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

Hip

Hip

Senior Member (Voting Rights)
I have just come across the buspirone challenge test, a straightforward blood test for ME/CFS which measures how much of the hormone prolactin is released into the bloodstream when a single dose of the drug buspirone is given orally (buspirone is an anti-anxiety drug).

I was so intrigued by this test (which I had not heard of before), that I put together a new MEpedia article detailing the buspirone challenge method of detecting ME/CFS.

As the article explains, ME/CFS patients release substantially more prolactin into their bloodstream when given buspirone, compared to healthy controls AND compared to depressed patients. So this test seems to reliably detect ME/CFS, and can clearly distinguish ME/CFS from depression.

The test involves giving patients a single oral dose of buspirone, typically around 35 to 60 mg, and measuring the prolactin levels in the blood just before giving this drug, and again an hour after administration of the the drug.

Everyone will release more prolactin into the blood when stimulated by buspirone, but you can see from the graphs in the article how ME/CFS patients release a lot more prolactin than healthy people. In one study, mean buspirone-stimulated prolactin levels in ME/CFS patients were 3 times higher than those of controls.

Buspirone activates the serotonin receptors in the hypothalamus (specifically the 5-HT1A receptors), and one theory posits that the serotonin receptors in the hypothalamus are more sensitive in ME/CFS patients, which is why it is believed buspirone stimulates the release of higher amounts of prolactin in ME/CFS patients compared to healthy people. Though this theory is contested.

The studies found ME/CFS patients often feel some lightheadedness and nausea when given buspirone, whereas healthy controls tend not to get these symptoms. So a lightheadedness and nausea response to an oral dose of buspirone is also to some extent diagnostic for ME/CFS.

I remember years ago when I tried buspirone to treat my generalized anxiety disorder, I became lightheaded and slightly dizzy literally within 20 minutes of taking a 10 mg buspirone tablet. At that time, I just thought this was a side effect of the drug, but now I realize the side effects I experienced actually help confirm my ME/CFS.




But the question I would like to ask is why isn't this testing being validated and deployed for clinical use? As we know, ME/CFS is considered a wastebasket diagnosis, and thus you will have people with other diseases misdiagnosed with ME/CFS. A simple and cheap test such as this could be very useful in clinical settings to verify an ME/CFS diagnosis.

There is a slight issue with using the buspirone challenge test on women, which is that you get variations in prolactin release depending upon the phase of menstruation; but one study found that provided you administer the test during the luteal phase, you get consistent results. With males, the test can be administered at any time.
 
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Interesting @Hip. Thanks for digging up the studies and setting them out in the MEpedia article.

I think this statement in your article needs to be a lot less certain:

ME/CFS patients release substantially more prolactin into the blood when given buspirone compared to healthy controls and depressed patients.
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more like, 'a number of small studies found that....'

I agree though that it would be good to have this work replicated and looked in to. I wonder why it hasn't been taken further.
 
I found a reference that said
prolactin levels are highest during sleep and shortly after waking up and during times of physical and emotional stress
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It's possible that if the trial participants with ME/CFS had altered sleep patterns, a trial done in the morning (as at least one seemed to have been) might have found different results based on that alone. Indeed one trial found that the patients with the most delayed sleep pattern had the biggest prolactin response.

It's also possible that the trial participants with ME/CFS were experiencing more physical and emotional stress than the healthy controls, simply from having to get up early, getting to the research centre and trying to be coherent and upright throughout. This too could have exaggerated the response to the buspirone challenge test.
 
Hutan said:
It's possible that if the trial participants with ME/CFS had altered sleep patterns
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You can say that again, i visited a sleep neurologist today, has no experience with ME induced circadian rhythm changes, wanted to give me a stimulant plus sleeping pill for the altered sleep patterns...
 
Any test with circadian abnormalities is problematic in ME, and needs a lot of research. The issue is we are not getting that research.

Serotonin is an escape valve for IDO inhibition, allowing the cell to remove tryptophan. There may be issues there but we are probably at least a year away from having even a preliminary understanding.

Much of the research in ME is now looking at challenge testing. At rest we are not a lot different from normal, but on challenge the differences are magnified a lot. So I would be happy to see more research on various challenge tests.
 
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alex3619 said:
A doctor unfamiliar with ME is likely to offer the wrong stimulants and sleeping pills at the wrong doses. Sigh.
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They can prescribe all they want, i'm not going t o take any of them, my sleep abnormalities are clearly ME related, as the ME gets wore the circadian rhythm gets worse in lockstep. Either its the coincidence of the millennium or A is causing B.
I get where they are coming from, their arsenal is rather small, stimulants, sleeping pills, antidepressants, CPAP and melatonin. And a few analogues of the above from an orexin antagonist to melatonin substitutes.
 
alex3619 said:
Since ME is very similar to African Sleeping Sickness we have opportunities to investigate this at the molecular level.
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Indeed though if we get an ME treatment it should treat the downstream symptoms as well. I was thinking about this earlier today, how does ME cause these sleep issues, i wish we knew but if i were dishing out funds the would go towards ME disease mechanism and developing drug treatments for it
 
Hutan said:
more like, 'a number of small studies found that....'
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Good point, I have updated the article accordingly.



Hutan said:
It's possible that if the trial participants with ME/CFS had altered sleep patterns, a trial done in the morning (as at least one seemed to have been) might have found different results based on that alone. Indeed one trial found that the patients with the most delayed sleep pattern had the biggest prolactin response.
Click to expand...

I guess that sort of thing might need to be checked in further studies (if this has not been checked already in these studies).
 
Hip said:
But the question I would like to ask is why isn't this testing being validated and deployed for clinical use? As we know, ME/CFS is considered a wastebasket diagnosis, and thus you will have people with other diseases misdiagnosed with ME/CFS. A simple and cheap test such as this could be very useful in clinical settings to verify an ME/CFS diagnosis.
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A very good question indeed. It would seem such a comparatively cheap and simple matter to replicate those studies and know one way or another.
Does anyone have any further information why this line of enquiry was dropped? Were the original studies badly designed/reported and not as conclusive as they appeared? Were there other studies, maybe unpublished, that showed the opposite?
 
MY recollection is that there was some trial in about 1997 which suggested the test was ineffective for showing the effects claimed. I always thought that was one of those tests designed to disprove anything remotely physiological. There is some discussion on the original Bakheit findings at p158 of Chronic Fatigue Syndrome 1993 Ciba Foundation Symposium. Sharpe questioned whether the effects were due to sensitivity to the non specific effects of buspirone rather than a specific abnormality in 5HT receptors. White waded in to question whether Behan's patients suffered from generalised anxiety disorder-his criteria could include someone with panic disorder. Perhaps Sharoe and White should have restricted their activities to teaching their grandmothers to suck eggs.

There is an interesting aside in this conversation; Behan at p157

" In rats infected with trypanosomes, Schulzberg et al 1989 looked for MHC (major histocompatibility complex) antigens on hypothalamic cells and found none. Thirty days after the trypanasome infection there was marked expression of MHC in two brain nuclei, the paraventricular and the supraoptic nuclei."

So trypanosomes were of interest even then.
 
Hi Hip and others
I have been asking in another thread what tests I could do to rule OUT a ME diagnosis
this looks like something I could do
however I am on an SSRI which I see may increase baseline prolactin levels
any thoughts as to whether being on an SSRI would influence the result of the test in terms of the increased prolactin release?
thanks in advance
Bertil
 
From the Wessely Hotopf Sharpe book it looks as though the research which put paid to the theory might have been

Sharpe M Clements A Hawton K Young A SargentPCowen P Increased prolactin response to buspirone in chronic fatigue syndrome. J Affect Disord. 1996; 41: 71-76

Patients apparently had significantly higher prolactin response but the growth hormone response did not differ. "This was interpreted as evidence against an increase in hypothalamic 5HT receptor sensitivity."
 
chrisb said:
From the Wessely Hotopf Sharpe book it looks as though the research which put paid to the theory might have been

Sharpe M Clements A Hawton K Young A SargentPCowen P Increased prolactin response to buspirone in chronic fatigue syndrome. J Affect Disord. 1996; 41: 71-76

Patients apparently had significantly higher prolactin response but the growth hormone response did not differ. "This was interpreted as evidence against an increase in hypothalamic 5HT receptor sensitivity."
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Yes, that is mentioned in the MEpedia article (in the Sharpe et al 1996 section).

But even though Sharpe et al cast a degree of doubt (with some caveats) over the theory of increased hypothalamic serotonin sensitivity in ME/CFS, and suggested an alternative theory based on dopamine receptors, what remains is the fact that buspirone elicits a substantially higher prolactin response in ME/CFS patients compared to controls, which the Sharpe study confirmed.

Indeed, the Sharpe study expanded our knowledge of the effects of buspirone in ME/CFS, showing not only is there a high blood plasma prolactin peak after buspirone stimulation in ME/CFS, but also that there is a much faster time-to-peak in ME/CFS patients (the 2nd graph in the article shows this clearly).


So though the mechanism of action is under dispute, it does not change the fact that the buspirone challenge test is shown in these studies to distinguish ME/CFS from controls.
 
Bertil said:
however I am on an SSRI which I see may increase baseline prolactin levels
any thoughts as to whether being on an SSRI would influence the result of the test in terms of the increased prolactin release?
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Hard to say, I guess it might do.

You might consider changing to an antidepressant which works on the dopamine system, at least during the period that you plan to take this test (assuming you are on the SSRI for depression). I have been using moclobemide for depression in recent months, which is which works on dopamine (it's a MAO-A inhibitor), and I am finding it pretty good; it has a sort "natural" feeling, as if I am not taking a drug; whereas when I tried TCA antidepressants, they feel more unnatural, and more like a drug. But I expect these things may be individual.

Although if Sharpe's alternative dopamine receptor theory of the mechanism of action of buspirone is correct, then dopaminergic antidepressants might also interfere.
 
Just been trawling through PubMed to find studies on other diseases showing exaggerated prolactin responses to buspirone.

It appears that non-ulcer dyspepsia patients and generalized social anxiety patients also have exaggerated prolactin responses.

Whereas patients with major depression or mania are no different to controls.

Schizophrenic patients without tardive dyskinesia had decreased prolactin responses to buspirone, but those with tardive dyskinesia were no different to controls.

I've added these studies to the article.


So exaggerated prolactin responses to buspirone are not unique to ME/CFS.
 
Hip said:
So exaggerated prolactin responses to buspirone are not unique to ME/CFS.
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I think this is one of the issues at work with ME biological abnormalities. If its not shown to be diagnostic then clinicians tend to ignore it. Its clearly, to them, not important. The fact we now have over two thousand biological abnormalities is not important as they don't know about them, do not have the science to understand them, have no proven clinical use, and do not clearly show an easily understood mechanism for ME.
 
Hip said:
It appears that non-ulcer dyspepsia patients and generalized social anxiety patients also have exaggerated prolactin responses.
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Hip said:
So exaggerated prolactin responses to buspirone are not unique to ME/CFS.
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I think these facts make it useless as a test for us. It all too easily allows doctors to simply re-diagnose us with social anxiety and/or dyspepsia - treatment - CBT.
 
Trish said:
I think these facts make it useless as a test for us. It all too easily allows doctors to simply re-diagnose us with social anxiety and/or dyspepsia - treatment - CBT.
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I have never come across anyone with ME/CFS being misdiagnosed with indigestion or social anxiety, which bear little symptomatic resemblance to ME/CFS.

For this test to be clinically useful, I think it would need to distinguish ME/CFS from the symptomatically similar diseases that are commonly misdiagnosed as ME/CFS, such as depression, celiac disease, anemia, hypothyroidism, systemic lupus erythematosus, hepatitis B and C, diabetes, multiple sclerosis, etc.

Thus it would require studies investigating the results of the buspirone challenge test on these diseases. If out of all these diseases it was only ME/CFS that came out positive on the buspirone challenge test, then you may have a useful tool in clinical diagnosis.
 
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