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

[Kitty]

I think that it needs to be borne in mind that I wouldn't sign up for any of this probably

I wouldn't suggest trialling it on severely affected people—it's not a treatment, so no one has a chance of benefits that might outweigh the risks.
It makes sense to try and recruit folk who can leave the house without a huge crash, and access the location without a long journey. There ought to be enough of those in a large city.

 

[Jonathan Edwards]

So it needs to be tested against people feeling physically unwell with some similar symptoms but not PEM, perhaps.

This is where I think looking at post-Covid fatigue might be important. If the response is not increased there it may help clarify what makes ME/CFS different. Testing other ill people is not easy to justify on human grounds (ethical if you like).

I think this may be an important argument for testing people with relatively 'mild' ME/CFS who are stable. Increased responses in severe cases are even more likely to be affected by non-specific or secondary factors.

 

[SugarSquared]

I apologise if this has already been covered. I haven't been able to keep up with this thread.

Is the test specific to ME/CFS? Do we need controls from other illnesses too?

This test is not specific to ME/CFS. However, the other conditions that have a similar exaggerated, prolactin rise following buspirone is actually really interesting. The main condition that has a lot of research on this is migraine, which has a similar female to male ratio as us. There are a couple studies on IBS, non-ulcer dyspepsia, and fibromyalgia. So, all conditions that have comorbidity or shared symptoms with ME/CFS.

I don’t remember which conditions have been studied and have been found to have a regular prolactin rise, but depression has a normal and possibly even blunted prolactin rise. One of the studies on ME/CFS used both healthy controls and depressed controls and found that are prolactin rise was significantly different enough from both. So, this test is unlikely to be just a reflection of feeling unwell.

One other group of conditions where an exaggerated prolactin rise was found are in people with sex disorders or people who have had their sexual organs removed. I could be wrong about that wording though because I don’t remember this part of the research as much. This along with the role that sex hormones play in prolactin regulation is the reason why @forestglip talks a lot about estradiol here.

This test is likely not specific enough to serve as a diagnostic marker (at least on its own), but that’s not why we’re interested in it. The overlap with other similar conditions, and the fact that it is a replicated finding in our disease, makes it a worthwhile venture for investigations into our pathology.

 

[forestglip]

One other group of conditions where an exaggerated prolactin rise was found are in people with sex disorders or people who have had their sexual organs removed. I could be wrong about that wording though because I don’t remember this part of the research as much.

I think the ones I've seen in that area showing an increased prolactin response were in disorders where the sex organs were not functioning normally. In females, it was only one or two studies of ovarian failure, but in males, there were several studies finding increased prolactin response in those with testicular failure (mainly low or absent sperm cell count). I don't recall any related to removal of sex organs though.

Agreed with the points in your post, well put.

 

[Trish]

Thanks @SugarSquared and @forestglip. A nice clear summary.

 

[forestglip]

We already have seen how prolactin response doesn't seem to be increased in depression in a comparable way to ME/CFS.

I did a quick look through the papers I have saved for OCD, since there have been a decent number of studies in that condition. I added short little summaries to the Google Doc, and I'll copy to here. I only quickly skimmed all of these, so there might be some relevant considerations I missed.

To summarize, I only found two studies of buspirone challenge in OCD, and the prolactin response did not differ from healthy controls. [Edit: One caveat is that the studies used 30 mg buspirone, which is a little lower than ME/CFS studies.] There were several studies testing prolactin response to m-CPP and fenfluramine, but the results were not consistent, with different studies finding increased, decreased, or normal responses. A few other neuroendocrine probes were also tested, with results varying between probes and studies.

One study found an increased prolactin response to clomipramine in those with OCD but without depression, while those with both OCD and depression had a blunted response. Thus, there's a possibility that depression is masking an increased prolactin response to probes like buspirone and fenfluramine in the other studies. However, both buspirone studies excluded patients with depression, so this seems unlikely.

In general, it looks to me like there is not good evidence in OCD of increased prolactin response to buspirone or fenfluramine, providing a little more evidence against the idea that just having health problems leads to increased prolactin response.

Serotonergic responsivity in obsessive-compulsive disorder. Comparison of patients and healthy controls (Zohar et al., 1987)

[Based on quick skim] OCD patients and healthy controls did not have significantly different prolactin responses to m-CPP (0.5 mg/kg, orally).​

Serotonin Function in Obsessive-Compulsive Disorder: A Comparison of the Effects of Tryptophan and m-Chlorophenylpiperazine in Patients and Healthy Subjects (Charney et al., 1988)

[Based on quick skim]​

​

Baseline prolactin significantly reduced in female OCD patients compared to female healthy controls, but no difference for male participants.​

​

Prolactin response to m-CPP (0.1 mg/kg, i.v.) was significantly smaller in OCD patients for females, but not males.​

​

Prolactin response to tryptophan (7 g, orally) was slightly greater in OCD patients.​

Serotonergic Responsivity in Obsessive-Compulsive Disorder: Effects of Chronic Clomipramine Treatment (Zohar et al., 1988)

[Based on quick skim] In OCD patients, several months (mean: 4.5 months) of clompiramine treatment did not significantly alter prolactin response to m-CPP (0.5 mg/kg).​

Prolactin and Cortisol Responses to MK-212, a Serotonin Agonist, in Obsessive-Compulsive Disorder (Bastani, 1990)

[Based on quick skim] OCD patients had significantly smaller increase of prolactin than healthy controls following administration of MK-212 (20 mg, orally), a 5-HT agonist.​

Effects of chronic fluoxetine treatment on behavioral and neuroendocrine responses to meta-chloro-phenylpiperazine in obsessive-compulsive disorder (Hollander et al., 1991)

[Based on quick skim] In OCD patients, prolactin response to m-CPP (0.5 mg/kg, orally), when tested before 12 weeks of fluoxetine treatment, may have been slightly blunted when compared to healthy controls. The prolactin response to m-CPP may have been slightly exaggerated after fluoxetine treatment.​

Metergoline blocks the behavioral and neuroendocrine effects of orally administered m-chlorophenylpiperazine in patients with obsessive-compulsive disorder (Pigott et al., 1991)

[Based on quick skim] This study did not include healthy controls. In OCD patients, the m-CPP-induced rise in prolactin and anxiety was blocked by pre-treatment with metergoline.​

Fenfluramine stimulation of prolactin in obsessive-compulsive disorder (Hewlett et al., 1992)

[Based on quick skim] OCD patients had significantly smaller prolactin response to DL-fenfluramine (60 mg, orally) when compared to healthy controls. The difference was primarily present in female participants.​

Serotonergic Function in Obsessive-Compulsive Disorder: Behavioral and Neuroendocrine Responses to Oral m-Chlorophenylpiperazine and Fenfluramine in Patients and Healthy Volunteers (Hollander et al., 1992)

[Based on quick skim] Compared to healthy controls, OCD patients had blunted prolactin response to m-CPP (0.5 mg/kg, orally), primarily driven by male participants (very few female participants in study).​

Prolactin response to DL-fenfluramine (60 mg, orally) did not significantly differ between groups.​

Multiple Endocrine Responses to Clonidine in Obsessive Compulsive Dissorder (Khanna et al., 1992)

[Based on quick skim] Prolactin response to clonidine hydrochloride (2 mcg/kg, i.v.) did not significantly differ between OCD and healthy controls.​

Buspirone induced prolactin responses in obsessive-compulsive disorder (OCD): Is OCD a 5-HT2 receptor disorder? (Lucey et al., 1992)

[Based on quick skim] OCD patients and healthy controls did not have significantly different prolactin responses to buspirone (30 mg, orally).​

[Obsessive-compulsive disorder and depression] (López-Ibor Aliño et al., 1995)

[Based only on abstract]​

​

OCD patients without comorbid depression had larger prolactin, growth hormone, and cortisol responses to clomipramine than controls.​

​

Patients with both OCD and depression had blunted response to clomipramine (the abstract does not specify whether all three hormones were blunted)​

Neuroendocrine responses to single doses of buspirone in obsessive-compulsive disorder (Norman et al., 1994)

[Based on quick skim] Prolactin response to buspirone (30 mg, orally) did not significantly differ when comparing OCD and healthy controls.​

Brain 5-HT function in obsessive-compulsive disorder: Prolactin responses to d-fenfluramine (Fineberg et al., 1997)

[Based on quick skim] OCD patients had a significantly larger increase of prolactin than healthy controls after administration of d-fenfluramine (30 mg, orally).​

Fenfluramine challenge test in obsessive-compulsive disorder—First results (Pidrman & Tůma, 1997)

[Based only on abstract] Comparing prolactin response to fenfluramine in OCD patients before and after 6 weeks of serotonergic antidepressant therapy (no healthy controls), OCD patients had decrease of prolactin 1 hour after fenfluramine before therapy, but not after therapy.​

Neuroendocrine and behavioral responses to mCPP in Obsessive–Compulsive Disorder (Khanna, 2001)

[Based on quick skim] OCD patients had significantly blunted prolactin response to m-CPP (0.5 mg/kg, orally) when compared to healthy controls.​

Neuroendocrine predictors of response to intravenous clomipramine therapy for refractory obsessive-compulsive disorder (Mathew et al., 2001)

[Based on quick skim]​

​

This study tested prolactin response to clomipramine in OCD patients both before and after 14 days of clomipramine treatment. Responders and non-responders to the treatment were compared.​

​

Before treatment, those who would go on to respond had a blunted prolactin response to clompiramine (25 mg, i.v.).​

​

After treatment, using a larger dose of clomipramine (250 mg, i.v.), the responders still had a blunted prolactin response compared to non-responders.​

Acute hormonal changes after IV citalopram and treatment response in OCD (Corregiari et al., 2007)

[Based on quick skim] OCD patients had blunted prolactin response to citalopram (20 mg, i.v.) when compared to healthy controls.​

Hypersensitivity of 5-HT2 receptors in OCD patients (De Leeuw & Westenberg, 2008)

[Based on quick skim] OCD patients had increased prolactin response to m-CPP when compared to healthy controls.​

Spoiler: References

• Anne McBride, P., DeMeo, M. D., Sweeney, J. A., Halper, J., John Mann, J., & Katherine Shear, M. (1992). Neuroendocrine and behavioral responses to challenge with the indirect serotonin agonist dl-fenfluramine in adults with obsessive-compulsive disorder. Biological Psychiatry, 31(1), 19–34. https://doi.org/10.1016/0006-3223(92)90004-J
• Bastani, B. (1990). Prolactin and Cortisol Responses to MK-212, a Serotonin Agonist, in Obsessive-Compulsive Disorder. Archives of General Psychiatry, 47(9), 833. https://doi.org/10.1001/archpsyc.1990.01810210041006
• Charney, D. S., Goodman, W. K., Price, L. H., Woods, S. W., Rasmussen, S. A., & Heninger, G. R. (1988). Serotonin Function in Obsessive-Compulsive Disorder: A Comparison of the Effects of Tryptophan and m-Chlorophenylpiperazine in Patients and Healthy Subjects. Archives of General Psychiatry, 45(2), 177–185. https://doi.org/10.1001/archpsyc.1988.01800260095012
• Corregiari, F. M., Gattaz, W. F., & Bernik, M. (2007). Acute hormonal changes after IV citalopram and treatment response in OCD. Psychopharmacology, 193(4), 487–494. https://doi.org/10.1007/s00213-007-0793-0
• De Leeuw, A. S., & Westenberg, H. G. M. (2008). Hypersensitivity of 5-HT2 receptors in OCD patients. Journal of Psychiatric Research, 42(11), 894–901. https://doi.org/10.1016/j.jpsychires.2007.09.001
• Fineberg, N. A., Roberts, A., Montgomery, S. A., & Cowen, P. J. (1997). Brain 5-HT function in obsessive-compulsive disorder: Prolactin responses to d-fenfluramine. British Journal of Psychiatry, 171(3), 280–282. https://doi.org/10.1192/bjp.171.3.280
• Hewlett, W. A., Vinogradov, S., Martin, K., Berman, S., & Csernansky, J. G. (1992). Fenfluramine stimulation of prolactin in obsessive-compulsive disorder. Psychiatry Research, 42(1), 81–92. https://doi.org/10.1016/0165-1781(92)90041-Z
• Hollander, E., DeCaria, C., Gully, R., Nitescu, A., Suckow, R. F., Gorman, J. M., Klein, D. F., & Liebowitz, M. R. (1991). Effects of chronic fluoxetine treatment on behavioral and neuroendocrine responses to meta-chloro-phenylpiperazine in obsessive-compulsive disorder. Psychiatry Research, 36(1), 1–17. https://doi.org/10.1016/0165-1781(91)90113-4
• Hollander, E., DeCaria, C. M., Nitescu, A., Gully, R., Suckow, R. F., Cooper, T. B., Gorman, J. M., Klein, D. F., & Liebowitz, M. R. (1992). Serotonergic Function in Obsessive-Compulsive Disorder: Behavioral and Neuroendocrine Responses to Oral m-Chlorophenylpiperazine and Fenfluramine in Patients and Healthy Volunteers. Archives of General Psychiatry, 49(1), 21–28. https://doi.org/10.1001/archpsyc.1992.01820010021003
• Khanna, S. (2001). Neuroendocrine and behavioral responses to mCPP in Obsessive–Compulsive Disorder. Psychoneuroendocrinology, 26(2), 209–223. https://doi.org/10.1016/S0306-4530(00)00048-2
• Khanna, S., Reddy, P. L., Subhash, M. N., Rao, B. S. S. R., & Channabasavanna, S. M. (1992). Multiple Endocrine Responses to Clonidine in Obsessive Compulsive Dissorder. Indian Journal of Psychiatry, 34(3), 264–272. https://pmc.ncbi.nlm.nih.gov/articles/PMC2982080/
• López-Ibor Aliño, J. J., Saiz Ruiz, J., López-Ibor Alcocer, M. I., & Viñas Pifarre, R. (1995). [Obsessive-compulsive disorder and depression]. Actas luso-espanolas de neurologia, psiquiatria y ciencias afines, 23(3), 97–113. https://pubmed.ncbi.nlm.nih.gov/7544059/
• Lucey, J. V., Butcher, G., Clare, A. W., & Dinan, T. G. (1992). Buspirone induced prolactin responses in obsessive-compulsive disorder (OCD): Is OCD a 5-HT2 receptor disorder? International Clinical Psychopharmacology, 7(1), 45–49. https://doi.org/10.1097/00004850-199200710-00006
• Lucey, J. V., O’Keane, V., Butcher, G., Clare, A. W., & Dinan, T. G. (1992). Cortisol and prolactin responses to d-fenfluramine in non-depressed patients with obsessive-compulsive disorder: A comparison with depressed and healthy controls. The British Journal of Psychiatry: The Journal of Mental Science, 161, 517–521. https://doi.org/10.1192/bjp.161.4.517
• Mathew, S. J., Coplan, J. D., Perko, K. A., Goetz, R. R., De La Neuz, M., Hollander, E., Liebowitz, M. R., & Fallon, B. A. (2001). Neuroendocrine predictors of response to intravenous clomipramine therapy for refractory obsessive-compulsive disorder. Depression and Anxiety, 14(4), 199–208. https://doi.org/10.1002/da.1067
• Norman, T. R., Apostolopoulos, M., Burrows, G. D., & Judd, F. K. (1994). Neuroendocrine responses to single doses of buspirone in obsessive-compulsive disorder. International Clinical Psychopharmacology, 9(2), 89–94. https://doi.org/10.1097/00004850-199400920-00004
• Pidrman, V., & Tůma, I. (1997). Fenfluramine challenge test in obsessive-compulsive disorder—First results. Acta Medica (Hradec Kralove), 40(4), 99–102. https://pubmed.ncbi.nlm.nih.gov/9481883/
• Pigott, T. A., Zohar, J., Hill, J. L., Bernstein, S. E., Grover, G. N., Zohar-Kadouch, R. C., & Murphy, D. L. (1991). Metergoline blocks the behavioral and neuroendocrine effects of orally administered m-chlorophenylpiperazine in patients with obsessive-compulsive disorder. Biological Psychiatry, 29(5), 418–426. https://doi.org/10.1016/0006-3223(91)90264-M
• Sallee, F. R., Richman, H., Sethuraman, G., Dougherty, D., Sine, L., & Altman-hamamdzic, S. (1998). Clonidine Challenge in Childhood Anxiety Disorder. Journal of the American Academy of Child & Adolescent Psychiatry, 37(6), 655–662. https://doi.org/10.1097/00004583-199806000-00016
• Zohar, J., Insel, T. R., Zohar-Kadouch, R. C., Hill, J. L., & Murphy, D. L. (1988). Serotonergic Responsivity in Obsessive-Compulsive Disorder: Effects of Chronic Clomipramine Treatment. Archives of General Psychiatry, 45(2), 167–172. https://doi.org/10.1001/archpsyc.1988.01800260081011
• Zohar, J., Mueller, E. A., Insel, T. R., Zohar-Kadouch, R. C., & Murphy, D. L. (1987). Serotonergic responsivity in obsessive-compulsive disorder. Comparison of patients and healthy controls. Archives of General Psychiatry, 44(11), 946–951. https://doi.org/10.1001/archpsyc.1987.01800230026006

 

[Sean]

The main condition that has a lot of research on this is migraine, which has a similar female to male ratio as us. There are a couple studies on IBS, non-ulcer dyspepsia, and fibromyalgia. So, all conditions that have comorbidity or shared symptoms with ME/CFS.

Including diet and gut function issues?

 

[bicentennial]

Oh well, I can avoid the drugs but not the drug studies, as it is dawning on me that there is more to a drug study than meets the eye. I suspect that conditions with similar symptoms (like drugs with similar effects) are worth examining to ascertain the differences. If one condition has a known process or cause, and the other does not, then the symptomatic difference could help to narrow scattered directions, excluding dead-ends to signpost and map the unknown processes in ME/CFS.

It was the thread on uni-centric, oligo-centric and multi-centric Castleman's disease got me thinking this, with its modes or phases: its milder local mode, its multi-regional mode and its pervasive systemic mode. Maybe I need a lymph biopsy, but my "thesis" on comparisons got buried in a pile of drafts. However, now the marvellous provision of Prolactin Notes (Google Doc) can expedite much exploration of the signals involved by several drugs in several conditions. It showed me that:

- there are several remarkable conditions, causes, processes, signals, receptors and markers, all of interest, involving hormonal and neural signalling. More specifically, I learnt that dopamine keeps prolactin in check. So presumably conditions with lowered dopamine might show a raised prolactin. I had no idea that "dopamine" was also named the "prolactin-inhibiting hormone". Literature on nicotine did not tell me that.

I gather that olanzapine (Zypraxa) can also increase prolactin levels, and it can exaggerate prolactin levels already raised by a number of possible causes. Some causes are unexplained. Some increases are not transient unless treatable. I fear that some psycho-active system-resets can be permanent if not reversible.

Although olanzapine causes an early dose-related rise in prolactin, this is less frequent and less marked than that seen with haloperidol, and is usually transient. A rise in prolactin is seen in about half of patients on olanzapine compared to over 90% of those taking risperidone, and enduring increases were less frequent in those taking olanzapine. (Wikipedia)

It was initially heralded as a new drug taking effect much sooner than the old drugs. Amongst the "substituted piperazines", we have:

two atypical anti-psychotics:
- olanzapine (search s4me)
- aripiprazole (search s4me, titles only)

and two anti-depressants:
- buspirone (search s4me, titles only)
- tradozone (search s4me, titles only)

Olanzapine is an atypical, 2nd generation anti-psychotic, also used for anxiety without psychosis. In young males it can lead to dystonia, in the elderly it can lead to death (but in 2008 the BBC found about half of 355 British doctors still helpfully prescribing it regardless for demented psychosis). In ME/CFS it could exacerbate ME/CFS heat-regulation problems upon hot baths, hot weather or strenuous exercise

Spoiler: Olanzapine data from Wikipedia

In 2023, it was the 167th most commonly prescribed medication in the United States, with more than 3 million prescriptions. It is on the World Health Organization's List of Essential Medicines [given in full by the WHO, here]

In the U.S., olanzapine comes with a black box warning for increased risk of death in elderly patients. It is not approved for use in patients with dementia-related psychosis.[39] A BBC investigation in June 2008 found that this advice was being widely ignored by British doctors.[40] Evidence suggested that the elderly are more likely to experience weight gain on olanzapine compared to aripiprazole and risperidone.[41]

Several patient groups are at a heightened risk of side effects from olanzapine and antipsychotics in general. ...

Young males appear to be at heightened risk of dystonic reactions, although these are relatively rare with olanzapine. Most antipsychotics, including olanzapine, may disrupt the body's natural thermoregulatory systems, thus permitting excursions to dangerous levels when certain situations (exposure to heat, strenuous exercise) occur.

 

[forestglip]

Here is some more evidence that increased prolactin response is at least somewhat specific. It's a study in which all participants previously had breast cancer. They compared prolactin response to buspirone between those with and without cancer-related fatigue. They did not detect a significant difference between groups in magnitude of prolactin response, though the peak might have been somewhat delayed in the fatigue cases.

Evaluation of Central Serotonin Sensitivity in Breast Cancer Survivors with Cancer-Related Fatigue Syndrome (Alexander et al., 2010)


One note is that they say the study, with 14 cases and 28 controls, might have been underpowered to detect an effect, so it's possible an effect was missed.

It might also be informative to see the reasons they think it was hard to recruit participants (the burden of the study, and in response to news of adverse effects from another study):

One reason for this disappointing accrual is probably that the study was perceived as being rather too burdensome for volunteers to complete. Women had to be prepared to give up two mornings of their time and fast from midnight before the assessment. Another barrier to accrual was the public reaction to an unrelated U.K. Phase I study of a monoclonal antibody, in which six previously fit young men suffered serious (life-threatening) adverse events.23 Unfortunately, the widespread bad publicity that this trial attracted in the British press undoubtedly had some effect on the willingness of women to volunteer for our own study.

 

[bobbler]

Here is some more evidence that increased prolactin response is at least somewhat specific. It's a study in which all participants previously had breast cancer. They compared prolactin response to buspirone between those with and without cancer-related fatigue. They did not detect a significant difference between groups in magnitude of prolactin response, though the peak might have been somewhat delayed in the fatigue cases.

Evaluation of Central Serotonin Sensitivity in Breast Cancer Survivors with Cancer-Related Fatigue Syndrome (Alexander et al., 2010)
View attachment 34480

One note is that they say the study, with 14 cases and 28 controls, might have been underpowered to detect an effect, so it's possible an effect was missed.

It might also be informative to see the reasons they think it was hard to recruit participants (the burden of the study, and in response to news of adverse effects from another study):

if it does turn out to be like-with-like when looking into the methodology and dose etc then that's even more interesting if that group showed a delayed peak of the same size as controls because weren't a lot of the ME/CFS ones showing not just 'spikes' that were larger peaks but them happenning fast/early by comparison to controls, or definitely not later than them?

If so it is fascinating given the push towards generic 'fatigue services' (or PPS) instead of ME/CFS in some areas under certain clinics that/how their 'transdiagnostic' is unhelpful and counterproductive if one group goes one way and the other another

 

[forestglip]

that's even more interesting if that group showed a delayed peak of the same size as controls because weren't a lot of the ME/CFS ones showing not just 'spikes' that were larger peaks but them happenning fast/early by comparison to controls, or definitely not later than them?

At least for Sharpe 1996, which used the same dose, the peak in ME/CFS was both larger and earlier than in controls. (Though that study seems a bit odd in how delayed the control peak was.)

It at least doesn't seem like the peak is delayed in ME/CFS from the available data in ME/CFS studies.

Though the delay in this breast cancer fatigue study might just be from randomness in a small sample.

 

[Jonathan Edwards]

Nice detail @forestglip

 

[SugarSquared]

One note is that they say the study, with 14 cases and 28 controls, might have been underpowered to detect an effect, so it's possible an effect was missed.

Didn’t the ME/CFS studies have around that number of participants? I don’t remember there being much more per study and they still found an effect.

I’m very happy you found this study. The ones where participants had similar results compared to the controls are just as important as the studies that found a difference. Like @bobbler said, it helps show that ME/CFS is not “fatigue+” but actually something distinct.

 

[Jonathan Edwards]

It also makes me think that we might find that Long Covid of less than 6 monyhs duration might mostly have normal responses. That would be a neat finding.

 

[SugarSquared]

It also makes me think that we might find that Long Covid of less than 6 monyhs duration might mostly have normal responses. That would be a neat finding.

It would be really cool if it could predict Long Covid short-term fatigue and those who go on to have ME/CFS.

 

[forestglip]

Didn’t the ME/CFS studies have around that number of participants? I don’t remember there being much more per study and they still found an effect.

Yeah, two of the buspirone studies were smaller. The Sharpe paper only had 11 males in each group. Still might be possible to miss an effect, so another study of fatigue might be good, but this at least means it's less likely there is an effect in fatigue on its own.

 

[forestglip]

My primary concern at this point is whether ME/CFS cases have higher prolactin simply because they have more nausea from buspirone. It just seems like an interesting point that this drug seems to fairly consistently cause both abnormally increased nausea and prolactin.

The evidence against that is that one ME/CFS study (Majeed 1996 thesis) found increased prolactin response but no one reported nausea (which actually seems a little surprising, considering the fairly large sample of 30 individuals in each group all taking the maximum prescribed dose of buspirone, 60 mg).

Also, neither of the fenfluramine studies that saw increased prolactin response reported anything notable about side effects.

It'd still be interesting to investigate why buspirone causes increased nausea even if that was the underlying reason, but it's definitely something important to nail down.

Maybe studies could verify that the increased prolactin response is there even when using drugs that don't cause nausea or other symptoms. Or maybe an anti-nausea drug could be given concurrently with buspirone to see if the prolactin effect is still apparent.

 

[SugarSquared]

My primary concern at this point is whether ME/CFS cases have higher prolactin simply because they have more nausea from buspirone. It just seems like an interesting point that this drug seems to fairly consistently cause both abnormally increased nausea and prolactin.

But wasn’t there that study of healthy females at the point in their menstrual cycle where estradiol was the highest and they also had nausea? There may be an aspect of ME/CFS making us more prone to nausea (I get more motion-sickness while in PEM), but I’d be suspicious of that being the reason our prolactin increases. And even if our prolactin rises due to nausea, that’d still be interesting to study.

 

[Jonathan Edwards]

My primary concern at this point is whether ME/CFS cases have higher prolactin simply because they have more nausea from buspirone.

I think this may be overthinking the problem. Increased nausea presumably indicates increased signallins somewhere around the hypothalamus. I am not sure that we have any evidence for the conscious sensation of nausea causing any further hypothalamic, autonomic or other signals beyond those that caused the nausea. Maybe it does but it might be hard to prove?

 

[Jonathan Edwards]

Nausea might possibly be a function of how rapidly the buspirone was administered/ absorbed. Not sure if this might vary.