Off label use of Aripiprazole shows promise as a treatment for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Crosby et al. 2021

[leokitten]

I know this has been discussed before, but maybe worth bringing up again.

Regarding ME treatment RCTs, I generally worry about the chances of success without at least some knowledge of pathophysiology. There is some likelihood that there are significantly different ME pathophysiological subsets and also many CCC diagnosed pwME who are misdiagnosed.

For example, it’s likely many pwME have comorbidities which affect their ME pathophysiology possibly making it quite different from others. So without knowing much about ME pathophysiology, I think most if not all drug trials that really could work for a subset are doomed.

I thought the same about the RituxME trial. There really could be a subset that have a real disease modifying or symptomatic response to rituximab that isn’t placebo effect. The trial results didn’t prove that this didn’t occur in a subset, and it would never be discovered with different subsets or other unknown confounders in the same trial.

Do people believe we need some pathophysiological discoveries before we can hope for RCT success? I’m feeling that way currently.

When I read, “ME clinicians need to spend resources to trial treatments instead of off-label prescribing”, maybe one reason ME clinicians don’t push for some drug trials is because they feel we need more knowledge of pathophysiology before doing so.

I also believe this is one reason many pwME are willing to experiment with treatments with their doctor, even if some initial studies don’t show great results when looking at the entire cohort.

 

[butter.]

I believe Abilify could have an effect via modulating bak1.

https://www.nature.com/articles/d41...SrFIO17h8iIAsYefqMh3cUnLY5xKuzBSb5WkkBQQd1NeI

I believe this (dysfunctional mitochondrial herniation) could be a big part of the me/cfs puzzle.

Saying that I also believe me/cfs is closer to the underlying pathology of Parkinsons than say MS, both Parkinsons and me/cfs could be the result of a dysfunctional mitophagy in nerve cells that might have similar (but different) downstream effects due to some variability of cells effected.

 

[Milo]

You’d wished that these people had a fit bit or actometer on. Clinical trials must have objective measures of improvements. Saying you are a little better should not be acceptable measure of success moving forward.

 

[leokitten]

You’d wished that these people had a fit bit or actometer on. Clinical trials must have objective measures of improvements. Saying you are a little better should not be acceptable measure of success moving forward.

I totally agree. But this is another problematic dimension regarding ME RCTs. Though even if you have well-crafted, physical quantitative endpoints etc, if there are subsets of people with different pathologies or misdiagnosed ME all mixed in the same trial nothing will save it.

 

[Perrier]

You’d wished that these people had a fit bit or actometer on. Clinical trials must have objective measures of improvements. Saying you are a little better should not be acceptable measure of success moving forward.

Bravo to you Milo. Yes, objective measures, and time lines. I am so tired of: do you feel 'a little better?' This disease is very unstable, and fluctuating. There has to be a way to measure outcomes.

 

[Mij]

You’d wished that these people had a fit bit or actometer on. Clinical trials must have objective measures of improvements. Saying you are a little better should not be acceptable measure of success moving forward.

Agree. A small CFS study for Immunovir where patients felt 'less fatigue' isn't a study at all. I went the complete other way when I took it and had a terrible relapse. I never returned to baseline.

 

[leokitten]

Agree. A small CFS study for Immunovir where patients felt 'less fatigue' isn't a study at all. I went the complete other way when I took it and had a terrible relapse. I never returned to baseline.

I totally agree. Given though what I and many others are (or have) experienced with low-dose Abilify really says to me that likely there are different ME pathophysiological subsets and/or people misdiagnosed with ME, since there were those in the Stanford retrospective study that had minimal or no benefit and others that had a much more substantial benefit (even though yep the endpoints were bad).

 

[Hutan]

Though even if you have well-crafted, physical quantitative endpoints etc, if there are subsets of people with different pathologies or misdiagnosed ME all mixed in the same trial nothing will save it.

That's not really true. If the trial has a reasonable size, then it's likely that any benefit in a substantial subset will bring the average response above that of the placebo treatment. If the changes are charted, it should be possible to actually see that a treated subset benefitted.

I'm concerned by recent reports over on Phoenix Rising about a named Stanford clinician.

Posts from a couple of clients of the Stanford clinic report:

• when they told the clinician that Abilify doesn't work for them anymore, the clinician said to keep using it because 'even though you don't feel the benefits, it's helping fight inflammation'
• the clinician seemed a lot more worried about why they hadn't come to the clinic regularly than that Abilify wasn't working
• patients are blamed for Abilify not working - because they did too much when it worked and then crashed
• the Stanford clinic is pushing Abilify 'aggressively' and it was said that 'they are absolutely championing Abilify now, the way they were doing with antivirals before'. Patients are worried that they might be dropped if they refuse to take Abilify.
• they are prescribing Abilify to people already taking multiple drugs affecting the central nervous system

Stanford clinic seems to prescribe a range of drugs, none of which have any credible evidence for being useful for ME/CFS.

I'm really surprised that Stanford University allows this to go on. I wonder if any US ME/CFS charities are concerned about this.

Link to the PR thread here

 

[vsou]

I agree @Hutan I have read similar reports on fb groups.

I am concerned about the same issues. It is surprising that Stanford would operate this way, but I had heard very negative accounts about the quality of treatment there even before abilify was in the limelight—enough so that I chose not to go there myself.

Dr. Montoya left the clinic abruptly in 2019–fired for sexual harassment and sexual misconduct—and Dr Bonilla who was already working there took over. I am not sure if the problem is Bonilla or the clinic was already having problems when Montoya was running it. I think it’s the latter, but it seems like abilify is Bonilla’s pet project and comes before good patient care.

Regarding ME charities having concerns, I don’t know what they privately think but don’t see anyone stepping in to raise concerns. That’s especially true now that Drs Davis and Dafoe are on the abilify bandwagon. So many people just don’t want to make waves no matter the consequences or dangers.

The other thing that bothers me is that I keep seeing PwME write that side effects won’t occur at the low doses of abilify being used for ME. They make it seem like low dose abilify is a brand new thing, just discovered. But low dose abilify has been used for years for other things including depression. And side effects can occur at low doses.

 

[leokitten]

Posts from a couple of clients of the Stanford clinic report:

• when they told the clinician that Abilify doesn't work for them anymore, the clinician said to keep using it because 'even though you don't feel the benefits, it's helping fight inflammation'
• the clinician seemed a lot more worried about why they hadn't come to the clinic regularly than that Abilify wasn't working
• patients are blamed for Abilify not working - because they did too much when it worked and then crashed
• the Stanford clinic is pushing Abilify 'aggressively' and it was said that 'they are absolutely championing Abilify now, the way they were doing with antivirals before'. Patients are worried that they might be dropped if they refuse to take Abilify.
• they are prescribing Abilify to people already taking multiple drugs affecting the central nervous system

Link to the PR thread here

From my understanding and reading of the PR thread (which I'm actively part of), the info you bullet pointed are all from posts from a single Stanford Clinic patient, whom I actually know pretty well. I do completely agree with you if Bonilla is exhibiting this behavior across many patients, though I feel if you are basing all of these conclusions mostly on the posts of a single patient then we should wait and see before raising such alarm without more evidence.

I even told the patient he shouldn't see Bonilla anymore, but let's not start entangling and conflating Abilify as a treatment for ME with bad doctors or clinics, they are not one and the same, and I feel this post is trying to do that.

 

[leokitten]

That's not really true. If the trial has a reasonable size, then it's likely that any benefit in a substantial subset will bring the average response above that of the placebo treatment. If the changes are charted, it should be possible to actually see that a treated subset benefitted.

What is a "reasonable" size? The RituxME trial was the largest so far with 151 ME patients, and I believe this would not be a large enough cohort to meet the statistical power necessary to show drug response efficacy if there are multiple unknown and confounding subsets with different pathologies or misdiagnosed ME in the cohort. I agree with you if the phase III trial has a really large cohort like we see for much better funded diseases, but my comment was reflective of ME clinical trial reality... small cohorts, small trials.

 

[Sid]

Years ago Stanford affiliated folk were enthusiastically pushing antivirals, then a gout drug, then naltrexone. Each was claimed to help many. Of course none of these treatments do anything beyond wishful thinking.

 

[leokitten]

Years ago Stanford affiliated folk were enthusiastically pushing antivirals, then a gout drug, then naltrexone. Each was claimed to help many. Of course none of these treatments do anything beyond wishful thinking.

Actually there are plenty of pwME who’ve claimed that antivirals were the cause of their remission. Whether it truly was antivirals or simply time or placebo effect is debatable, but if it were placebo effect they might’ve never taken antivirals if it hadn’t been for a doctor at Stanford recommending they try.

Maybe it was because their herpes virus serology results and the feeling that antivirals would make the difference they got the placebo effect they needed to overcome whatever they had (if it was ME or something else), but you don’t get placebo effect from doing nothing, you need the sugar pill

I know, the same could be said for people who’ve been harmed by a medication, but there are few if any cases of physical/medical harm from antivirals or LDN for example. IMO I don’t care that they recommended antivirals I took them for years and don’t feel jipped.

 

[Hutan]

From my understanding and reading of the PR thread (which I'm actively part of), the info you bullet pointed are all from posts from a single Stanford Clinic patient, whom I actually know pretty well.

There were two patients. Sure, that's a small number, but we've also seen the published paper that appeared overly confident about the utility of Ablify and that suggested that patients were being lost to followup.

let's not start entangling and conflating Abilify as a treatment for ME with bad doctors or clinics, they are not one and the same, and I feel this post is trying to do that.

Yes, the utility of a drug and the ethics of doctors promoting it are not always related issues. But if people are being strongly encouraged to use a drug by a clinician, if they are being told that this drug does really work, that will affect how patients view the drug. It will affect how they report about it publicly. Is it just the Stanford Clinic that is prescribing Abilify? Are other ME/CFS clinics actively promoting its use?

 

[Jonathan Edwards]

What is a "reasonable" size?

To confirm the an impression from pilot studies is real the size does not need to be that large. If a moderate sized trial shows nothing it either means that the pilot observations were just over-egged coincidence or that the triallists failed to set up inclusion criteria to match what they based their pilot study choices on. If you need a huge study to get a noticeable difference then by definition it would not have been noticed in pilot studies. You cannot have it both ways! If moderate sized trial comes out negative the clinicians must have been fooling themselves that they could notice benefit.

The situation where you need a large study is where there are theoretical reasons to think a treatment might work and the study is based on these, not on pilot study promise.

The placebo response is almost certainly of no use to people and you do not need a sugar pill as far as we know. The same effect occurs with talking in CBT, although I admit seems pretty feeble. Most of what is called the placebo effect is probably patients saying they are better through not wanting to upset the health professional in case they get discharged from care or not wanting to look as if they have wasted money maybe.

 

[leokitten]

Is it just the Stanford Clinic that is prescribing Abilify? Are other ME/CFS clinics actively promoting its use?

From discussions with my ME doctor and other doctors or hearing about other practices from her, US ME doctors and clinics found the Stanford news on Abilify very intriguing, but are only cautiously trialing Abilify with specific patients if the patient request the trial and requirements are met (other drugs that could interact, other conditions which would preclude Abilify use, etc)

And they are starting patients at the lowest dose possible 0.25 mg (or even 0.1 mg) and wait and see for a couple weeks at a time or longer before titrating up the next 0.25 step, and so on. Dr Levine told me the other doctors she’s in contact with are all being very cautious and taking it slowly with each patient.

At these very low doses we have yet to see even a single case of a serious side effect that didn’t reverse upon discontinuation.

Most side effects reported in ME patients on the FB group are what were expected and not immediately serious: weight gain, some increased irritability, insomnia, tachycardia, restlessness, headache.

But these are from very small polls, only a handful of votes in each category, and there’s no clinical or demographic data, no dosage info, no comorbid med use info, no info on if votes across multiple side effects come from the same people, etc, all the things that are really needed to tie into the side effect data points to make more sense of it.

I for one have not experienced any side effects, so I think a lot of factors determine if you will experience any, particularly your dosage.

 

[vsou]

if you are basing all of these conclusions mostly on the posts of a single patient then we should wait and see before raising such alarm without more evidence.

No from what I have read in fb groups these are not things that are occurring with just one (or a few) patients.

but let's not start entangling and conflating Abilify as a treatment for ME with bad doctors or clinics, they are not one and the same,

But they are entangled already. Didn’t Stanford start using abilify for ME, and now patients around the world are asking their doctors to prescribe that medication according to the “Stanford protocol”. And it’s Bonilla pet project.

 

[leokitten]

The other thing that bothers me is that I keep seeing PwME write that side effects won’t occur at the low doses of abilify being used for ME. They make it seem like low dose abilify is a brand new thing, just discovered. But low dose abilify has been used for years for other things including depression. And side effects can occur at low doses.

I believe this is an misinterpretation of the facts. Yes people with depression have taken Abilify as an antidepressant add-on at dosages of 5-10 mg/day. They have not taken Abilify at dosages of 0.25-2 mg/day.

There is not one single scientific paper or piece of evidence that describes the extent and nature of side effects at this very low dosage range. Of course even at 0.25-2 mg/day some people are experiencing side effects, no one was stating that there wouldn’t be any side effects, just the much lower incidence and severity risk at this very low dosage range.

I (and many others) have yet to see a single case of a pwME taking Abilify who experienced one or more side effects that weren't completely resolved by discontinuing the medication or adjusting down the dosage.

So far, the vast majority of reported side effects are pretty minor, in line with what you see with pretty much any drug.

 

[leokitten]

But they are entangled already. Didn’t Stanford start using abilify for ME, and now patients around the world are asking their doctors to prescribe that medication according to the “Stanford protocol”. And it’s Bonilla pet project.

I believe they are not, and conflating them together and their success or failure together is a construct invented by people.

Abilify was trialed by pwME before Stanford was doing it, and there are likely hundreds like myself who don’t go to Stanford Clinic and are trialing it for ME on our own or with another ME doctor.

I believe doctors and clinics trying the Stanford protocol are going to have enough independent clinical thinking skills to not follow-up with their patients in the same negative way Bonilla seems to be doing so. I honestly think this is a Bonilla personality issue and shouldn’t be connected to the the important discussion of Abilify the drug as a treatment for ME.

Just because the protocol of very low dose was popularized at Stanford, they don’t own anything about it and it’s now in the wild for anyone to use it as they see fit.

 

[Jaybee00]

I (and many others) have yet to see a single case of a pwME taking Abilify who experienced one or more side effects that weren't completely resolved by discontinuing the medication or adjusting down the dosage.

Some people have had withdrawal issues and needed to restart Abilify to control symptoms (RLS) even though Abilify was no longer effective for MECFS.

With psychotropic meds a lot of time the problems (akathisia/TD) are associated with withdrawal not with side effects while taking.