The buspirone challenge test clearly distinguishes ME/CFS patients from healthy controls: why is it not being developed and deployed?

[Silip]

We considered doing this several years ago but Buspirone was very difficult to get in Australia (we wanted to do around 2022 but it had left the shelves several years prior). It has actually only recently been brought back last year.

We do have the ability to do the challenge test. It comes down to funding if we do it as a separate trial or time if we weave it into an existing.

Thank you very much for your reply.

I have a friend here in Canada who has taken buspirone, so I thought it was easily available. Good to know it is back in Australia.

You may already be aware of this, but Solve ME currently has a funding opportunity. As far as I can tell, it’s not geographically restricted.

Please let us know if there is anything we can do to help you in doing this study (including donations if necessary). I am very committed to making this a reality.

Is there a chance that the OMF could fund something like this?

If not maybe someone with good contacts to them could try to set something up with the WE&ME foundation as their grants are ~ the amount of money that would be needed and they seem to value input from this forum.

 

[Jonathan Edwards]

If not maybe someone with good contacts to them could try to set something up with the WE&ME foundation as their grants are ~ the amount of money that would be needed and they seem to value input from this forum.

I am hoping that we are making progress in this direction at UCL. Various things seem to be opportune for grafting this on to existing resources and projects. I need to discuss things in house but will report back.

 

[Kitty]

Various things seem to be opportune for grafting this on to existing resources and projects.

That's probably the best way to do it if possible. And if findings are consistent with previous studies and raise interesting questions, it might put the bit between the teeth of those involved.

 

[MelbME]

The trial would be quite unusual for the ME/CFS world. Should give concrete results, low cost / low risk, and above all it won't take years.

Maybe be the sort of thing a patient charity might be able to part-fund itself, and fundraise the rest?

Well I'm not sure it's low cost. Depends how you would run it I guess. Clinical research is not cheap unfortunately.

Probably easiest would be to stitch in to an upcoming trial we have funding for. This work really fits well with our preliminary imaging findings around hypothalamus inflammation, especially the neuroendocrine abnormalities associated.

The trial we are finishing is looking at hypothalamic metabolites, MAO-B levels, brain blood flow. We also have blood samples before and after exertion that we will be analysing for steroids and a few other hypothalamic influenced hormones (including prolactin).

Could look to see how difficult it would be to reconsent these patients. There are actually quite a few endocrine stress tests we have considered: Buspirone, glucagon, acth

 

[SugarSquared]

Probably easiest would be to stitch in to an upcoming trial we have funding for. This work really fits well with our imaging findings around hypothalamus inflammation, especially the neuroendocrine abnormalities associated.

Are you at liberty to share what this trial is? The use of imaging is exciting and something that others have talked about previously on this thread (though there's so many different types of imaging that I may be talking about something completely different).

Also, in case you haven't seen it because this thread is very long, I recommend reading forestglip's PDF. He's done a fantastic job searching for neuroendocrine studies in a variety of conditions.

The other changes were minor, but included adding some wording to the abstract and conclusion about the limitations of the existing evidence. I also added the minor data discrepancies that I identified in the Bakheit study to an appendix, which seems a better place than citing a forum post. And I added some references about prolactin response research in fibromyalgia and social anxiety disorder.

Link to document on Github

 

[MelbME]

Is there a chance that the OMF could fund something like this?

If not maybe someone with good contacts to them could try to set something up with the WE&ME foundation as their grants are ~ the amount of money that would be needed and they seem to value input from this forum.

It's certainly possible they would fund it and I'll discuss it. I think it can be done within existing project funding though already. I usually try to be as efficient as possible with clinical work because of how expensive it is.

WE&ME seems like a great opportunity for less-resourced groups in the field to get project funding (there are many and we are doing ok for the moment). But I would be happy to support a young post doc working with us to apply.

 

[ScoutB]

We also have blood samples before and after exertion that we will be analysing for steroids and a few other hypothalamic influenced hormones (including prolactin).

That's good to hear. It'll already be interesting to have a new datapoint on the prolactin response to exercise in ME/CFS.

And yea, speaking of forestglip's PDF, there's one previous study of an exercise challenge in table 2. Sounds like in that study prolactin minimally increased in the ME/CFS patients while it more than doubled in controls.

 

[MelbME]

Are you at liberty to share what this trial is? The use of imaging is exciting and something that others have talked about previously on this thread (though there's so many different types of imaging that I may be talking about something completely different).

Also, in case you haven't seen it because this thread is very long, I recommend reading forestglip's PDF. He's done a fantastic job searching for neuroendocrine studies in a variety of conditions.

The trial is this one:

ANZCTR - Registration

Study comes from our interest in glutamate and glutamatergic neurons in the brain, especially how they connect neuroinflammation and impact on hypothalamus. We think glutamate is being stretched across its many roles, we that is having a systematic impact.

So we are looking at brain blood flow, impact of standing included (FDG-PET) neuroinflammation proxy is reactive astrogliosis (elevated MAO-B) through another PET tracer and some hypothalamus MRS. We also do some in task measures of brain activity. We took blood samples before and after including cells to assess hormones, hormone impact on cell metabolism, cell viability, proteomics, cellular lipid changes, etc.

It's a large study and recruitment ends this year, assays happening over 2027.

 

[forestglip]

reactive astrogliosis (elevated MAO-B)

Maybe if reactive astrocytes are seen, it would fit in with a hypothesis discussed previously to try to explain prolactin findings: astrocytes responding to brain damage (or just damage-related signals) release estrogens, which leads to larger prolactin response.

The review says that brain damage of seemingly any type increases aromatase expression around the damaged area, leading to increased estrogen levels. The estrogens are produced primarily in reactive astrocytes and radial glia. Estrogens appear to help protect against and repair damage.

I’m thinking it’s more likely to be one of the pathways that gets triggered by brain damage, but getting activated in the absence of actual brain damage (a cytokine or extracellular glutamate or something like that).

It's probably a long shot as we don't have good evidence that estrogens are involved in abnormal prolactin response, and if they are, we don't know if it'd be related to this brain damage signal idea. But maybe something to watch.

 

[MelbME]

Maybe if reactive astrocytes are seen, it would fit in with a hypothesis discussed previously to try to explain prolactin findings: astrocytes responding to brain damage (or just damage-related signals) release estrogens, which leads to larger prolactin response.



It's probably a long shot as we don't have good evidence that estrogens are involved in abnormal prolactin response, and if they are, we don't know if it'd be related to this brain damage signal idea. But maybe something to watch.

Yes that's certainly a possibility. It is hard to pull out cause and effect and we are trying to characterise the whole cycle as a shift. But it does feel intuitive that the reactive astrogliosis subset is a response to a stressor in the brain that is mounting a peripheral stress response.

 

[forestglip]

But it does feel intuitive that the reactive astrogliosis subset is a response to a stressor in the brain that is mounting a peripheral stress response.

I might be forgetting something, but when you say the reactive astrogliosis subset, are you referring to an existing study that found reactive astrogliosis in a subset of ME/CFS patients?

 

[MelbME]

I might be forgetting something, but when you say the reactive astrogliosis subset, are you referring to an existing study that found reactive astrogliosis in a subset of ME/CFS patients?

Not published

 

[V.R.T.]

This is really exciting. Simultaneous replication attempts in London and Melbourne could help give more certainty about whatever is found.

This work really fits well with our preliminary imaging findings around hypothalamus inflammation, especially the neuroendocrine abnormalities associated.

Very interesting! Do you have any idea when we'll see those findings in (pre)print?

 

[MelbME]

This is really exciting. Simultaneous replication attempts in London and Melbourne could help give more certainty about whatever is found.


Very interesting! Do you have any idea when we'll see those findings in (pre)print?

Well we've not done a preprint yet. If we do preprint then next year, if we publish first then could be 2028.

Maybe we should start doing preprints

 

[Utsikt]

Maybe we should start doing preprints

DecodeME has been very useful as a preprint. If there’s useful data that others would benefit from, I don’t think anyone mind that it hasn’t been peer reviewed or set in stone yet. And readers might spot things that should doubled checked, clarified of corrected for the final version.

 

[EndME]

Maybe we should start doing preprints

I think the answer to that is straightforward: YES!

 

[Jesse]

Well I'm not sure it's low cost. Depends how you would run it I guess. Clinical research is not cheap unfortunately.

Probably easiest would be to stitch in to an upcoming trial we have funding for. This work really fits well with our preliminary imaging findings around hypothalamus inflammation, especially the neuroendocrine abnormalities associated.

The trial we are finishing is looking at hypothalamic metabolites, MAO-B levels, brain blood flow. We also have blood samples before and after exertion that we will be analysing for steroids and a few other hypothalamic influenced hormones (including prolactin).

Could look to see how difficult it would be to reconsent these patients. There are actually quite a few endocrine stress tests we have considered: Buspirone, glucagon, acth

Sounds like great stuff! Looking forward to the results.

 

[Jonathan Edwards]

I have been a bit slow about this but wanted to check with others a thought that is growing in my head.

As far as I can tell the buspirone test and similar ones were popular because they provided a clever way to perturb 5HT signalling in brains and get a chemical read out in blood rather than just a subjective report.

And this was popular at a time when there was a view that not enough 5HT made you sad and maybe loads of 5HT made you happy. I think this may even relate to quite a common view that somehow emotions are directly related to the presence of chemical transmitters, as if the brain could 'taste' or 'smell' the flavour of a sweet transmitter or a sour one. There are people who actually build theories on this.

But maybe the test is interesting in ME/CFS because the reporter prolactin pathway is interesting. Maybe prolactin just happens to be tweaked by dopamine and 5HT so buspirone is a way to look at its regulation but 5HT and dopamine could equally have been GABA and ACh. Even the prolactin would not be causing symptoms. The symptoms are determined by electrical patterns in cells that happen to be dependent on particular nerve pathways.

The key point though, would be that this test might be interesting to us because it perturbs hypothalamic pathways rather than because is perturbs 5HT or dopamine. Maybe the test fell out of fashion because nobody realised that it was the reporter pathway, not the transmitter type that was the seat of the problem?

 

[hotblack]

The key point though, would be that this test might be interesting to us because it perturbs hypothalamic pathways rather than because is perturbs 5HT or dopamine. Maybe the test fell out of fashion because nobody realised that it was the reporter pathway, not the transmitter type that was the seat of the problem?

Yes. One thought I had while down the pituitary and FS cell rabbit-hole is maybe similar? There may even be something wrong with there, a lot looks quite appealing, but what if it isn’t the problem so much as the response that causes symptoms (or maybe a combination). If there is a prolactin surge (for whatever reason) this is noticed and there has to be a counter-surge of dopamine to bring things back into the normal range. So presumably part of the brain (the hypothalamus I guess) is going ‘this ain’t right, quick lads do something’ in its response to what happens in the pituitary/lactotrophs. And what else is in that pathway? What is the brain deciding is going on when it sees this surge? What messages get sent and what are the effects? What other neurotransmitters need to ramp up?

We see that our levels are normal, there is a spike, they become normal again. The brain/body is doing its job, well done, but at what cost? Again it sort of fits in with the ‘dysregulation of the HPA axis’ talk but in a biological way rather than psychosocial. And no amount of happy thoughts will fix a broken substation (to use my earlier analogy).

 

[V.R.T.]

I have been a bit slow about this but wanted to check with others a thought that is growing in my head.

As far as I can tell the buspirone test and similar ones were popular because they provided a clever way to perturb 5HT signalling in brains and get a chemical read out in blood rather than just a subjective report.

And this was popular at a time when there was a view that not enough 5HT made you sad and maybe loads of 5HT made you happy. I think this may even relate to quite a common view that somehow emotions are directly related to the presence of chemical transmitters, as if the brain could 'taste' or 'smell' the flavour of a sweet transmitter or a sour one. There are people who actually build theories on this.

But maybe the test is interesting in ME/CFS because the reporter prolactin pathway is interesting. Maybe prolactin just happens to be tweaked by dopamine and 5HT so buspirone is a way to look at its regulation but 5HT and dopamine could equally have been GABA and ACh. Even the prolactin would not be causing symptoms. The symptoms are determined by electrical patterns in cells that happen to be dependent on particular nerve pathways.

The key point though, would be that this test might be interesting to us because it perturbs hypothalamic pathways rather than because is perturbs 5HT or dopamine. Maybe the test fell out of fashion because nobody realised that it was the reporter pathway, not the transmitter type that was the seat of the problem?

If this is the case, will the team doing buspirone study that is hopefully being setup be well placed to follow that lead and find out where it goes?