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

[forestglip]

I'm not sure how useful a diagnostic lab test would be unless and until it can help guide treatment decisions.

Maybe this was too dismissive. I could see how there could be value if a person with ME/CFS could get a prolactin response test and their doctor could see something clearly abnormal. I'm thinking in terms of doctors, family, and insurance/disability being more willing to accept that something is wrong that does require limiting exertion.

I'm not sure if it could possibly be counterproductive for the people for whom it gives a false negative result. Would a doctor see that and say "well ME/CFS is a biological disease with a biomarker, and you don't have the marker, so it's likely you're fine to go back to work"?

But anyway, I think the more important thing is trying to use it to help identify treatments, which will provide a lot more value in the long run.

 

[hotblack]

I’m also concerned about the negative impacts on severely affected patients of evoking this response. You don’t want a test that triggers worsening symptoms and it seems like this does for at least some, even if temporarily. It just doesn’t sound like a viable diagnostic test to me. More a research tool.

But anyway, I think the more important thing is trying to use it to help identify treatments, which will provide a lot more value in the long run.

That does sound like it could be useful.

 

[V.R.T.]

Maybe this was too dismissive. I could see how there could be value if a person with ME/CFS could get a prolactin response test and their doctor could see something clearly abnormal. I'm thinking in terms of doctors, family, and insurance/disability being more willing to accept that something is wrong that does require limiting exertion.

I'm not sure if it could possibly be counterproductive for the people for whom it gives a false negative result. Would a doctor see that and say "well ME/CFS is a biological disease with a biomarker, and you don't have the marker, so it's likely you're fine to go back to work"?

But anyway, I think the more important thing is trying to use it to help identify treatments, which will provide a lot more value in the long run.

Just for clarity, how specifically do you envisage this finding helping to identify treatments? Helping to pinpoint the mechinism and also as a marker for clinical response if it does change with severity, as you say in your previous post?

If the former I'm wondering if there is a post in this thread that explains how we could use this test and others like it to figure out what's causing MECFS.

Asking from interest not skepticism

 

[forestglip]

Just for clarity, how specifically do you envisage this finding helping to identify treatments? Helping to pinpoint the mechinism and also as a marker for clinical response if it does change with severity, as you say in your previous post?

Yeah, mainly the mechanism thing. If it's a real finding, then we have a specific starting point for research, and can then start testing many things related to it: Do other drugs have similar effects? Is there anything abnormal about the pituitary or hypothalamus on imaging? Are any genes upregulated in the prolactin-secreting cells?

If any of the above results in identifying another abnormality, then we have another clue to help think of other things to test. If, for example, the estrogen receptor is upregulated in the pituitary, then we could test if the same receptor is upregulated in other parts of the brain.

And we iterate on that and consider those findings together with other ME/CFS findings until one of the things that makes sense to test next is a specific treatment that we might expect to work when considering all the previous clues.

If the former I'm wondering if there is a post in this thread that explains how we could use this test and others like it to figure out what's causing MECFS.

I'm not sure if there's a post, but I don't really consider it much different from something like a causal gene identified in a genetic study. It's a clue, and we try to figure out why it's abnormal or what kind of treatment might help by connecting it with other research.

 

[ScoutB]

I'm thinking in terms of doctors, family, and insurance/disability being more willing to accept that something is wrong that does require limiting exertion.

Yeah it could be very interesting depending on how it plays out. My sense is having a lab test that captures 80% of patients is often enough to make the disease 'real' to doctors and they feel more comfortable diagnosing people who fit the profile well even if they have a negative test (in cases where it makes sense). Perhaps this also comes from the clinical experience of using the test allowing them to 'learn' what the disease looks like more deeply. So if we're lucky a test could have benefits even for those with a negative result.

The other possible outcome I see is that it could reduce the emphasis on clinical tests that really don't seem well grounded. I've had regular family doctors (i.e. not alternative health folks) raise the idea of testing for MCAS and POTS when I describe my symptoms. It's clear this is stuff they've heard about through the grapevine and they are just trying to find something 'medical' (where a lab test feels 'medical') to offer. And patients of course want a positive test due to the cultural pressures we talk about all day on here (disbelief, illness not being seen as legitimate unless in falls into an accepted category, etc). If a prolactin test could meet some of that need I bet we'd see less focus on tests that don't work. And maybe, as a result, more patient (and research) focus on things that seem more strongly associated with ME/CFS.

 

[Jonathan Edwards]

My guess is that if the prolactin response proves reproducible and that there is not more than about 30% overlap with normals further use is likely to reveal that it correlates with various clinical aspects, like time since onset, presence of major pain, OI, or other features. With time it is likely that it would prove to be of additional prognostic value, beyond the virtues mentioned above. And ultimately diagnosis is all about refining prognosis. For RA, the rheumatoid factor test is not diagnostic but it has some extra prognostic value. We talk of seronegative and seropositive RA. It might turn out to be useful to talk of Buspirone positive and negative ME/CFS.

 

[SugarSquared]

My guess is that if the prolactin response proves reproducible and that there is not more than about 30% overlap with normals further use is likely to reveal that it correlates with various clinical aspects, like time since onset, presence of major pain, OI, or other features. With time it is likely that it would prove to be of additional prognostic value, beyond the virtues mentioned above. And ultimately diagnosis is all about refining prognosis. For RA, the rheumatoid factor test is not diagnostic but it has some extra prognostic value. We talk of seronegative and seropositive RA. It might turn out to be useful to talk of Buspirone positive and negative ME/CFS.

I think this is the more realistic version, and it also can leave room for the fact that ME/CFS is not the only illness that has an exaggerated prolactin response to buspirone. Migraine has more literature about this than ME/CFS. So, what I could imagine is that this test would exist alongside a symptom questionnaire that can distinguish ME/CFS and similar conditions. Hopefully there can be some other biological marker that can confirm an ME/CFS diagnosis, like an MRI or a genetic test if anything proves to be specific enough. The prolactin response cannot be a biomarker on its own.

 

[forestglip]

A question/answer from 2021 on ME Association's website. I cut out the less relevant parts:

Question
I didn’t think there was a blood test for ME. However, my doctor wants to arrange for me to have what is called a buspirone challenge test. If this test can be used to confirm a diagnosis of ME, why isn’t it being used more widely?

Answer
[...]
The buspirone challenge test was first assessed as a research-based investigation by my late friend and colleague in Glasgow, Professor Peter Behan. The results indicated that it can be used to distinguish ME/CFS from depression. And the abnormality which was identified, involving the function of a small gland in the brain called the hypothalamus, is important because this gland helps to control sleep, appetite, temperature and hormonal regulation – all of which are affected in ME/CFS.

However, the potential use as a diagnostic test for ME/CFS has never been properly pursued by other independent research groups and confirmed. It is not therefore recommended as a diagnostic test for ME/CFS by either NICE or the ME Association in our current state of knowledge. The value of this test in your individual situation is something that you clearly need to discuss with your doctor.
[...]

 

[Robert 1973]

I'm surprised that Charles hasn't pushed for more research into these findings to date, or why Peter Behan didn't. I assume there must be reason.

 

[Utsikt]

A question/answer from 2021 on ME Association's website. I cut out the less relevant parts:

The thread is from 2018 and was started by @Hip. MEA was aware of the results in 2021. @bobbler rediscovered the thread in 2022. Then finally @ChronicallyOverIt found it again this May.

I’m trying not to think about what could have been if someone were able to pursue this earlier. The work by @forestglip and co has been outstanding, but others could hopefully have done the same years ago. I’m still very grateful it has been done now!

 

[hotblack]

I’m trying not to think about what could have been if someone were able to pursue this earlier. The work by @forestglip and co has been outstanding, but others could hopefully have done the same years ago. I’m still very grateful it has been done now!

Agreed. It is very hard not to dwell on the past and what could have been, with this, with genetic research, etc. I suspect there was always likely to be a bit of that when we crack this puzzle.

But given our limited energy let’s be practical and try to focus that on the future and what we can do, or what we can hopefully persuade others to do!

 

[SugarSquared]

I'm surprised that Charles hasn't pushed for more research into these findings to date, or why Peter Behan didn't. I assume there must be reason.

I’m surprised too. However, a few months ago, @forestglip and others emailed people who were part of these studies. (You could find those posts in this thread somewhere around May and June of this year.) None of the responses seemed to indicate that there was some unpublished negative finding. It seems to be more of the mundane story of people choosing other career paths along with the dying hype for 5-HT neuroendocrine tests.

 

[forestglip]

Charles Shepherd also wrote about it in his 2008 book, Living with ME:

 

[forestglip]

After a bit more time, trying to come back to these questions:

- Why has prolactin response been studied in illnesses in general in the past?

I think basically to test for any alterations in neurotransmitter systems. Most of the research happened in psychiatric studies, which is probably where they most expected such alterations.

- Why has it come out of favour of being studied

A citation I added to my review gives some insight about that from researchers more recently doing neuroendocrine challenge tests (Duval et al., 2013).

Here are some of the suggested reasons (quick summary: hard to find drug-naive participants for psychiatric patients, lack of standardization of tests, and lack of selectivity of probes. d-fenfluramine was a good, selective probe for serotonin receptors, but was withdrawn from the market in 1997.)

Nowadays, it is rare to have the opportunity in psychiatry to evaluate psychotropic drug-naïve hospitalized patients, this is probably the major limiting factor in the use of neuroendocrine strategy in the assessment of specific neurotransmitter function.

Another important issue, is the lack of strict standardization of the challenge tests (e.g., with regard to the dose of the compound administered, assay used to measure hormones, threshold for abnormal response, and the moment in the day when the test is performed) that limit the comparability of results from different studies. At present, it seems hardly possible to create international databases in psychiatry from the results of neuroendocrine tests, contrary to what is achieved in other branches of medicine. This explains why the introduction of endocrine parameters in diagnostic algorithms, although theoretically desirable, is not feasible because of methodological obstacles inherent to these investigations.

Moreover, when evaluating the neurotransmitter activity at postsynaptic receptor sites, the selectivity of the pharmacologic stimuli used is often questionable: this greatly limits the pathophysiological value of the results. For instance, 5-HT activity has been evaluated with m-chlorophenylpiperazine (m-CPP), but this compound stimulates 5-HT1B/2C receptors, antagonizes 5 HT2A receptors, binds to α2, α1 and β-NA, DA receptors and stimulates the catecholamine release. Buspirone, gepirone, ipsapirone, as probes of 5HT1A function appear to be of limited value since the responses are also mediated by DA receptor blockade. Flesinoxan, was a specific 5HT1A agonist, but has not been marketed. Clomipramine (at low dose), like citalopram or its S-enantiomer (escitalopram), inhibits 5-HT uptake; but since these compounds are not 5-HT releasers, the hormone responses are rather weak. Fenfluramine (FEN) promotes a rapid release of 5-HT and inhibits its uptake, and may function as an indirect 5-HT receptor agonist (via the 5HT1A/2 receptors). Both d-FEN and the racemate (dl-FEN) have been used, but the former was a more specific 5-HT probe, lacking the DA and NA action of dl-FEN. In depressed patients, especially those with a history of suicidal behavior, PRL and HPA-hormone responses were blunted, suggesting impaired 5-HT activity in such patients (Corrêa et al., 2002). However, dl-FEN and d-FEN were withdrawn from the market in 1997, and since that time clinicians and researchers have been waiting for specific and efficient neuroendocrine tests in the evaluation of 5-HT system in psychiatric patients.

and why in particular did it not get studied further in ME/CFS?

¯\_(ツ)_/¯

Maybe they really wanted to continue trying d-fenfluramine, but in 1997 it was withdrawn. That's around the time the flurry of ME/CFS studies ended.

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.

I at least got the sedentariness part into my review. There is a possibility it is due to deconditioning. I'm a bit doubtful, because then I think we'd expect depressed patients, who are probably fairly sedentary, to also have increased prolactin responses. But in the original Bakheit PVFS paper, where the PVFS participants in both sexes had clearly increased prolactin responses, the depression patients' responses were instead nearly indistinguishable from healthy controls. Several other studies have tested prolactin response to buspirone in depression. Of the papers I've seen, all found blunted or normal prolactin response to buspirone, not increased like in ME/CFS (see spoiler).

Spoiler: Buspirone/prolactin studies in depression

Cubała, W. J., & Landowski, J. (2014). Prolactin response to buspirone is not impaired in drug-naïve first episode patients with major depressive disorder. Journal of Affective Disorders, 152–154, 468–473. https://doi.org/10.1016/j.jad.2013.08.005

McAllister-Williams, R. H., Alhaj, H. A., Massey, A., Pankiv, J., & Reckermann, U. (2014). Somatodendritic 5-hydroxytryptamine1A (5-HT1A) autoreceptor function in major depression as assessed using the shift in electroencephalographic frequency spectrum with buspirone. Psychological Medicine, 44(4), 767–777. https://doi.org/10.1017/S0033291713001475

Meltzer, H. Y., & maes, M. (1994). Effects of buspirone on plasma prolactin and cortisol levels in major depressed and normal subjects. Biological Psychiatry, 35(5), 316–323. https://doi.org/10.1016/0006-3223(94)90035-3

Mobayed, M., & Dinan, T. G. (1990). Buspirone/prolactin response in post head injury depression. Journal of Affective Disorders, 19(4), 237–241. https://doi.org/10.1016/0165-0327(90)90100-M

Moeller, F. G., Steinberg, J. L., Fulton, M., Kramer, G., & Petty, F. (1994). A Preliminary Neuroendocrine Study with Buspirone in Major Depression. Neuropsychopharmacology, 10(2), 75–83. https://doi.org/10.1038/npp.1994.9

Navinés, R., Gómez-Gil, E., Martín-Santos, R., de Osaba, M. J. M., Escolar, G., & Gastó, C. (2007). Hormonal response to buspirone is not impaired in major depression. Human Psychopharmacology: Clinical and Experimental, 22(6), 389–395. https://doi.org/10.1002/hup.862

Sevinçok, L., & Erol, A. (2000). The prolactin response to buspirone in poststroke depression: A preliminary report. Journal of Affective Disorders, 59(2), 169–173. https://doi.org/10.1016/S0165-0327(99)00143-3

I haven't thought about the other potential confounders, like sleep patterns, yet.

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?

It seems like depression was one of the main areas of interest. A 1992 review (Power & Cowen, 1992) describes around 10 or 15 studies of prolactin response. It's not consistent, but seems to be blunted more often than increased. I haven't really gone in depth into the depression research, but there might be something real there as well. The conflicting results might have to do with depression being a heterogenous illness.

But I have yet to find good evidence of prolactin challenge findings leading to meaningful insights in any diseases.

Though for all of the above, I'll just add that I'm certainly not an expert. In depression research alone, there's a small mountain of papers I haven't read yet that could probably answer more of these questions.

By the way, I hope my previous comment about you asking tough questions wasn't taken as me being upset about it. On the contrary, those are the best questions. I might not know the answers, but knowing the questions is half the battle. (That's pretty good. I should put that on a t-shirt.)

 

[EndME]

By the way, I hope my previous comment about you asking tough questions wasn't taken as me being upset about it. On the contrary, those are the best questions. I might not know the answers, but knowing the questions is half the battle. (That's pretty good. I should put that on a t-shirt.)

It was not taken that way at all, I'm honoured you considered the questions tough. The thanks goes to you for coming back after some time thinking about the questions and responding. Thanks! Now it's my time to read through what you responded and digest it

 

[V.R.T.]

I’m trying not to think about what could have been if someone were able to pursue this earlier. The work by @forestglip and co has been outstanding, but others could hopefully have done the same years ago. I’m still very grateful it has been done now!

Yeah it's pretty heartbreaking to think about! Best to focus on what we can do with this stuff now.

Plus if it replicates Michael Sharpe is going to look completely myopic and incompetent which is a nice added bonus!