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Mirtazapine helps POTS - or so it seems!

Discussion in 'Problems Standing: Orthostatic Intolerance; POTS' started by SDSue, Apr 3, 2015.

  1. SDSue

    SDSue Southeast

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    I may have found what's been instrumental in helping my POTS. (Sorry - lengthy post)

    Due to elevated liver enzymes, my doc asked me to wean off Mirtazapine (used as needed for sleep) as well as Famvir. (I've been completely off famvir for about a month, off mirtazapine for about 2 weeks)

    I've been getting progressively worse during this time, to the point I'm back in bed. My POTS has been horrid. I blamed the lack of Famvir and viral reactivation, but I may have been wrong.

    Last night, unable to sleep at all, I broke down and took half of a mirtazapine at 4:30 am. Today, my POTS is much better. Few palpitation, resting HR back under 60, even took a shower (sitting, of course, but it counts!) My question is this:

    Does anyone know which of the following mechanisms of mirtazapine might be responsible for the control of POTS? I need to find a drug that can work without raising liver enzymes. (I failed on florinef, midodrine, salt and fluid loading) Needless to say, doctors are clueless and I need to guide mine in this process. What I wouldn't give for a good POTS doctor!!!

    The following Mirtazapine mechanisms of action are from Drugs.com

    Yohimbine is in this class, but I think it's peripheral in action? It makes symptoms much worse!

    5-HT2 antagonists include ketanserin, an antihypertensive.
    5-HT3 antagonists include drugs used to combat chemo-incuded emesis.

    Drugs in this class include ketotifen, meclizine, and promethazine among others.

    Drugs include the antihypertensive Reserpine, thought to deplete sympathetic amines in both the central nervous system and periphery.

    Includes mebeverine (IBS) trihexyphehidyl (anti-parkinson"s) diphenhydramine (good old Benadryl)

    Where's a good pharmacologist when we need one? Fortunately, it takes nearly 10 days for mirtazapine to completely clear the body, so it may be possible to take a low dose infrequently and still achieve clinically significant help with POTS. Side note: I have also on a very low dose of Atenolol for a few months, and that dose did not change during the above unintended "experiment".
     
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  2. zzz

    zzz Senior Member

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    Retired. I'm referring to Dr. Jay Goldstein. But fortunately he has written a number of books, and in Tuning the Brain, he talks about mirtazapine (Remeron) in quite a few places. Like most of his drugs, it can address most or all ME/CFS symptoms in some people. One mode of action that Dr. Goldstein notes that you haven't mentioned is that mirtazapine is an antagonist of the glycine co-agonist site of the NMDA receptor. This means that it is effectively an NMDA antagonist, and NMDA antagonists (such as magnesium) are typically very helpful in addressing autonomic disorders such as POTS. (Note that magnesium typically has to be taken in high doses through nebulization or injection to have this effect; many people would have to work up to these doses gradually.)

    I have also found it interesting that one of the few people I noticed from my Web searches for stories of recovery by a self-administered version of Dr. Goldstein's protocol had listed mirtazapine as one of his four main medications. Chlorzoxazone, which decreases the presynaptic release of glutamate, which is the major excitatory neurotransmitter of the NMDA receptors, was also present in the list of drugs of all the people I found who used this protocol successfully. They typically reported full remissions after a few years.

    Dr. Goldstein also found that ME/CFS patients were typically low in norepinephrine, so mirtazapine's effect in increasing norepinephrine levels could also be helpful here. Norepinephrine is tricky, though; it has to be increased in just the right amounts in just the right places in the brain, or else it can have negative effects.

    ETA: As for alternatives to mirtazapine, on one hand, magnesium therapy for POTS would seem like it would be very helpful for you. If you're looking for another antagonist of the glycine co-agonist site of the NMDA receptor, guaifenesin is the best. Dr. Goldstein recommends the 1200 mg extended release version of guaifenesin, which is available in the U.S. under the Mucinex brand. (Mucinex has patented the extended release feature.)

    For increasing norepinephrine safely, I find the drug desipramine to be extremely helpful, and highly underrated. It actually has very slight sedative properties, so it is helpful in getting to sleep as well as maintaining sleep. It is also a very effective anxiolytic. I find that small doses of 5 to 10 mg when needed are very helpful.
     
    Last edited: Apr 3, 2015
  3. *GG*

    *GG* Senior Member

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    I take Mirtazapine for sleep, been on it since 2009!

    GG
     
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  4. SDSue

    SDSue Southeast

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    @zzz Thanks so much for your informative post! You always have such good, informed suggestions.

    This has been the closest thing I've had to an "aha" moment in my ME/CFS journey. It just occurred to me that I also took a swig (technical term for 60 mg dose) of XR dextromethorphan last night. Did I hit upon a combo effect? I'm not getting cocky by any means, but the contrast between sleeping on my bathroom floor one day and showering the next is pretty astounding!

    I'm learning to check new drugs on the National Library of Medicine's Liver Tox page. It's not perfect but it does give a general idea of which drugs are more problematic. Until I can get my Famvir dosage right, with no liver issues, I can't afford to add anything questionable.

    My plan now is threefold:
    1. Go without mirtazapine until symptoms return so I can figure out the lowest, least often dosing pattern.
    2. Figure out the dextromethorphan thing. Coincidence? Contributing factor?
    3. Begin nebulizing Mg

    I may need to trial guafenesin, too, as I have some handy and it seems low risk since I used it in my healthy days. But this will have to wait.

    @ggingues Do you suffer dysautonomia, too? Have you tried going without mirtazapine for a couple of weeks to see what happens? That's what it took for me to get it out of my system and determine what effects it was actually having (other than the 10 extra pounds!) And yes, it is a miracle worker for sleep!
     
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  5. Sidereal

    Sidereal Senior Member

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    Dextromethorphan is an NMDA receptor antagonist like ketamine and other drugs known to be useful for "neurosomatic disorders", to use Goldstein's term.
     
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  6. Sidereal

    Sidereal Senior Member

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    Overstimulation? Yohimbine is a notorious panic attack inducer in susceptible people. Mirtazapine seems less likely to be detrimental because it acts on other receptors at the same time as the alpha 2a adrenergic receptor. Crucially, the NMDA receptor, as @zzz points out. Also, as you point out, a centrally acting drug would have quite different properties.

    Very interesting, @zzz, as usual. I have some of this lying around in my Goldstein drug stash. May give it a try and report back. I do think some would get worse on this based on the norepinephrine U-shaped curve problem. Too much or too little would produce executive dysfunction, concentration problems, dizziness, etc. Some do well from antagonism of this receptor (it's an autoreceptor so actually it raises norepi) while others would be better served from agonists of this receptor like clonidine or guanfacine.

    I've tried guaifenesin a couple of times and have noticed nothing from it, btw.
     
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  7. heapsreal

    heapsreal iherb 10% discount code OPA989,

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    There was a study a couple yrs back showing dxm effective for fibro pain. This research seems to have stalled. Maybe because the drug cant be patented so not profitable.
     
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  8. adreno

    adreno PR activist

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    Yes, it works for me, too! Sadly it also makes me feel like Ted Bundy.

    The mechanism is almost surely alpha-1 agonism. Alpha-2 (autoreceptor) antagonism disinhibits norepinephrine release, increasing activity at other adrenergic receptors.

    Conversely, alpha-2 agonism (clonidine, for example) inhibits norepinephrine release.
     
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  9. Sidereal

    Sidereal Senior Member

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    Yohimbine is an alpha 1 antagonist which perhaps explains why it makes @SDSue's symptoms worse.
     
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  10. SDSue

    SDSue Southeast

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    Last night around 9, my symptoms began returning. I took dextromethorphan alone. No effect. I can rule that out as a singular cause of symptom relief. (remember, I am having to be cautious with mirtazapine until my liver gets settled)

    What a choice - feel halfway normal and want to slaughter people, or feel sick and let them live. :wide-eyed: Have you found anything else that works as well?

    The question is, what is mirtazapine's overall effect on norepi? If it is inhibiting, it seems that would confirm that I have hyperadrenergic POTS? I seem to fit that classification best but have not had adequate testing.

    I use this simplistic chart often. Over time, I've been Rx'd drugs from each class. (what does that say about doctor's understanding of ME/CFS?)

    My body likes alpha 1 agonists and beta 1 antagonists. I've yet to try Clonidine, which is a alpha 2 agonist - does anyone know if that would act similarly to mirtazapine? My doc is open to clonidine even though it can lower BP quite a bit because I've got some wiggle room there. According to LiverTox it's easier (than mirtazapine) on the liver.



    f2c4e0fe72e8e84344ef20593a309879.jpg

    @ sidereal this gives a good visual of the norepi U-shape you mentioned.

    Thanks everyone for your valuable insight as I unravel this puzzle!​
     
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  11. *GG*

    *GG* Senior Member

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    @SDSue I have not been diagnosed with dysautonomia, perhaps this is why? When I was working, I would feel more faint/dizzy upon standing some times, that is about it. My heart rate seems fine, except for probably being higher at resting compared to when I was healthy and could exercise more regularly.

    GG

    found this:

    http://www.medhelp.org/posts/Dysautonomia-Autonomic-Dysfunction/POTS-and-Insomnia/show/1444473

    http://treato.com/Remeron,Dysautonomia/?a=s
     
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  12. adreno

    adreno PR activist

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    It's not as simple as that. Antagonism of presynaptic autoreceptors causes increased release (disinhibition) of neurotransmitters. So alpha-2 antagonism will increase norepinephrine release. Since alpha-2 is blocked postsynaptically, norepinephrine will that target the other adrenergic receptors (alpha-1 and beta).

    No, as I said before, clonidine (and other alpha-2 agonists) will have the opposite effect - they will decrease norepinephrine release (but will also activate postsynaptic alpha-2 receptors).

    So the effects of alpha-2 antagonists and alpha-1 agonists are somewhat similar. Same goes for alpha-1 antagonists and alpha-2 agonists.
     
    Last edited: Apr 4, 2015
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  13. Sidereal

    Sidereal Senior Member

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    I wouldn't touch clonidine if mirtazapine helps you. This drug would do the opposite.

    For what it's worth, Goldstein recommends nimodipine (a calcium channel blocker) as one of his top ME/CFS meds. May be something worth considering. I noticed from reading online that some docs who treat patients with unexplained vertigo and dizziness use this med. I know it sounds counterintuitive because you'd expect a BP lowering drug to make you more dizzy.
     
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  14. SDSue

    SDSue Southeast

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    And this is why I run these things past others and my doctor. I'm pretty cautious with two things: the heart and electricity - both can kill me!

    Do we know (or care) what effect nimodipine has on NE? I'm so confused. Based on my response to mirtazapine, can we determine whether I have high or low NE? That is, am I hyperadrenergic POTS or not? Or is there no way of knowing that without a TTT complete with blood draws?

    I'm not trying to be confrontational, I'm just having a hard time putting this all together! :eek: I appreciate the feedback!
     
  15. adreno

    adreno PR activist

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    I understand if this is a bit confusing. Here is a diagram showing the norepinephrine synapse. As you can see, alpha-2 receptors sit on both sides of the synapse. The ones on the presynaptic side are called auto receptors and act as "brakes" on norepinephrine release when they are activated. When auto receptors are blocked, the "brakes" are removed and more neurotransmitter is released.


    [​IMG]
     
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  16. Sidereal

    Sidereal Senior Member

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    Sorry, I introduced a new concept here. I don't know what effect nimodipine has on norepinephrine specifically. It has a different mechanism of action: calcium channel blockade. This is a much more basic mechanism than modifying levels of neurotransmitters like mirtazapine does, totally different. It would have bazillion downstream effects. There was a study showing its effectiveness in treatment resistant panic disorder which is a hyperadrenergic state. Goldstein says he's found it helpful in some CFS patients.

    What are your symptoms?
     
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  17. SDSue

    SDSue Southeast

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    No worries @Sidereal - You're welcome to introduce anything that might help!

    When upright, I rapidly develop tremors, anxiety, increased BP and pulse, lowered pulse pressure, purple feet, and the need to, ahem , pee every time I stand up. My mind and body are of one single focus - SIT DOWN!!!

     
  18. adreno

    adreno PR activist

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    @SDSue

    The problem with POTS is most likely autoantibodies blocking alpha-1 receptors, and the nervous system trying to compensate by pumping out more norepinephrine.

    So paradoxically, you could have overall elevated norepinephrine, but still not be able to sufficiently activate alpha-1 receptors to deliver the needed pressor response.

    Perhaps by using drugs such as mirtazapine it's possible to somewhat overwhelm the autoantibody mediated blocking, at the cost of a higher sympathetic tone.
     
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  19. zzz

    zzz Senior Member

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    This paints a rather clear picture of magnesium deficiency, which is endemic among PWME. It also fits in perfectly with your response to mirtazapine. As I mentioned in my previous post, mirtazapine is an indirect NMDA antagonist, and as such, has been helping to keep your POTS symptoms at bay. Remove the mirtazapine, and without sufficient magnesium, the NMDA receptors become hyperactive, potentially producing the whole array of POTS symptoms, as well as symptoms of dysautonomia in general. Proper supplementation of magnesium has been known to reduce or eliminate POTS symptoms in many people. Based on the symptoms you describe and your response to mirtazapine, I think it would make a very big difference for you.

    A while ago, I sent you a very detailed PM on increasing magnesium supplementation. I'd recommend that you follow through on that; I think that that's the fastest and best way to resolve your symptoms. Please contact me via PM if you have any questions about the procedures I described.
     
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  20. SDSue

    SDSue Southeast

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    You don't have to tell me twice! (you have to tell me about 6 dozen times - one of my worst symptoms is the inability to make decisions!) Thanks so much for following thru, zzz. I ordered my supplies just a few moments ago, so I'm certain to be contacting you for further information. (You've still got time to run and/or change your name. You've been warned!) Thank you thank you thank you!

    @adreno Thanks to you, also. You are a man of few words, but those words are always valuable! I appreciate your input greatly!
     
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