Abilify tolerance

[YippeeKi YOW !!]

Abilify is an very likely an antagonist at adrenergic receptors, like all antipsychotics are if they have any affinity for those receptors.

And if they don't have any affinity for adrenergic receptors, what is their mode of action ???

 

[Hip]

This is probably the best description of the mode of action of antipsychotics, particularly, that I've read so far

It is only the so-called third generation of antipsychotics which work in this way. Third generation antipsychotics act as dopamine stabilizers, meaning they amplify the softer musical notes, but reduce the volume of the loud musical notes.

Amisulpride (a French drug) was the original third generation antipsychotic; and Abilify is also a third generation antipsychotic.

Although in medical literature there is some inconsistency with this third generation terminology, as sometimes these drugs are referred to as second generation antipsychotics.

 

[YippeeKi YOW !!]

Although in medical literature there is some inconsistency with this third generation terminology, as sometimes these drugs are referred to as second generation antipsychotics.

Yes, I've found that confusing, and have come to ignore it, since the focus seems to be on Abilify, at least ever since the Stanford experiments ...

 

[Mary]

THIS THREAD IS BEING REOPENED. PERSONAL ATTACKS WILL NOT BE TOLERATED. PLEASE KEEP THE FOCUS OF THE DISCUSSION ON THE TOPIC AT HAND AND AVOID ALL PERSONAL REMARKS.

 

[leokitten]

What do the +++ symbols represent in that Exhibit II table, the receptor binding affinity? That will not tell you whether Abilify acts as an agonist or antagonist.

I wrote this in another thread too, just repeating here for others...

The intensity of yellow color and number of pluses means intensity of partial agonism, and blue corresponding color and pluses the intensity of antagonism. I believe they try to combine the affinity and intrinsic activity into one visual summary. They wrote in the footnote, “Antagonism and inverse agonism are indicated by blue color whereas partial agonism by yellow. The number of crosses and color intensity are correlated to binding affinity.”

 

[Hip]

It's interesting to try to connect the benefits of Abilify for ME/CFS with Prof Andrew Miller's low dopamine theory of ME/CFS from back in 2014.

Miller proposed that low dopamine may result in a hypersensitivity to brain inflammation, since dopamine modulates the neuroinflammatory response. This hypersensitivity to neuroinflammation may then cause the symptoms of ME/CFS.

Cort briefly touches upon Abilify and Miller's theory in this recent blog. Andrew Miller's low dopamine theory of ME/CFS is more fully detailed in previous blogs from Cort, here, here and here.


Low-dose Abilify would appear to have two mechanisms which increase the dopamine response: it's direct agonism of the dopamine D2 and D3 receptors, as well as the antagonism of 5-HT1A, which indirectly raises dopamine in the medial prefrontal cortex, striatum, and hippocampus, according to Wikipedia.

The recent paper from Stanford does not mention 5-HT1A, but focuses on the dopamine D2 receptor which Abilify targets. The paper points out the fact that D2 modulates neuroinflammation and microglial activation.

It could be that both the D2 and 5-HT1A effects of Abilify are working in tandem, as both act to ramp up the dopaminergic response, which might address low dopamine issues in ME/CFS.

Miller said regular dopaminergic drugs like MAOIs may not do much to rectify the low dopamine, because the inflammation is blocking dopamine synthesis, possibly by inflammatory cytokines and oxidative stress reducing BH4 levels (BH4 is necessary for dopamine synthesis).


If depleted BH4 is playing a role, this suggests the Prof Martin Pall anti-peroxynitrite protocol might be good to take alongside Abilify, as this protocol reduces levels of the oxidant peroxynitrite which depletes BH4.

 

[leokitten]

It could be that both the D2 and 5-HT1A effects of Abilify are working in tandem, as both act to ramp up the dopaminergic response, which might address low dopamine issues in ME/CFS.

These are the strongest, and most important, Abilify receptor targets (taking together affinity with intrinsic activity at the receptor);

Partial agonist/functionally selective: D2, D3
Partial agonist: 5-HT1A, 5-HT2C
Antagonist: 5-HT2A, 5-HT2B, 5-HT7

I wonder how all these serotonin receptors in various brain areas interplay with Abilify and how their networks connect to dopamine networks and affect its function.

 

[Hip]

@mitoMAN just mentioned elsewhere that he tried the 5-HT1A partial agonists quetiapine, amphetamine and methylphenidate as well as the full agonist vortioxetine without experiencing the benefits that he is now just starting to get from low-dose Abilify.

 

[leokitten]

@mitoMAN just mentioned elsewhere that he tried the 5-HT1A partial agonists quetiapine, amphetamine and methylphenidate as well as the full agonist vortioxetine without experiencing the benefits that he is now just starting to get from low-dose Abilify.

Again because in Abilify its a partial agonist (so agonizes, antagonizes, and/or stabilizes depending on brain location) and also deductive reasoning doesn’t really work when it comes to psychotropic meds acting differently on all kinds of receptors and at different locations. It’s to complex to break it down into independent atomic parts and make any kind of analysis of the related to the whole.

 

[leokitten]

Another cliche, “greater than the sum of its parts” , works here too. Everything working together at all these targets must have many additional effects than comparing to a drug that only works on one of those targets

 

[Hip]

It’s to complex to break it down into independent atomic parts and make any kind of analysis of the related to the whole.

It might well be the case that it is too complex to unravel; but sometimes the pathways turn out to be quite simple. Most of established medical science is the low-hanging fruit, where the pathways are relatively simple. Unless you start throwing a few ideas around, you are not going to uncover a simple pathway, if indeed the pathway is simple.

A simple pathway to explain the benefits of Abilify for might just be the dopamine system stabilization, as mentioned before. This dopamine stabilization involves the fairly unique way drugs like Abilify and amisulpride operate at the dopamine autoreceptors.

These drugs block the dopamine autoreceptors, and thereby prevent dopamine from being removed by the dopamine transporter (DAT). Autoreceptor stimulation activates DAT, so if you block the autoreceptor, you inhibit DAT, and thus conserve dopamine.

This form of dopamine preservation via autoreceptor blocking is quite unique, to my knowledge. It is only the dopamine stabilizer drugs which boost the dopamine response in this particular way. Maybe it is this mechanism of dopamine conservation which overcomes the low dopamine proposed by Andrew Miller.

If it is the dopamine stabilization and autoreceptor blocking of Abilify that is responsible for the benefits, then that hypothesis would predict that amisulpride would also work for ME/CFS, even though amisulpride has a quite different profile to Abilify with regard to its serotonin receptor binding, as that excellent antipsychotic drug receptor binding table that you linked to earlier indicates.

We already know from a small scale study that the dopamine stabilizer amisulpride seem to boost energy in ME/CFS.

 

[leokitten]

We already know from a small scale study that the dopamine stabilizer amisulpride seem to boost energy in ME/CFS.

The thing with Abilify is that it's not giving me a boost in energy in the way people might think it works. I've tried to explain it clearly in my posts, but to me it feels it simply doesn't work like that. It significantly reduces the chronic onslaught of ME symptoms I experience every moment of every day, pushes them to a more manageable background and, most importantly, when I physically or mentally exert it prevents symptoms from getting worse afterwards (PEM from rearing its ugly head)

A good analogy would be that pre-Abilify I was with this huge boulder on my back, or on an IV slowly and constantly filling me with poison, and I got constant symptoms caused from that so I had no energy or functional capacity to do anything. Now the boulder I'm carrying on my back is much smaller, or the IV bag isn't filling me with nearly as much poison, so this veil has been partially lifted and I feel I’ve gone some steps in the direction toward normal. I don't consider that the drug is giving me energy, but reducing the symptoms that were sucking away energy from me. Hope that makes sense.

 

[Hip]

I don't consider that the drug is giving me energy, but reducing the symptoms that were sucking away energy from me. Hope that makes sense.

I appreciate the distinction you are making.

You can get "false energy" from a caffeine drink, which gives you a temporary buzz by manipulation of neurotransmitters.

But if something is preventing or reducing PEM, it suggests it is working at a deeper bodily level.



Did you ever try Mestinon (pyridostigmine), by the way? That has had potent anti-PEM effects in some patients (see this post).

 

[Judee]

The thing with Abilify is that it's not giving me a boost in energy in the way people might think it works. I've tried to explain clearly it in my posts, but to me it feels it simply doesn't work like that. It significantly reduces the chronic onslaught of ME symptoms I experience every moment of every day, pushes them more to a more manageable background

A bit of a sidetrack but this so similar to what I said on a licorice thread sometime back..."This is a hard one for me because nothing really gives me any energy. Instead what I get from some things is a lessening of the symptoms that make it hard to get things done..."

Also, I'm not smart enough to understand all this stuff but I keep wondering why the doctors just don't try a different schedule of dosing? Maybe instead of everyday where it stops working at 4 months, what about every other day or third day??

 

[leokitten]

Did you ever try Mestinon (pyridostigmine), by the way? That has had potent anti-PEM effects in some patients (see this post).

I haven’t mainly because I don’t have significant POTS since the first year of ME, and I also read it can come with a number of side effects. I’m currently doing better on the meds and dosages I’m taking now than I’ve ever done on anything else ever, so not going to rock the boat since life is really much better now. Hopefully this lasts a very long time and if not I’m riding this wonderful wave until it’s over.

 

[leokitten]

And if they don't have any affinity for adrenergic receptors, what is their mode of action ???

Abilify does have some (fairly weak) affinity for adrenergic receptors and acts as an antagonist at these receptors

 

[kangaSue]

As with many chronic conditions, maybe it's "all in the guts".
https://www.nature.com/articles/s41398-019-0466-x

 

[Hip]

Another thing to consider is the fact that ME/CFS patients are using low-dose Abilify.

Remember that low-dose Abilify (and low-dose amisulpride too) is in effect a different drug to regular dose Abilify, because of the dopamine autoreceptor action.

At low doses, these drugs preferentially block the presynaptic dopamine autoreceptor, which actually results in increased activation of the dopamine system. But at regular doses, these drugs start to block the postsynaptic dopamine receptor, which results in decreased activation of the dopamine system.

So a low doses, these drugs act as if they were dopamine agonists, but at regular doses they turn into dopamine antagonists.



If ME/CFS patients benefiting from low-dose Abilify were to try regular doses, and if at regular dose levels the benefits disappeared, this would suggest it is the activation of the dopamine system which is providing the therapeutic effect.

 

[Push Fwd]

Hi,
it‘s me again asking something for Martin. ;-)
While he is on the drug holiday, we are very careful not to ruin it with some other stuff, but at the same time to improve his situation as much as possible.

So at the moment we are trying to work on his sleep. We would like to try it with John‘s Wort (i hope this is the correct translation for Johanniskraut), but after i googled how it works, i’m not so sure if this could be counterproductive for the drug holidays. What do you think? Or has someone good ideas for sleeping better that won‘t ruin the drug holidays?
On our List is also passion flower, 5-HTP, hop, L-tryptophan, glycin, GABA, theanine, taurine and i also read that some antidepressants could work at a low dose, but again not so sure about these things in combination with the drug holidays. Would be very happy about any ideas & tips.

 

[sb4]

@Push Fwd Has Martin gotten worse than he was pre abilify?