirtazapine, that have no significant serotonergic activity, are no more likely to cause ST than is vitamin C

PK Gillman, 2010 PDF (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3550296/pdf/13181_2010_Article_84.pdf)

Presumably, its effect on noradrenaline/norepinephrine release is not that great either.

BTW-Gillman is even less impressed (http://psychotropical.info/anti-depressants/other) with the mirtazapine antidepressant claim than I am:


There must be major doubts about its ability to act as an effective antidepressant because there is no established plausible mechanism by which it could achieve that effect. If it is an antidepressant, then new ideas are required to explain how it achieves this effect.

Which doesn't mean it isn't a useful med. It can be, but just not for the reasons claimed.

[Maca44]

I have been taking Mirt for 4mths now and am very impressed with it because it has lifted my depression greatly and helped control my chronic anxiety, I am so much better.

I know it may not work for some but I think you can get too wrapped up with how it works or how it doesn't work it will suit some people and i'm one of them. The internet is full of reports or study into drugs and most either try to diss them or praise them but if it works it works and it's all you need to know sometimes.

I would hate to put someone off of this drug when I know how well it has worked for me.

[panic_down_under]

I would hate to put someone off of this drug when I know how well it has worked for me.

Sure. To expand on the last sentence of my previous post, mirtazapine can be an effective med for anxiety, anxious depression and very severe, almost catatonic depression, but that effectiveness seems to be driven by factors other than an antidepressant effect.

[Maca44]

Sure. To expand on the last sentence of my previous post, mirtazapine can be an effective med for anxiety, anxious depression and very severe, almost catatonic depression, but that effectiveness seems to be driven by factors other than an antidepressant effect.

I was so depressed 4 mths ago that I was planning how I could call it a day as the chronic anxiety was making life unbearable, I had been given CBT on the NHS and although this helped it was short so I'm now waiting for counselling but I have been waiting ages for this to start. I guess i'm so pro Mirt because it has enabled me to live a fairly normal life again so I have been able to keep my job and interact with people again so for me it has been a life saver.

My only gripe is the Carb cravings which has caused me to put on a stone but this is something I can deal with by changing my diet also it caused me to feel really sedated to start with but this went away about a week into starting.

[MyNameIsTerry]

I was so depressed 4 mths ago that I was planning how I could call it a day as the chronic anxiety was making life unbearable, I had been given CBT on the NHS and although this helped it was short so I'm now waiting for counselling but I have been waiting ages for this to start. I guess i'm so pro Mirt because it has enabled me to live a fairly normal life again so I have been able to keep my job and interact with people again so for me it has been a life saver.

My only gripe is the Carb cravings which has caused me to put on a stone but this is something I can deal with by changing my diet also it caused me to feel really sedated to start with but this went away about a week into starting.

Being open minded about meds is the best way. Understanding how to manipulate a drug through it's dosage variations, like discussed here, is also useful since so many GP's don't understand it themselves.

The med I'm on was an utter nightmare, and remained so for years. I've seen a couple of others have my experience but I've also seen people say the same as you therefore I'm always of the opinion that these meds are too individual for anyone to ever say how we will respond, only how we could or are expected to. The rest is the gamble of the meds minefield.

I've seen threads by people hospitalised by this med. But then I've known people who've had the same experince with Sertraline. This is one of the big problems we all face as our GP's are working through treatments they just don't understand based on guidance and for some it's a box ticking exercise until they get to a med that helps.

In your position, I would expect anyone to speak highly of this med. But I also don't doubt you understand it's failures too.

[SmilingAlbert]

Interesting discussion.

I seem to recall reading that, even now, the science is not definite as to why any modern ADs 'work' (or work for many/most people - modern defined as anything post Fluoxetine) - certainly the endless legalistic printouts with modern ADs say stuff like "thought to..." and "believed to..." rather than any hard and fast statements.

Whereas the science behind, say, benzos (valium etc.), is fairly clear, as is the same for alcohol, which are not unrelated in active effect and indeed in chemistry, as I understand it.

This is problematic, since Benzos and indeed alcohol 'work' for more or less everyone. If the guys in ER/A&E need to calm someone down quickly, they inject valium. Works 99.9999% of the time. If you want a great party, supply a lot of alcohol. Works 99.9998% of the time.

But both come with a whole world of problems with prolonged use including tolerance and dependence. Many would argue that these factors come into play for modern ADs, but of course not all modern ADs work for everyone, in contrast.

Genome and related research could make an enormous contribution here, I suggest. It could be in a decade or two the frankly absurd 'you won't know until you try it' approach currently taken (and advanced here ad nauseam) will be consigned to the dustbin, and not before time. It could improve lives far quicker, and save countless others from undergoing unsuitable treatments in the first place. We could shortcut this to an extent; e.g. if your brother responds well to say fluoxetine, I *suggest* that it makes it more likely that you will too. But the social/confidentiality aspect might preclude this shortcut.

We have a ton to learn still about that most complex of muscles, the human brain.

Albert

[hanshan]

The whole serotonin theory of depression (and related mood disorders) is definitely a work in progress. There is still much that does not make sense and much that is unknown. It is not simply a case of depression = lack of serotonin. We know that multiple neurotransmitters and mechanisms are involved, but they haven't given up all their secrets yet.

Nevertheless, there is a plausible mechanism for the serotonergic power of mirtazapine - that it blockades alpha 2 heteroreceptors in serotonergic nerve terminals, causing a release of serotonin. This is the standard account in all the published pharmacology that I can see.

I realise that Dr Gillman disagrees with the above account, but it is a case of him versus the scientific establishment (which he admits). He writes many papers, but they are fundamentally reviews, based on the original research of others. By training, he is a retired psychiatrist.

Can I add, that even if one were to agree with Dr Gillman concerning mirtazapine and serotonin, he cites a paper that states that mirtazapine increases noradrenaline and dopamine concentrations by the mechanism stated above.

[Blinkyrocket]

I believe Mirtazipine's actions at 5-HT2a, 5-HT2c, and 5HT3 receptors can all be possible mechanisms of its antidepressant effect. Antiemetics like Ondansetron have even shown antidepressant effects, with it somehow being related to the fact that the 5-HT3 receptor is an ion channel, like the NMDA receptor. At least, I think. Also, antagonizing the 5-HT2a receptor somehow causes neurogenesis through the AMPA glutamate receptor, I think. And then the 5-HT2c receptor blockade might also cause neurogenesis and the increase of BDNF but I know for sure that it disinhibits the receptor's effect on dopamine and norepinephrine release, thereby raising their levels. The cause for the increased anxiety at a higher dose would have to be the alpha 2 adrenergic receptor antagonism, which would cause anxiety in a manner similar to the way Yohimbine does.

My theory is that the relief of depression comes down to 2 things, the relief of negative affect/emotions and the increased capacity and propensity for the Nucleus accumbens and other "Reward Pathway" parts of the brain to activate. A lot of different neurotransmitter pathways regulate these systems, and all of them might be useful as a target of antidepressants, there's likely not any one simple answer for how to treat depression and how it happens, because there are tons of different answers. So it seems anyway.