Abilify tolerance

[Martin aka paused||M.E.]

So
for most of us (2/3?) Abilify builds up (pharmarkokinetic?) tolerance.
Any theories why?
Maybe workarounds possible?

Let's discuss it.
@Hip @leokitten ?

Best of all
Martin

 

[hmnr asg]

Just to see the real percentage, how about adding a poll also ?
A) tried abilify, got benefits but built tolerance
B) tried abilify , got benefits, didn't built tolerance
C) tried abilify, didn't get benefits
D) tried abilify and got worse

Also I think whether or not people develope tolerance or how quickly they do depends on their dosage and if they're taking it in conjunction with another psych meds, like antidepressants that could have synergistic effects with abilify.

 

[jaybee00]

Tried to get a discussion here

https://www.s4me.info/threads/mechanism-for-drug-tachyphylaxis-poop-out-in-me-cfs.17890/

 

[andyguitar]

and if they're taking it in conjunction with another psych meds, like antidepressants that could have synergistic effects with abilify.

It's a good point. Also any interactions with supplements.

 

[YippeeKi YOW !!]

for most of us (2/3?) Abilify builds up (pharmarkokinetic?) tolerance.
Any theories why?

Abilify was originally intended as an anti-psychotic .... it's a partial dopamine agonist as opposed to a dopamine antagonist or blocker like most of the earlier, first-generation antipsychotics.

Like benzos, which work by providing artificial, exogenous GABA, Abilify encourages dopamine either by juking your natural dopamine, or by providing additional exogenous dopamine, os possibly both.

In either case, I would assume that it would eventually down-regulate dopamine and 5HT2A receptors, just as benzos down-regulate GABA receptors, creating tolerance withdrawal as a result.

 

[Push Fwd]

Hi,
as some of you already know, I'm Martins girlfriend and because he is having al really bad crash, he can't write much at the moment. But he wants to let you know what he thinks, why Abilify builds up tolerance:
If it would be a problem with receptors then a break should help to let the brain rebuild it. But it seems that this doesn't work. Maybe it's an enzymatic problem that the body gets used to the active ingredient and metabolizes it too fast (detoxification). So maybe another drug that is metabolized by the same enzyme would slow this process down?

 

[YippeeKi YOW !!]

If it would be a problem with receptors then a break should help to let the brain rebuild it.

Hiya @Push Fwd and @Martin aka paused||M.E. ....

I'm so sorry that what started out so well, then turned into a moderate downturn, has now progressed so disastrously .... God knows, your courage and determination deserve better ....

Based on how long it takes GABA receptors to reset to the point of tolerating anything that reacts on them, it's possible that the length of time that the dopamine receptors would need to recover might be counter productive to someone in a serious crash, and looking for something to ease it.

The brain is plastic, but highly complex, and once it's been fiddled with recovery isn't an overnight, or even over-several-months kind of thing. A lot of re-wiring and un-wiring has been done, and needs to be undone, before it can react normally to something that once again interferes with its normal functioning.

It would be possible to slow the metabolizing of one drug by adding another that would inhibit the inducement of that drug, but that would also inevitably eventually fail, and that's how Drs get patients on the merry-go-round of multiple, often contradictory and vastly damaging, drugs.

Do you have access to the Flockhart or other chart of inhibitors and inducers? You'd probably be able to find what you;re looking for there ... ... there's another good one, the edsi chart, and the Selleck charts, which are buried back in my IE 11 browser, I'll see if I can dig them up for you and will come back and post the links here ....

 

[Hip]

for most of us (2/3?) Abilify builds up (pharmarkokinetic?) tolerance.
Any theories why?
Maybe workarounds possible?

It would be interesting to see if the Abilify loss of effect reverses itself after discontinuing the drug for some weeks, or whether the loss of effect is permanent.

In ME/CFS it is sometimes reported that drugs which have helped stop working after some time (like after a few weeks or months), and that even if you take a break from these drugs, they still will not work again when you restart, because the tolerance somehow becomes permanent.


I had this permanent tolerance appear when I tried one of Dr Jay Goldstein's ME/CFS drugs: Wellbutrin (bupropion), an antidepressant with stimulant properties. For the first two weeks on low-dose Wellbutrin, I found my brain fog was not only banished, but I my concentration was even better than when I was healthy. And my mood and mental energy were also riding high. I thought I'd found my personal escape from ME/CFS.

Then exactly two weeks after starting this drug, it's benefits just vanished, even though I made no changes to any of my regimen. I was never able to get Wellbutrin to work again, even after a two month break from it.


I really wanted to get to the bottom of this mystery, as Wellbutrin worked so well for me, but was unable to. I looked at things like down-regulation of G protein receptor tolerance (see this post), which Dr Goldstein thought might explain the loss of effect phenomenon in ME/CFS, and tried some of Goldstein's suggestions to prevent the tolerance, but to no avail.

In any case, I don't think permanent loss of effect can be due to ordinary day-to-day receptor down-regulation and up-regulation, because such mechanisms are dynamic, and for short-term use of drugs, receptor populations normally rebound once the drug is stopped.


We need to consider mechanisms which once set become permanent, to reflect the permanent loss of effect experienced. So one obvious area might be epigenetic mechanisms, as these are long-lasting.

What epigenetic mechanisms might be at play in permanent down-regulation of receptors?

Well in the down-regulation of GABA receptors caused by benzodiazepine use, it appears to be histone deacetylation (an epigenetic mechanism) which is responsible. See this study.

If the loss of effect of Abilify also involves histone deacetylation, then possibly histone deacetylase (HDAC) inhibitors might act to restore the effect of Abilify. HDAC inhibitors have been shown to reduce morphine tolerance.

Valproic acid is one HDAC inhibitor, and there are several other HDAC inhibitor drugs available. Butyrate is another HDAC inhibitor. The probiotic Clostridium butyricum is a butyrate-producing bacterium.



An interesting article on preventing drug tolerance is here.

 

[wigglethemouse]

Well in the down-regulation of GABA receptors caused by benzodiazepine use, it appears to be histone deacetylation (an epigenetic mechanism) which is responsible. See this study.

If the loss of effect of Abilify also involves histone deacetylation, then possibly histone deacetylase (HDAC) inhibitors might act to restore the effect of Abilify. HDAC inhibitors have been shown to reduce morphine tolerance.

Valproic acid is one HDAC inhibitor, and there are several other HDAC inhibitor drugs available. Butyrate is another HDAC inhibitor. The probiotic Clostridium butyricum is a butyrate-producing bacterium.

Neil McGregor believes HDAC is involved.

The Tie That Binds…
McGregor then shifted gears and proposed – using a gene expression exercise study by Whistler et. al. – that the tie that binds all this together may be massive levels of something called histone deacetylation (performed by histone deacetylase enzymes or HDACs). He noted that histone acetylation/deacetylation regulated the top twenty genes found altered in Whistler’s study. A similar outcome was found in a genetic polymorphism study.

Source : https://www.healthrising.org/blog/2...gregor-metabolism-chronic-fatigue-glycolysis/

He also talked about it ~28mins in at the 2019 Australia ME/CFS Conference
https://mecfsconference.org.au/videos/neil-mcgregor/

 

[YippeeKi YOW !!]

Does anyone have a practical suggestion for @Push Fwd and @Martin aka paused||M.E. , who's in a really bad crash at the moment? They could use something concrete right about now .... like a rec for anythng that night help him that they could research and maybe try in reference to stopping the fall or even moving the needle up a bit ....

I'm stumped. ALso, looking for the Flockhart and edsi et al, and will be back with something late tonight .....

 

[jaybee00]

From the threads from @Hip maybe inositol might work.

 

[Hip]

Neil McGregor believes HDAC is involved.
Source : https://www.healthrising.org/blog/2...gregor-metabolism-chronic-fatigue-glycolysis/

That's an interesting article, I had not come across the suggestion HDAC might be involved in ME/CFS. McGregor says:

people with ME/CFS are having trouble “acetylating”; i.e. using acetyl groups to regulate our gene expression.

 

[Push Fwd]

I told Martin what you guys already posted (thank you so much!) and he wrote down some notes:

"I don't think that it has something to do with the plasticity of the brain. Because how I understand it is something completely different, but I'm no expert in this field (of course not).

If I'm not wrong I remeber that Abilify is metabolized by CYP3A4. Shizandra too, so that could be a safe bet to proof my theory.
As it goes for benzos: 2 Weeks off and they work exactly as they did before withdrawal.

But of course with dopamine this could be a completely different thing.

@Hip : I have experienced the same with 3 other drugs (not for M.E. and long time ago) but after years they still don't work. We will look into your links, thank you so much for your help! I will ask my doc for HDAC!"

 

[Martin aka paused||M.E.]

This article/meta-study might be interesting... can’t read it due to my condition
https://journals.sagepub.com/doi/full/10.1177/0269881116654697

 

[jaybee00]

Maybe pindolol might help. It’s used to augment antidepressants.

“..pindolol is an antagonist of the serotonin 5-HT1A receptor.” from Wikipedia.

Pindolol also was one of Jay Goldstein’s drugs

 

[YippeeKi YOW !!]

If I'm not wrong I remeber that Abilify is metabolized by CYP3A4.

If that's accurate, it's the same enzyme that metabolizes benzos, so anything that inhibits the metabolizing of benzos should do the same, at least to some degree, for Abilify ...

As it goes for benzos: 2 Weeks off and they work exactly as they did before withdrawal.

If you're speaking from personal experience I'd have to agree. But that's not the experience of anyone that's reported on their experience with benzo withdrawal. Once most systems have been sensitized by tolerance or cold turkey withdrawal, their response to benzos is altered for a very long time, and the incidence of tolerance withdrawal greatly increased and accelerated with future use.

Havent forgotten the Flockhart et al info re inducers and inhibitors. Have been having some computer issues which has made even the simplest things a lot tougher ....

 

[hmnr asg]

Once most systems have been sensitized by tolerance or cold turkey withdrawal, their response to benzos is altered for a very long time, and the incidence of tolerance withdrawal greatly increased and accelerated with future use.

I would have to agree with this. I have been taking benzos for a long time and initially it helped my cfs tremendously. But after a while it stopped working. I then decided to take a break but no matter how long i waited during each break, it barely made a dent. Nowadays taking a benzo barely does anything for me.

It would be interesting to see if the Abilify loss of effect reverses itself after discontinuing the drug for some weeks, or whether the loss of effect is permanent

In my case abilify worked AMAZING for two months and when it started to lose its effect I stopped in order to take a break and restart again. This time around it took me longer than the first time to notice any improvements (more like three weeks, rather than a week). And the benefits have not been like the first time (maybe half). But it has helped pull me out of a major crash and im glad i started it. This time I will stay on it indefinitely.

Note: I am taking 1mg of abilify, I also take cymbalta 40mg. I took a break for about a month and then restarted again. I have been on it for about a month now.

 

[leokitten]

I think a plausible theory is that Abilify could be improving some dysregulation in the brain that’s a downstream effect of the unknown root pathophysiology of ME. But it’s not actually targeting what’s fundamentally driving the illness, and after some time the drug doesn’t work anymore because this dysfunction has such substantial effects it eventually cancels out what Abilify is doing.

So it might not be tolerance, and another reason I think so is that it’s really unheard of for dopamine or serotonin targeting drugs to build up tolerance so soon, so instantaneously, and so completely (doesn’t work at all). Even for drugs that do not target a part of the root pathophysiology (which seem to be most as we don’t have a fundamental understanding of so many diseases). Tolerance for most classes of drugs build up more slowly and also not all of a sudden like it’s working great one day and suddenly boom it’s not working at all anymore.

I had the same thing happen when I did the ketogenic diet, nothing of the probably 100+ things I tried before or after ever had any effect. Within a few days on the diet I felt most symptoms start melting away and my brain completely rebooted and I could think again.

It was amazing, happened quickly, and I had totally forgotten what it felt like to be the normal me. I immediately just started living me life again because I felt mostly normal and my body and brain had energy again. But within a couple weeks or so after starting the diet I had a crash. The diet hid any overexertion PEM or other symptoms that before would tell me I was doing too much, now I was crashing out of nowhere.

It was a sudden saddening realization that oh shit this diet doesn’t significantly improve some crucially important dysfunction driving this illness. The diet continued to give a pretty amazing improvement for a few months though I kept crashing. The second saddening realization was that improvements slowly started to fade after that.

I don’t think it’s out of the realm of possibility that overexertion and crashing might play a role in causing a treatment that has some efficacy but doesn’t target the root pathophysiology to not work anymore. ME patients and clinicians all know from our experience that enough overexertion and crashing eventually lead to permanent worsening of disease severity. So chronically doing significantly more activity than your energy envelope allows likely affects the root pathophysiology making it more dysfunctional, which then causes stronger negative downstream effects causing drugs targeting those effects to lose efficacy.

If you are taking a treatment like Abilify where too much activity still causes crashes but you don’t get any overexertion signals like PEM then it makes sense it was masking the negative effects overexertion has on the disease process, otherwise you wouldn’t crash.

It doesn’t take a big mental leap from this to postulate that even if you aren’t crashing on Abilify you could still be chronically overexerting and not realize it, all the while it having a big negative effect on the disease process until suddenly the drug doesn’t work anymore.

Abilify could truly raise your energy envelope somewhat compared to before treatment, but it’s really hard and time consuming to figure this out, because how can you experiment to find what the new threshold is if you aren’t getting signals anymore that you are doing too much? Also, it’s really difficult to quantify every type of exertion to compare how much more you are doing than before treatment. Really the only way to do it is very slowly with small incremental increases in exertion and staying at each new level for a long time to sense if it’s having a negative effect on the illness before increasing another step.

 

[leokitten]

What epigenetic mechanisms might be at play in permanent down-regulation of receptors?

Well in the down-regulation of GABA receptors caused by benzodiazepine use, it appears to be histone deacetylation (an epigenetic mechanism) which is responsible. See this study.

Though why do we not see any such rapid tolerance for other conditions for which Abilify is prescribed? No drug would last on the market if for most people it showed far lower efficacy or completely stopped working after only a few months, except for very few drug classes where we already know tolerance builds up quickly when used often (and they aren’t meant to be used daily or often).

For drug classes which target the brain and specific receptor types it isn’t an apples to apples comparison. For opioid receptor targeting drugs we know that tolerance builds up very quickly (in days). But for long-term opioid users if they take a very long break they will work again. For GABA receptor targeting drugs tolerance builds up more slowly than opioids. Though long-term use of benzos can cause permanent tolerance. But dopamine and serotonin receptor targeting drugs (which Abilify is a member of) do not build up a tolerance so quickly at all, otherwise all these drug classes would fail.

 

[YippeeKi YOW !!]

If you are taking a treatment like Abilify where too much activity still causes crashes but you don’t get any overexertion signals like PEM then it makes sense it was masking the negative effects overexertion has on the disease process, otherwise you wouldn’t crash.

A depressingly plausible possibility ....

But wait, there's more ...

It doesn’t take a big mental leap from this to postulate that even if you aren’t crashing on Abilify you could still be chronically overexerting and not realize it, all the while it having a big negative effect on the disease process until suddenly the drug doesn’t work anymore.

This makes sense, logically, even as I hope that it's totally wrong.

It's an interesting hypothesis ....

Damn damn damn. Drat.