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

[OrganicChilli]

I had a go at putting it into a Word document in case it helps with that process, but it lacks a title, authorship, etc.

If @forestglip thinks it might be useful, I can post it here.

@hotblack has been playing around with typst. Do you have a template you can publish? We could then use it for this document.

 

[Trish]

@hotblack has been playing around with typst. Do you have a template you can publish? We could then use it for this document.

That is under discussion in the committee.

 

[Jonathan Edwards]

An excellent summary @forestglip. Would it be worth working towards publishing it in a context where it would be picked up on academic searches as well as general web searches, be it either in a peer reviewed journal or on a preprint site?

It might be worth asking Audrey and Charlie what they think might be options for creating a formal publication. I have lost touch with the mechanics of this.

 

[hotblack]

It might be worth asking Audrey and Charlie what they think might be options for creating a formal publication. I have lost touch with the mechanics of this.

That’s a great idea. I think submitting a preprint to medrxiv or biorxiv is probably lowest barrier and would get a doi and things, but it would be great to get some advice from people who’ve done it. Presumably it wouldn’t stop us ‘publishing’ it ourselves too? What do you think @chillier ?

 

[obeat]

Would the neuro radiologists who published the hypoxia paper be interested in this in case there is some potential scanning technique?

PETscans and DRD2 were mentioned.


@SNT Gatchaman
@NiFab

 

[forestglip]

Ok, I've made a PDF version. I made a few changes, mostly fairly minor. Added a couple sentences here and there.

Thank you for this detailed and well rounded summary, which is well worthy of publication. You have put in a lot of work and one can see that!

Having not followed the full discussion I was wondering if it was possible to include 2 smaller sections or additional links on the historical context which I find quite important given that these are old findings which have been lying around for some time.
- Why has prolactin response been studied in illnesses in general in the past?
- Why has it come out of favour of being studied and why in particular did it not get studied further in ME/CFS?

The second question might be particularly hard to answer as it might be related to unpublished results and historical context none of us might know, but in this case it might be worth writing something like "it is unclear why these results weren't further investigated". Perhaps it would also be wise to include a sentence on whether this response might be related to being physically less active or other variables like sleep patterns, timing of testing, drug usage, BMI as these are the usual candidates to explain results in ME/CFS research. If it for instances is impacted by stress then pwME/CFS might be under more stress during hospital visits. I know you've thought all of these things through, maybe the summary could have a section on these explanations, in a "limitations section" or similar. I understand that including all of this might also make the summary unattractively long and you've already gone over the character limit.

You mention other diseases where prolactin response has been measured. Have you been able to get a feel for how reliable these results are in other contexts, for example are there illnesses where you tend to always see the same results and where large replication studies have shown this or is it rather a bit mixed with spurious results appearing all over the place?

I can always count on you for the tough questions.

Most of this, I won't be able to answer adequately, and I'll try to keep it in my mind to think about these questions as I continue reading.

My impression, though, is that nothing much came out of prolactin response being abnormal in any condition. Maybe in conditions where prolactin is overly high in general, such as the hyperprolactinemia seen from long-term antipsychotic use, it might have helped develop better drugs that don't do this. But as far as acute prolactin response to drug challenges, I don't get the sense that anyone really had a good idea of what it meant. Findings in most of the conditions where this is seen also don't appear to be very consistent, making interpretation harder.

Though note that I haven't been focusing much on blunted prolactin response. There might be other insights there. I've got almost 200 studies saved about prolactin response studies in different conditions, so there's plenty more reading to do.

I did add a little conclusion that at least notes that it's not clear why the research was stopped:

It is not clear why research into abnormal prolactin response in ME/CFS has appeared to stall, with almost all studies of this phenonemon being conducted in the 1990s, and with no studies directly testing prolactin response in ME/CFS in over 15 years. Through careful consideration of study design and consultation with experts in endocrinology and neurology, future research into prolactin response may uncover important insights about the pathophysiology of ME/CFS, a condition that has, so far, eluded explanation.

For the confounders you mentioned, I agree it'd be good to mention it in the write-up. But that's a task for another day. I believe that several studies at least try to avoid patients taking brain-related drugs in the time before the test. For stress, it's possible, but I think it's probably unlikely that stress would be the cause of such consistent results in ME/CFS, but show nothing similar in pretty much any other health condition, including depression and anxiety.

As far as why prolactin response has been studied in the past, I agree that could be included in the paper, after I've better got a sense of the answer to it.https://pubmed.ncbi.nlm.nih.gov/6804899/

Edit: Newer version of PDF in post #452.

 

[Kitty]

But as far as acute prolactin response to drug challenges, I don't get the sense that anyone really had a good idea of what it meant.

Seems likely, doesn't it.

But we do know a bit more now, at least about what ME/CFS isn't. And we might be able to reach people with specific expertise that the original researchers couldn't manage to engage—who themselves probably know more than was known back then.

 

[forestglip]

Thanks for all the work on this forestglip. Is there any chance that your summary could be put into a PDF format? I suspect that it would be easier to share like that.

Yes, I've put it into a PDF in my previous post.

Would it be worth working towards publishing it in a context where it would be picked up on academic searches as well as general web searches, be it either in a peer reviewed journal or on a preprint site?

Maybe. I see some parts missing from my write-up that make it pretty far from a "polished" paper though, like a more extensive introduction and conclusion section, so it could take a while before it'd be ready for that, if I do decide to do that. Maybe if I collaborated with someone with experience in writing scientific papers, so they could help with structuring it in a more professionally organized way. But I need to recover from all this writing for now.

Does anyone know what the implications of this biological finding are for health?

In my opinion, this is just scratching the surface of the mechanism of ME/CFS, and what we have so far is very far from being able to provide any meaningful insights, so needs to be tested in more ways.

 

[V.R.T.]

Could this finding have any use as a biomarker for research? since its replicated.

I assume it wouldn't be appropriate for clincal use

 

[forestglip]

Could this finding have any use as a biomarker for research? since its replicated.

I assume it wouldn't be appropriate for clincal use

Depends on whether prolactin response goes back to normal after improvement. A single case report suggests that is the case, but it'd be good to have more evidence. But if so, then yes maybe it'd be good to see how it changes and correlates to symptom improvement in drug trials.

 

[chillier]

It might be worth asking Audrey and Charlie what they think might be options for creating a formal publication. I have lost touch with the mechanics of this.

That’s a great idea. I think submitting a preprint to medrxiv or biorxiv is probably lowest barrier and would get a doi and things, but it would be great to get some advice from people who’ve done it. Presumably it wouldn’t stop us ‘publishing’ it ourselves too? What do you think @chillier ?

I think Qeios and Bioarxiv make sense as you say for getting a doi and I'm pretty confident you don't need an institutional affiliation or money for either of those. I don't know about whether you need institutional affiliation for other journals but the big barrier is probably is more likely to be the cost.

I wonder whether this particular kind review would work well as a systematic review where the process for selecting (and rejecting) papers is outlined and quantified.

 

[forestglip]

I wonder whether this particular kind review would work well as a systematic review where the process for selecting (and rejecting) papers is outlined and quantified.

Hmm. It's been a very unstructured search so far, as far as searching for every single possible prolactin response paper in any condition. It's been through searching a large variety of terms on PubMed and Google Scholar, and through finding relevant citations in papers.

If we're talking about just the ME/CFS-related papers though, I'm pretty sure I found every paper that tested this, as there aren't that many, and I could probably figure out how to replicate the searches.

I think Qeios and Bioarxiv make sense as you say for getting a doi and I'm pretty confident you don't need an institutional affiliation or money for either of those.

I'd be nervous about my ability to respond to peer reviews on Qeios, as there's still a lot of relevant context that I don't really feel I can respond to sufficiently, like with EndME's questions above.

 

[V.R.T.]

Depends on whether prolactin response goes back to normal after improvement. A single case report suggests that is the case, but it'd be good to have more evidence. But if so, then yes maybe it'd be good to see how it changes and correlates to symptom improvement in drug trials.

Oh i hadn't even thought about that aspect, I was thinking about cohort selection!

If it goes back to normal after improvement it could be really valuble!

 

[forestglip]

Oh i hadn't even thought about that aspect, I was thinking about cohort selection!

Oh yeah, good point. That might work too. It's not a perfect biomarker, but it might be good to exclude those with normal response as being at least less likely to have the same exact condition.

 

[V.R.T.]

Has anyone contacted Fluge and Mella's team about this? Perhaps they might want to use it in their trials.

The Germans also seem like they are always looking for biomarker type metrics for their trials.

 

[Andy]

Yes, I've put it into a PDF in my previous post.

Fantastic, thanks.

 

[Utsikt]

This is so impressive, @forestglip !

 

[SugarSquared]

Having not followed the full discussion I was wondering if it was possible to include 2 smaller sections or additional links on the historical context which I find quite important given that these are old findings which have been lying around for some time.
- Why has prolactin response been studied in illnesses in general in the past?
- Why has it come out of favour of being studied and why in particular did it not get studied further in ME/CFS?

If I may, I’d like to add my thoughts on this. There seems to have been a big amount of hype surrounding 5-HT and serotonin back in the day and researchers thought the buspirone prolactin test could elucidate that mechanism. You see Bakheit et al 1992 bring that up as their reasoning for the exaggerated response in ME/CFS. Sharpe et al. 1996 did not seem to buy into the hype. They instead suggested something to do with dopamine.

The basis for me saying there was a lot of hype surrounding 5-HT is this blog post that was previously brought up here. I might be off about this though, because the blog post focuses on the 5-HTTLPR transporter gene, not the 5-HT receptor, for which the hype began with a study in 1996. Still, I think the overemphasis of serotonin in both cases might still apply here. @forestglip has looked into the role of serotonin in regulating prolactin and its release, and it’s been unimpressive. It seems to have a smaller or less direct role compared to dopamine or estriadol.

 

[forestglip]

You see Bakheit et al 1992 bring that up as their reasoning for the exaggerated response in ME/CFS. Sharpe et al. 1996 did not seem to buy into the hype. They instead suggested something to do with dopamine.

Yes, they said this in Sharpe et al. 1996:

Our data question whether the enhancement of buspirone-induced prolactin release in CFS is a consequence of increased sensitivity of post-synaptic 5-HT,, receptors. It is possible that the increased prolactin response to buspirone in CFS could reflect changes in dopamine function.

But interestingly, the next year, they went back to serotonin, after seeing an increased prolactin response with the serotonin drug, d-fenfluramine in Sharpe et al. 1997:

Raised brain serotonin activity might explain the excessive fatigue experienced by patients with the chronic fatigue syndrome

What it seems like to me is that all of these authors were debating the wrong thing. It's like they considered this a one step process: activate receptor > prolactin goes up. And thus if prolactin goes up too much, it must mean the receptor is abnormal. So researchers were spending their time debating about whether buspirone increases prolactin through the dopamine or through the serotonin receptor. Or how it must all be related to abnormal serotonin if d-fenfluramine causes a response, since that drug is specific to serotonin receptors.

But for some reason - and this still seems so odd to me that I fear I'm the one misunderstanding something - barely anyone was considering that prolactin release is not a one step process. I'm not an expert in these processes, but there are very many steps involved, any of which could be not working right:

The drug binds to the serotonin GPCR. This leads to inhibition of adenylyl cyclase. This decreases cAMP release. This decreases activity of protein kinase A. This decreases positive ion flux into the neuron. This leads to a smaller likelihood of generating an action potential. Assuming this is a dopamine neuron, then this means fewer vesicles bind to the membrane and release their payload of dopamine. Fewer dopamine molecules cross the synapse to reach the lactotroph. There is less inhibition of adenylyl cyclase at the lactotroph. So there is more of all the processes that eventually lead to prolactin vesicles being released.

Why does it have to be the serotonin receptors, and not anything else in that list? Why not "oversensitive" adenylyl cyclase? Or vesicles that bind to the membrane too readily? Or upregulation of dopamine receptors? Or abnormal ion channels? Or a generally sensitized lactotroph?

It very well could be serotonin receptors that are abnormal. The problem is that no one seems to have considered any of the other possibilities.

 

[Hutan]

Has anyone had any luck yet in attracting a good researcher to take this forward e.g. as a proposal for the WE&ME 2026 funding round?