Off label use of Aripiprazole shows promise as a treatment for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Crosby et al. 2021
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The clinicians at Stanford could have done a decent study for not much more than it cost them to do the useless study that they published. They had patients willing to try Abilify, patients presumably with insurance to pay for the drugs and the clinician time to screen and prescribe - surely they could have just enrolled those patients in a cross-over study with a placebo treatment.
So, let's do them elsewhere. We have a global community willing to help. I'm sure that a trial of Abilify could be organised in Australia for 10% of the figure Ron has suggested, probably considerably less. It doesn't need to be a big trial to be convincing and justify more research, it just needs to be well-done. Researchers might surprised at what could be achieved if they started working more closely with patients.
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The study was “not good”, but it was not useless.
It was not useless because it was at least something, with some data, however imperfect. Can you imagine if they applied for a grant for a 3 million dollar study with NO basis to back it up?
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I actually think the paper was worse than useless, because it muddied the waters. It didn't move us closer to understanding if Abilify can help patients. Just like the PACE trial, it combines a lack of blinding with subjective outcomes. If I, a person with ME/CFS who really wants a useful treatment, can write off such a study as providing no evidence that Abilify works, it's certainly too easy for people in the NIH who don't believe ME/CFS is worth researching to do the same.
They don't need to jump to such a large and expensive trial. What I've been trying to say is that clinicians could incorporate useful studies into their normal care of patients. Having got patient approval, the patient could enter into a double blinded crossover study. So, 2 months on the treatment or a placebo, then 2 weeks wash out, and 2 months on the placebo or the treatment - or something like that.
I understand I'm a long way away and don't know a lot. But why wouldn't that work? What are the hurdles preventing it? People could still tweak the dosage during the treatment period if they wanted to.
I'm sure most patients would be fine with a trial structure like that as it gives them a better idea as to whether the treatment actually helps them personally.
It sounds like a crappy situation, but I wonder if they are not in contact with the right people. For example, there was recently a double-blinded drug trial registered for Solriamfetol specifically in the treatment of ME/CFS (ref). If it's possible to get this done for this type of drug it should be possible to do something similar with Abilify. The trial is run by a psychiatrist, but if that's the best route to get these types of drugs trialed, I wouldn't mind it.
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Andy
Senior Member (Voting rights)
Responding to questions about Abilify
"Some doctors in the US are prescribing Aripiprazole, but it is not licensed for use in the UK. It's very important to reiterate that Aripiprazole has not been sufficiently tested in robust, large, clinical trials to know if it's effective in relieving the symptoms of M.E. – you can read more about why clinical trials are essential on our medications page (scroll to the last section).
A trial to test Aripiprazole would need significant investment, and it’s not something Action for M.E. has the funds or expertise to take forward alone. We are always willing to work in partnership with others to achieve shared goals and would be willing to consider an approach from an organisation wanting to take forward a clinical trial for this or any other medication that potentially shows promise for people with M.E."
https://www.actionforme.org.uk/news/responding-to-questions-about-abilify/
"Some doctors in the US are prescribing Aripiprazole, but it is not licensed for use in the UK. It's very important to reiterate that Aripiprazole has not been sufficiently tested in robust, large, clinical trials to know if it's effective in relieving the symptoms of M.E. – you can read more about why clinical trials are essential on our medications page (scroll to the last section).
A trial to test Aripiprazole would need significant investment, and it’s not something Action for M.E. has the funds or expertise to take forward alone. We are always willing to work in partnership with others to achieve shared goals and would be willing to consider an approach from an organisation wanting to take forward a clinical trial for this or any other medication that potentially shows promise for people with M.E."
https://www.actionforme.org.uk/news/responding-to-questions-about-abilify/
Doctors prescribing low doses of antipsychotics to ME/CFS patients has been going on since the 1990s. There doesn't seem to be a single randomized trial, just this retrospective study of aripiprazole.
There are a few clinical trials of antipsychotics for fibromyalgia (and a Cochrane review by Brian Walitt), but the trials and the results do not seem very impressive.
There are a few clinical trials of antipsychotics for fibromyalgia (and a Cochrane review by Brian Walitt), but the trials and the results do not seem very impressive.
SugarSquared
Established Member (Voting Rights)
Does anyone know if an RCT for low dose abilify is happening any time soon? I’m surprised there’s been no follow-up.
The two clinics that treat ME/CFS in BC (Canada) use this paper as evidence for prescribing it off-label. I feel like a proper trial with a placebo would be important since so many people are taking this medication.
Is there a reason it’s not happening? Is the side effect profile too daunting? Mestinon and LDN both have RCTs in the works. Why not LDA?
The two clinics that treat ME/CFS in BC (Canada) use this paper as evidence for prescribing it off-label. I feel like a proper trial with a placebo would be important since so many people are taking this medication.
Is there a reason it’s not happening? Is the side effect profile too daunting? Mestinon and LDN both have RCTs in the works. Why not LDA?
Ron Davis was quoted as saying a high quality full blown trial would cost $10 million USD.
But not sure why no one has attempted at least a smaller maybe not super high quality trial. This is a low hanging fruit.
Real head scratcher. Frustrating.
Utsikt
Senior Member (Voting Rights)
I suspect the doctors that belive in LDA know deep down a trial won’t work, so they’d rather continue with «it might work».
The people that don’t think LDA works have no reason to do a trial when there are so many other things to spend resources on.
I know @Jonathan Edwards has expressed this view many times, but I have a hard time accepting it. Mind you, I don't have an alternate explanation for why we haven't seen even a poor quality trial, however - it really is baffling. It doesn't seem likely to be about money - there are many other supplements and drugs that are less likely to generate a response (and from which clinics surely make far more money) that do get shit-quality trials (and occasionally not-so-shit), why not LDA? If they were sure it didn't work and just wanted to keep promoting it, surely they know that even failed studies throw up enough smoke and noise that they can be spun as successes, but they haven't even tried that.
From the outside (I've not tried LDA) and to someone as ignorant as I am, LDA certainly seems more promising than, say, LDN. As @hotblack notes, all the recent noise circling around dopamine really seems to make it an appealing area to explore... but apparently that's not happening.
ChronicallyOverIt
Senior Member (Voting Rights)
I feel like I see dopamine referenced for LDN all the time, but years ago when I looked the research was shaky. There was a monkey study that saw LDN increased prolactin I believe and it was thought it was dopamine prolactin feedback loop. LDA has a much clearer dopamine signal.
Interestingly dopamine and prolactin are interconnected.
AI google search overview:
The two hormones exist in a reciprocal negative feedback loop: dopamine inhibits prolactin release, while rising prolactin levels signal the brain to produce more dopamine
Here’s the study(maybe this could be a thread? I’m on mobile if someone else could help, otherwise I will tonight!):
Behavioural and endocrine effects of naltrexone in male talapoin monkeys - PubMed
The effect of treating captive male talapoin monkeys with naltrexone hydrochloride (500 micrograms/kg intra-muscular injection twice daily) was studied both in socially living and singly caged animals. The behaviour of the group males and endocrine changes in all treated animals were monitored...
pubmed.ncbi.nlm.nih.gov
SugarSquared
Established Member (Voting Rights)
Honestly, this is what I think too. Keep it at their original paper that says it’s great and don’t go further.
But then at the same time, this is exactly what I think too! It seems like a no-brainer considering how many people are taking it. I don’t understand how one drug is getting multiple trials and another has 0.
Once Nacul’s LDN paper is out, I might email him asking about a similar LDA study. He used to work at the BC Women’s Complex Chronic Disease Program where they currently prescribe LDA. I don’t know what his next plans are, but it’s worth asking I think. Do any of you have ideas of who else to reach out to?
Laurel Crosby of Stanford usually replies to emails.
Utsikt
Senior Member (Voting Rights)
I’m an economist, I think in incentives.
The alternative is that the doctors truly don’t understand basic trial methodology, or just think that wanting to help is good enough.
I don’t know what is worse. I just know I don’t want anything to do with either of them.
While not an economist, I certainly agree that this is an excellent way to approach the matter. I have been largely disabused of any notions concerning either the good intentions or the basic competence of many of the clinicians and researchers involved, so I have no problem believing that some/many/all would want to forego a trial in order to avoid potentially inhibiting their ability to Rx a money-making drug (whether that money comes directly from the drug or from its ability to attract patients to a given clinic) - that makes sense to me. What makes significantly less sense is why these same people do pursue trials for medications and supplements (e.g. LDN) that are even more widely sought after and Rx'd, while simultaneously being less likely to produce a favorable result.
hotblack
Senior Member (Voting Rights)
Who says motivations, in economics or otherwise, are rational? We are all immensely good at fooling ourselves.
Utsikt
Senior Member (Voting Rights)
They might not even need to be making money off of it directly. It could be as simple as feeling like they are doing a good thing. Or just staying in a secure job market because you’re not one to change jobs frequently.
ScoutB
Senior Member (Voting Rights)
Yeah basically just to repeat hotblack's point with more words:
I think a lot of what has and has not been tested in ME/CFS has to do with cultural factors (i.e. what was popular, what biology the researchers with the means to run a trial were interested in) rather than a clear-eyed evaluation of what is most likely to work or even make for a good, career-advancing paper.
My guess is we're seeing 4 LDN trials at once because it's been popular in some alternative-ish** research circles for a while, and thanks to LC, some of those groups have a bit more of the social/political sway needed to get a trial set up. LDA may just have been a little too late on the scene. I am also frustrated by this outcome, to be clear haha
(**We see a lot of questionable 'alternative' ME/CFS research but also a lot that seems well-intended just under-resourced, so I don't mean this in a bad way. Unfortunately, thanks to the stigma, it's been hard historically to do research on us that isn't automatically cast as 'alternative'.)
I think a lot of what has and has not been tested in ME/CFS has to do with cultural factors (i.e. what was popular, what biology the researchers with the means to run a trial were interested in) rather than a clear-eyed evaluation of what is most likely to work or even make for a good, career-advancing paper.
My guess is we're seeing 4 LDN trials at once because it's been popular in some alternative-ish** research circles for a while, and thanks to LC, some of those groups have a bit more of the social/political sway needed to get a trial set up. LDA may just have been a little too late on the scene. I am also frustrated by this outcome, to be clear haha
(**We see a lot of questionable 'alternative' ME/CFS research but also a lot that seems well-intended just under-resourced, so I don't mean this in a bad way. Unfortunately, thanks to the stigma, it's been hard historically to do research on us that isn't automatically cast as 'alternative'.)