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

[leokitten]

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

From my understanding of this patient and their posts on PR, they had RLS before Abilify and they weren’t treating it or other meds they were taking weren’t helping or making it worse.

Then they started Abilify for ME and were happy that it effectively treated the RLS. Now that the Abilify built up tolerance for ME after months, they feel they still need to take it to continue to control RLS.

So to me this isn’t an Abilify caused problem. They had RLS pre-Abilify and it wasn’t treated or well treated. Then Abilify happened to treat it effectively but didn’t continue to work for ME after 4 months.

 

[vsou]

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. Let's stick to real facts and evidence and not total speculation. 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.

No I am not misinterpreting the facts. Actually yes people have been prescribed abilify for depression at lower doses of 1-2 mg and have experienced side effects.

Whether or not there is anything published on this is not something I have researched, but I would be surprised if absolutely nothing has been.

Also pr is not the only place PwME are posting on this topic, and I have read numerous comments in fb groups saying or implying that at the lower doses no serious side effects will occur.

I was prescribed low dose abilify about 10 years ago for depression, and once I increased from 1 to 2 mg I had side effects—intrusive suicidal thoughts—which continued when I reduced back to 1 mg, so I then discontinued it.

My experience with abilfy makes me concerned it’s being prescribed widely to desperate and depressed PwME without enough precautions and warnings. It took me a while to realize that my suicidal thoughts were being caused by abilify. Also I was not at that time feeling suicidal. But obviously if someone is already feeling suicidal and doesn’t realize the medication is also changing or exacerbating their thoughts, abilify could definitely result in suicide. So I consider this a very serious side effect.

 

[FMMM1]

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.

I agree i.e. about +ve scoring (by patients) when subjective outcomes measures (questionnaires) are used:
It's about being interested in making their (people with ME) lives better - that's why people score the intervention positively - the person (health care professional) is showing an interest --- no one else has shown an interest since most people consider that these people (people with ME) should just get off their ass and get on with life --- it seems to be the Hawthorne effect https://en.wikipedia.org/wiki/Hawthorne_effect

 

[Sid]

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.

If people are claiming positive effects from very low doses, does it not logically follow that side effects could occur at those same doses? ME patients are very sensitive to medications.

 

[leokitten]

If people are claiming positive effects from very low doses, does it not logically follow that side effects could occur at those same doses? ME patients are very sensitive to medications.

Im not debating whether side effects occur or not. Where I ever stated that side effects won’t occur in any post?? Side effects occur in a subset of patients with almost every drug at almost every dosage. In fact with almost anything you swallow or put on your skin, pharmaceutical or not.

It’s about the risk of significant side effects, their incidence, and severity at this very low dosage range compared to the higher dosages and also compared to other commonly used psychotropics.

And this is not a discussion of individual experiences and trying to extrapolate that to the risk to the entire ME population or a larger cohort, it’s about group level differences in the risk, incidence, and severity of side effects at the 0.25-2mg dosage range compared to higher Abilify dosages and to other commonly used drugs like antidepressants, anticonvulsants, etc.

The scientific evidence of risk and incidence of serious side effects at this very low dosage range at the group level just isn’t there. That is what I’m stating.

 

[leokitten]

Whether or not there is anything published on this is not something I have researched, but I would be surprised if absolutely nothing has been.

There is not one paper or other evidence in the scientific literature, I looked all over Pubmed for any research on very low dosage Abilify, because there isn’t (other than the Stanford paper).

Has anyone seen anywhere on the PR, S4ME, or FB Abilify groups were pwME have had such serious side effects with Abilify such as suicidal thoughts or others that weren’t completely reversed by discontinuation?

 

[leokitten]

If people are claiming positive effects from very low doses, does it not logically follow that side effects could occur at those same doses? ME patients are very sensitive to medications.

Abilify is a special case, it’s a drug that pharmacologically works very differently at low doses than at higher doses, so no this does not hold.

 

[vsou]

Has anyone seen anywhere on the PR, S4ME, or FB Abilify groups were pwME have had such serious side effects with Abilify such as suicidal thoughts or others that weren’t completely reversed by discontinuation?

If the side effects lead to suicide, whether or not the side effects would have gone away had abilify been discontinued is a moot point.

 

[vsou]

The scientific evidence of risk and incidence of serious side effects at this very low dosage range at the group level just isn’t there. That is what I’m stating.

There is not one paper or other evidence in the scientific literature, I looked all over Pubmed for any research on very low dosage Abilify, because there isn’t (other than the Stanford paper).

So the scientific evidence isn’t there because it hasn’t been studied. From that we can’t and shouldn’t conclude that serious side effects cannot occur at low doses. Whether or not you are concluding that, other PwME are.

Also, when scientific studies are not available, experiences of individual patients is relevant, that’s why doctors write up and publish case studies, though apparently even that hasn’t been done on this subject.

 

[Trish]

Since this thread has generated more interest than I expected for an only mildly promising retrospective clinic review, I decided to look more closely at the article, and have come up with some questions:

1. Is it a legitimate approach to clinical data to divide patients retrospectively into those who have 'improved' and those who haven't - and to base conclusions on this?

2. Is it legitimate in reporting on outcomes to include those who have only had a very short time on the treatment so far, so it's too early to tell whether the effects are lasting?

3. Is it legitimate to only include those who returned for a second visit. What about all those who only attended once, found the treatment ineffective or had too many side effects, and never went back. This possiblilty, not addressed, could significantly impact the numbers reporting lack of effect and/or side effects, and is simply unknown.

4. Is it legitimate to class as 'improvement' tiny increments on a ten point subjective scale? Surely they need to decide what is clinically significant improvement, and only include those as 'improved'.

5. Is it legitimate to include changes in symptoms that might have been affected by other changes made to treatment or management at the same time? For example, sleep - it seems likely in the clinic visit sleep meds will have been reviewed, and possibly new medications prescribed at the same time as the drug being assessed here. Similarly it seems likely that lifestyle management advice will be given, including pacing to reduce frequency of PEM. And both these factors would also have an impact on the other 2 symptoms being rated - fatigue and cognitive function, both of which are likely to improve with better sleep and pacing. There is no mention in the article of any assessment of such possible confounding factors.

6. Is it legitimate in a study of this kind to report numbers who suffered side effects or adverse events during, and possibly after, taking the drug, if no attempt is made to follow up patients who did not return to the clinic. There is no indication in the article that any attempt was made to address this, even with a simple phone call to ask the patient.

7. Is frequency of episodes of PEM a legitimate test of illness severity? My experience is that as I have got sicker I have been forced to change my life in a way that actually means I am more able to pace and avoid crashes. So for me, frequency of PEM is inversely related to severity of illness.

I ask all these question because it seems to me that even for a retrospective review of clinic data, the person doing the review makes choices about how to analyse the data that can significantly skew the outcomes reported.

What if they had analysed the data differently?

For example:

1. When assessing effectiveness, only assess as effective if the change cannot be explained by other changes in medication or daily symptom management. So omit patients whose improvements can be attributed to concurrent changes in sleep medication and/or pacing.

2. When asssessing effectiveness, only include as effective if the reported improvement is clinically significant (eg 2 or more of the listed symptoms improve by 2 or more points on the 10 point scale, and the patient reports that they have been able to significantly increase their cognitive and/or physical activity)

3. When assessing effectiveness, only include those whose improvement has been sustained for a given time, say 6 months.

4. When assessing worsening, include those have adverse events, whose symptoms get significantly worse, or who give up because of side effects, including tracking down those who dropped out.

Note: I'm as keen as anyone to find a treatment that works for a significant number of pwME. I just what honest reporting of reality, not sugar coating.

 

[Sid]

Abilify is a special case, it’s a drug that pharmacologically works very differently at low doses than at higher doses, so no this does not hold.

How do we know this? Where are the pharmacodynamic studies of these near-homeopathic doses? I'm not talking about "low dose" aripiprazole as understood in psychiatry, I am talking about these ultralow doses being used in ME/CFS.

 

[5vforest]

One thing I'll add to Trish's list:

As this was a retrospective study, some records from patients contained descriptive statements (e.g., feeling “better” or “worse”), or had missing values for one or more symptoms.

Surely they must have known they were considering a retrospective analysis, and they could have done a better job with ensuring patients answered completely and in the correct format.

I also strongly agree with #6, how hard would it have been to follow-up with a phone call to patients who didn't return for a visit?

I am actually really pleased to see clinical data being analyzed and published, as in my experience (especially in Lyme world) there are a lot of doctors who are happy to treat patients with any various combination of medications, only backed up with "well I've seen it work for my patients before" without any sort of data behind that statement.

(This is why I am a "fan" of Horowitz's publications [https://www.s4me.info/threads/effic...nt-lyme-disease-syndrome-2020-horowitz.19307/], since the alternative is usually nothing at all.)

My own bias as a former software guy is that careful, considered use of technology could make it very efficient for doctors to collect these data points, if they are truly interested in finding out.

There are a handful of doctors that I have seen and never returned to, and not once have I been called or emailed to ask "why not?" I (cynically) suspect that many practitioners simply don't want to know; if they have enough patients to fill a waiting list, then losing one to follow up is not their concern.

 

[Mij]

The only phone call I ever received during and after abx treatment was from the pharmacist. She was genuinely concerned that I was taking the proper dose and asked how I was feeling in detail.

 

[leokitten]

How do we know this? Where are the pharmacodynamic studies of these near-homeopathic doses? I'm not talking about "low dose" aripiprazole as understood in psychiatry, I am talking about these ultralow doses being used in ME/CFS.

Please look in the Abilify threads here and on PR and you will find plenty of linked scientific papers discussing this. I'm not talking about homeopathy, Abilify is a functionally selective, dopamine and serotonin system partial agonist (aka dopamine-serotonin system stabilizer). It acts on presynaptic (auto) receptors and postsynaptic receptors in different ways. Within each neurotransmitter system it also appears to function different depending on brain area. So real, studied science with in vitro, animal model, and human in vivo evidence suggesting its functionality in the brain and how it functions differently at low dose than at higher doses.

 

[leokitten]

Since this thread has generated more interest than I expected for an only mildly promising retrospective clinic review, I decided to look more closely at the article, and have come up with some questions:

Some of the discussion here about side effects etc I think doesn't belong here then and maybe in the general Abilify thread? Because not directly discussing results of the paper. I surely wasn't in any of the last posts I made.

 

[Sid]

Please look in the Abilify threads here and on PR and you will find plenty of linked scientific papers discussing this. I'm not talking about homeopathy, Abilify is a functionally selective, dopamine and serotonin system partial agonist (aka dopamine-serotonin system stabilizer). It acts on presynaptic (auto) receptors and postsynaptic receptors in different ways. Within each neurotransmitter system it also appears to function different depending on brain area. So real, studied science with in vitro, animal model, and human in vivo evidence suggesting its functionality in the brain and how it functions differently at low dose than at higher doses.

In other words, there are no papers showing what it does at 0.25 mg.

 

[Sid]

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.


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?

Thank you for bringing these patient reports to our attention. Those are incredibly disturbing posts which to my mind discredit this retrospective chart review. It would seem, based on these reports, that at least some patients attending that clinic feel under immense pressure to say to this doctor that his/her treatments are working even when they aren't to stay in the doctor's good graces.

In general I am far less inclined to believe information that comes from "ME/CFS expert" clinics because there are so few doctors in the world who believe us that patients are terrified of being fired by such a doctor who may be helping them with pain meds, disability claims etc.

 

[leokitten]

In other words, there are no papers showing what it does at 0.25 mg.

The linked relevant papers are in the threads I’ve pointed to.

Science does not currently have the technology to determine, in humans in vivo, the exact function of most drugs, particular psychogenic drugs that work predominantly in the brain. We don’t have the technology to directly look at and figure out exactly what you are asking in live humans at the synapse level.

We have to use other technologies and methods to indirectly suggest what is happening in humans in vivo. There are multiple papers in those threads discussing this evidence. For example, there are two landmark papers which performed PET scans of humans taking Abilify at a number of different dosages. Those papers give us some really useful and suggestive evidence and information about how Abilify works at different dosages. I think the lowest dose the papers analyzed was 0.5 mg/day (at steady state concentration after 2 weeks of dosing). There are also papers looking at cell lines and in vitro neurons examining the functions I’ve mentioned and at lower and higher concentrations (equivalent to humans taking lower and higher dosages).

 

[Trish]

Moved from this thread

I was very disappointed that the Stanford clinic published paper on Abilify was not good in scientific terms. It seemed like a huge missed opportunity to set up a proper trial with some of their patients, rather than simply going on prescribing without doing the sort of thorough record keeping including recording outcome measures and long term follow up, and having a control group. As a result we are really no further forward with knowing whether the drug is effective long term, what it's downsides might be, and what proportion of people do well on it.

 

[wigglethemouse]

I was very disappointed that the Stanford clinic published paper on Abilify was not good in scientific terms. It seemed like a huge missed opportunity to set up a proper trial with some of their patients, rather than simply going on prescribing without doing the sort of thorough record keeping including recording outcome measures and long term follow up, and having a control group. As a result we are really no further forward with knowing whether the drug is effective long term, what it's downsides might be, and what proportion of people do well on it.

To run the type of study they want to do at Stanford would cost $3million. This was the sum mentioned by Ron Davis in the Puzzle Solver book talk that I attended on zoom hosted by Stanford on May 14th but which I've not seen subsequently posted online.

I think the clinic wanted to publish the retrospective paper as a tool for applying for grants to do a "proper" study. So they published the records Dr Bonilla at the Stanford CFS clinic provided.

When key NIH people don't believe ME is real and refuse to allow submission of an application for an Abilify clinical trial researchers are left with very few other places to go for funding of this size?



The US is pretty expensive to do clinical trials.