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

[SugarSquared]

So we have 10 pages of interesting comments and leads. And I have my own messy pile of notes and links and papers. Would it be worth trying to collectively organize the info we've found so far, as well the list of things we're thinking about doing or looking into more? It could just be some unpolished google doc that starts out being basically a todo list?

I’d love to contribute! I doubt I can add much of note, but I’d love to play whatever part I can, even if it’s just formatting.

 

[forestglip]

So we have 10 pages of interesting comments and leads. And I have my own messy pile of notes and links and papers. Would it be worth trying to collectively organize the info we've found so far, as well the list of things we're thinking about doing or looking into more? It could just be some unpolished google doc that starts out being basically a todo list?

Good idea. For newcomers to the topic, 10 pages is probably overwhelming to read through, so it might be good to have something more focused and organized.

One main thing I'm thinking it could include is a list of every ME/CFS-related prolactin response paper, but also all papers about other conditions, plus papers purely about mechanism of the involved systems.

It might work to just make a new thread where the first post would be that document, and the thread starter would just update it based on suggestions added as posts on the thread, to keep it all together with the forum. There's a 20,000 character limit per post though, so it might be good to have several first posts.

A wikipedia-style page where multiple people could directly edit might be good too. Or a Google Doc, as you suggested.

Edit: The forum software has support for something called "Article threads":

Sometimes, threads are less about discussion and more about imparting knowledge. In these cases, article threads allow the first post in a thread to be afforded special treatment.

The first post in an article thread has extended limits on the number of embedded media items and attachments, has a greater character limit to allow very long textual content to be posted, and has different styling applied to make it appear distinct from subsequent posts in the thread.

Subsequent posts made to an article thread are considered to be comments on the article. At the point that the comments extend beyond a single page, a compressed version of the article will be shown at the top of each page, rather than being shown only at the top of the first page as would be the case with a discussion thread.

Article threads may be posted within article forums, or mixed-type forums in which articles are permitted.

That might be worth trying. I think this is an example of an Article thread on the official Xenforo forum: https://xenforo.com/community/threads/xenforo-2-2-8-patch-1-and-add-on-updates-released.200874/

 

[forestglip]

Edit: The forum software has support for something called "Article threads":
That might be worth trying. I think this is an example of an Article thread on the official Xenforo forum: https://xenforo.com/community/threads/xenforo-2-2-8-patch-1-and-add-on-updates-released.200874/

Maybe that's too complicated. Whoever starts the thread, unless they're a moderator, wouldn't be able to edit it past whatever the edit time limit is. And it'd require changing something on the backend to allow those threads.

Maybe if one of us just creates a google doc linked from here it'd be fine, at least to start with. We could always copy somewhere else later.

 

[SugarSquared]

Maybe if one of us just creates a google doc linked from here it'd be fine, at least to start with. We could always copy somewhere else later.

Would it be a good idea to make a publicly accessible link though? Maybe we can do viewable to anyone but you have to request permission to edit it.

 

[forestglip]

Would it be a good idea to make a publicly accessible link though? Maybe we can do viewable to anyone but you have to request permission to edit it.

Yeah, that's what I was thinking.

 

[ScoutB]

One main thing I'm thinking it could include is a list of every ME/CFS-related prolactin response paper, but also all papers about other conditions, plus papers purely about mechanism of the involved systems.

You've summarized exactly what I was thinking, agreed.

Maybe if one of us just creates a google doc linked from here it'd be fine, at least to start with. We could always copy somewhere else later.

Yeah I have been going back and forth in my head. It is really nice how low-friction google docs makes it for multiple people to edit and comment, and then there doesn't have to be a mod in charge of editing. Agree it could just be to start and then maybe something more polished could go in a post.

Have fried my brain so going to rest but will be back. I made a test google doc to play around with access permissions (like @SugarSquared is saying) so could set that up later if we want to go with that.

 

[ChronicallyOverIt]

GitHub? Owner approved pull requests?

 

[Jaybee00]

Why are you all more interested interested replicating the prolactin response with antagonizing meds rather than trialing the dopamine agonists mentioned above that might make symptoms better?

 

[forestglip]

Why are you all more interested interested replicating the prolactin response with antagonizing meds rather than trialing the dopamine agonists mentioned above that might make symptoms better?

Which dopamine agonist are you referring to? The one that showed the significant prolactin effect in the migraine study, nomifensine? I'd like that to be tested too. Though as you said, it's been withdrawn from the market, but maybe something similar would be good to try. Maybe even Abilify, which seems to reduce prolactin, though I'm not sure if it's an immediate effect, like these other drugs.

 

[Jaybee00]

I wonder if the opposite effect would also be seen: less of a decrease in prolactin in ME/CFS after taking a prolactin-inhibiting drug. Here are two D2 agonists which inhibit prolactin, according to Wikipedia:

• Bromocriptine
• Cabergoline

I mean too much prolactin is bad, right?

 

[forestglip]

I mean too much prolactin is bad, right?

I think too little is bad too. But these tests are just for a few hours, so I doubt it's that dangerous one way or the other.

But yeah, I'd like too see all those agonists tested too.

 

[Alinda]

I can help contribute to the document!

 

[SugarSquared]

Why are you all more interested interested replicating the prolactin response with antagonizing meds rather than trialing the dopamine agonists mentioned above that might make symptoms better?

If I understand your question right, you’re wondering why we’re more interested in running a test that would make symptoms worse versus running a trial for a med that would make symptoms better.

I would like to think they go hand in hand. We know so little about the biology behind ME/CFS, and given that previous studies, all seemed to point towards the same excessive proactive response, this could be a really good lead. It could help us better understand the pathophysiology that would then give credit to trialling medications that would help make symptoms better. If the prolactin response is replicated and still holds true, it also opens the door for other similar tests, like with different medications or comparing to similar diseases. Also, this would likely be an easier test to run than a proper phase one or phase 2 clinical trial. It just seems so simple and like something really good could come from it. Hopefully it would help boost the ME/CFS research field. That’s my reasoning.

 

[SugarSquared]

GitHub? Owner approved pull requests?

I would personally vote for Google Docs with no better reason than I don’t know how to use GitHub. Also, we could make a shared folder on Google Drive with the shared document but then also pdf of all of the papers. I can help download all of the ones behind a paywall/login with my university login.

 

[OrganicChilli]

Would it be worth setting this up as a sort of Wiki for readers? So instead of having one document with all the information and different subsections, there could be links to other documents. It could then be served via GitHub pages. The authors would only have to keep track of the documents and comments would remain in the document as well, but it might be beneficial for readers. I'd be happy to set up the infrastructure.

 

[Utsikt]

I think starting with a minimum viable product (MVP) might be a good idea. Google Docs/Sheets and a Drive folder is the easiest and has virtually no barrier to entry.

If people don’t want to dox their gmail they can just create a new one (like [username]S4ME@gmail.com) and use that for this work.

 

[forestglip]

Would it be worth setting this up as a sort of Wiki for readers? So instead of having one document with all the information and different subsections, there could be links to other documents. It could then be served via GitHub pages. The authors would only have to keep track of the documents and comments would remain in the document as well, but it might be beneficial for readers. I'd be happy to set up the infrastructure.

That might eventually be good. As Utsikt says, I think the priority should be about just getting words on paper first to keep things simple. Also, I just discovered that Google Docs can do document tabs, so that makes things a little neater, where not everything has to be in one document, kind of like the wiki idea.

But yeah, maybe when the document is more polished, it'd be good to port it over to a more official and accessible platform.

 

[forestglip]

Taking a look at a study of sulpiride, a D2 antagonist, to test prolactin response in social anxiety disorder (SAD), since there was at least one study that found an increased prolactin response to buspirone in SAD (Condren 2002), and a different study found that migraine patients showed an increased prolactin response to sulpiride (Murialdo 1986).

The response to sulpiride in social anxiety disorder: D2 receptor function (2012, Journal of Psychopharmacology)

The main takeaway is that there was no difference between SAD and controls for prolactin response from sulpiride.

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Spoiler: Extended notes

Cohort definition:

23 patients with generalized SAD were recruited by advertisements in a social phobia support group newsletter, and an article in a free local newspaper describing the symptoms of social anxiety

diagnosed with SAD according to DSM-IV criteria

no other current Axis I conditions, no neurological disorder and no history of head injury or any serious physical illness that would contraindicate the use of sulpiride.

Both test days [sulpiride and placebo] occurred at the follicular phase of the menstrual cycle (days 3–12).

Matched controls:

Healthy controls were matched as closely as possible to the social phobia group on measures of age, sex, ethnicity, and years of education.

Both placebo and sulpiride were given, with the order random for each individual:

Each subject received the selective D2 antagonist, sulpiride, on one test day and placebo on the other. The order in which subjects received the sulpiride or placebo was randomly allocated

400 mg sulpiride or placebo at 9:30am

At 09.30 a blood sample was taken for baseline PRL. They were then given 400 mg of sulpiride or placebo orally.

Since they had a placebo for each individual, they could calculate the effect as the prolactin increase over and above the increase from placebo:

the effect of sulpiride was calculated as the difference in the PRL response to sulpiride compared with placebo

Differences in the effect of sulpiride between the SAD group compared with the healthy control group were tested using a paired t-test.

A few patients were on medications:

Six patients with SAD were on antidepressants for treatment of their social phobia at the time of the study. These subjects had had no change to the antidepressant dose over the 6 weeks prior to the study and had ongoing symptoms of SAD. Two of these patients were also taking beta blockers, and one patient was solely taking a beta blocker. One subject with SAD was on an ACE inhibitor, and one was taking a calcium channel blocker for treatment of hypertension. Two patients with SAD and one healthy control were taking an oral contraceptive pill. Two controls were on asthma inhalers, one control was on thyroxine, and one control took antihistamine tablets.

Normal baseline prolactin:

no significant differences between the PRL levels at baseline between the SAD group and the control group on either test day.

No significant difference in prolactin response, even after excluding less severe participants, or when testing males and females separately.

no significant difference between the SAD and healthy control groups in terms of the effect of sulpiride, i.e. maximum change in PRL level (t=0.4, p=0.69) and AUC (t=0.4, p=0.72). In view of the fact that the study included six subjects with LSAS scores of less than 60 the analysis was repeated excluding this less severe group (and their matched healthy controls), with similarly no significant findings detected (p-values all >0.8).

There was no significant difference in the PRL response to sulpiride between the SAD and healthy controls groups when male and female genders were analyzed as separate data sets.

Plot of sulpride response in the two groups, showing a peak at 60 minutes, as they had expected, but no difference between groups:


Antidepressant use didn't lead to a difference either:

There was no significant effect of antidepressant treatment on the maximum change in PRL level (F=0.072, p=0.790) or AUC (F=0.018, p=0.894) as a measure of response to sulpiride.

Females had a significantly larger prolactin increase than males:

Females responded to sulpiride with a significantly greater PRL increase compared with males (Figure 3).

The authors also hypothesized that there would be an effect of sulpiride on symptoms, but this did not happen.

There was no significant effect of sulpiride (as compared with placebo) on changes to the rating scale scores on any measure (LSAS, FNE, SSAI, STAI, POMS, SHPS, SHRS – p-values all >0.2). There was no significant difference between groups on the association of sulpiride on any changes to rating scale scores (p-values all >0.1).

They say this replicates two previous studies:

These findings replicate the negative findings of two previous neuroendocrine studies in SAD (Condren et al., 2002; Tancer et al., 1994)

And they say a previous study found a larger prolactin response to sulpiride in those with depression (Verbeeck 2001).

different from a previous study in depression which reported an enhanced PRL response to sulpiride (25 mg IV) in subjects with depression compared with healthy controls.

They say different doses might have opposite effects, which might be good to consider for other studies. Lower doses might increase dopamine while higher doses might block receptors.

There has been debate about the interpretation of these findings which may relate to the dose of sulpiride used. At lower doses (50–100 mg) sulpiride has effects at the presynaptic D2 receptor, effectively increasing DA transmission, whereas at higher doses its effects are predominantly postsynaptic D2 blockade.

Just a note about evidence for dopamine dysfunction in SAD:

The most convincing evidence for reduced DA function in humans has been shown by SPECT neuroimaging studies which reported reduced striatal DA reuptake sites (Tiihonen et al., 1997) and, like the subordinate primate study, reduced D2 receptor striatal binding (Schneier et al., 2000, 2008).

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Maybe for the prolactin response document, the formatting per study could be split into little sections like this, to make it easy to quickly scan for relevant details:

The response to sulpiride in social anxiety disorder: D2 receptor function (2012, Journal of Psychopharmacology)
Caroline Bell, Shamina Bhikha, Helen Colhoun, Frances Carter, Chris Frampton and Richard Porter

Cohort
Generalized social anxiety disorder (SAD), diagnosed by DSM-IV. No other axis I conditions or neurological disorders.

Recruited by advertisement.

Controls matched as closely as possible for age, sex, ethnicity, and years of education.

Neuroendocrine probe
400 mg sulpiride or placebo at 9:30am (each participant received one or the other on different days, with the order randomized per participant). Effect on prolactin calculated as difference between sulpiride and placebo.

Females tested at follicular phase (days 3-12).

Findings
No significant difference in baseline prolactin or prolactin change after sulpiride.

No effect on symptoms of SAD one hour after taking sulpiride.

Larger prolactin increase due to sulpiride in females than males.

Author interpretation
Similar sensitivity or availability of D2 receptors in SAD compared to healthy controls.

Notes
The authors point out that the effect of sulpiride on dopamine may differ depending on dosage used, with lower doses (50-100 mg) acting more as agonists and higher doses acting more as antagonists.

 

[neophyte32]

I’ve been following your spirited discussions—thank you all. But could you explain to me the potential significance of discovering a buildup of prolactin following Buspirone use? A biomarker? Understanding which pathway is involved in ME/CFS? Does this really strike you as promising?

 

[forestglip]

But could you explain to me the potential significance of discovering a buildup of prolactin following Buspirone use? A biomarker? Understanding which pathway is involved in ME/CFS? Does this really strike you as promising?

I would assume that the prolactin itself isn't very interesting or relevant to ME/CFS. It's more about seeing what happens when you mess with the neurotransmitters controlling the prolactin. Those same neurotransmitters control many other things in the brain that could be more relevant, but which are harder to measure.

So for example, if this was all related to serotonin (it's easier to consider serotonin, since the effect of dopamine on prolactin is backwards - more dopamine=less prolactin, but some evidence is pointing to it being about dopamine instead):

More prolactin is released from the pituitary gland when more serotonin binds to cells of the gland. Buspirone acts like serotonin and binds to the receptors on the pituitary gland, leading the gland to release prolactin as if serotonin levels had increased. This is the case for everyone. But in the ME/CFS studies, the prolactin increased more in the patients than in the healthy controls. This suggests that the serotonin receptors on the pituitary gland might be overly sensitive in ME/CFS, to where the same amount of serotonin leads to a greater effect on the gland.

But there are serotonin receptors in many more places in the body than just the pituitary gland. Maybe they are overly sensitive in other parts of the brain or in the gut as well, and the pituitary was just the only place it was easy to see this by measuring what happened to prolactin.

It does strike me as promising in terms of identifying pathways involved. There's always the possibility that there is some uninteresting explanation for the findings, like being sedentary, but the findings are too consistent to not explore to find out what exactly is going on. It might help highlight specific neurotransmitters and pathways involved in ME/CFS.