One of the steps in the Cortene group's hypothesis is a desensitization of the 5HT1A receptors. Wouldn't this suggest that a 5HT1A agonist could be another possible drug target? I know the drug Buspirone is a 5HT1A agonist but I have heard that pwME dont tolerate it very well. Thoughts?
There seem to be 3 steps in the model, CRF 2 overexpression, 5HT1A autoreceptor desensitization and UNC1 failure. There are 2 drugs that are full agonists, cross the bbb and impact the limbic system, or at least the raphe nucleus. One is the antidepressant Vortioxetine and one is the arousal stimulant Flibanserin. However, as I mentioned earlier in the thread, in mice, over a week of agonism of the autoreceptor lead to desensitization of it. Therefore, the agonist may only work for a week, or may not stimulate already desnsititzed receptors. I could find no comments of those drugs improving ME/CFS online, although even if I did, I wouldn't put much stock in that kind of analysis.
More problematic for me is this model. Childhood trauma primes CRF-2 expression, leading to stressful life event and viscious cycle. We even have a handbreak metaphor. As it stands, there is admittedly evidence for an underpowered, but not pathologically, HPA axis. In terms of direct evidence, there is none. The mouse models/and the mouse drug experience being similar is quite ambiguous. To quote Alan Light, "we had to stop studying mice in CFS, because you couldn't ask them if they were not moving because they were fatigued or they were not moving because they were scared" or bored or depressed.
If the peptide is CRF-2 agonist, it would increase anxiety in the mice, and as Van Elkzzor tweeted, that anxiety can superficially be observed as CFS. But, all this might be true (I will read some of the Vernon paper another day). The bigger question I have is with the biology. I am a layman. But is it not unremarkable for the 5HTA1 receptor to become desensitized? It occurs in at least some types of PTSD, anxiety, depression and scizophrenia. In fact, it must happen quite a bit naturally, and it seems to be the mechanism of action of the most commonly presribed class of drugs in human history. And while, again you can superficially list the side effects of anti-depressants and say they are similar, anyone with half a brain can tell you ME/CFS is not that.
Correct me if I'm wrong, but the second part of their model for CFS is the mechanism of action of SSRIs. The hand-break metaphor.
The high levels of serotonin produced cause the 5HT1A “brake” to fail. Once that happens, high serotonin levels prevent the release of UCN1 and the re-establishment of homeostasis.
When you take an SSRI you wait 2 weeks to feel better, the reason being, as far as I understand it, your brain is being overloaded with serotonin, and as a result your 5HT1A receptors are trying to block it, but eventually the drug wins and your 5HT1A receptor becomes desensitized. This is not limited to SSRIs.
And the first part is equally problematic with this information.
In situations of intense stress (e.g., infection, trauma, emotional distress), high levels of CRF in the raphe nuclei (and limbic system) propel serotonin promoting CRF2 receptors to the surface of serotonin producing neurons.
Because SSRIs are given, frequently, during situations of intense stress coinciding with depression. Intense stress is not rare. They haven't desribed a pathology to CFS, they've described what is probably a not uncommon neuro-pathology resulting in feeling bad I'm sure, an anxiety type if I had to bet, but I'm doubtful it's feeling like ME/CFS. And, of course, we have to everyone with CFS had such intense trauma to break the CRF 2 expression, and then again to break the 5HTA1 receptors
in excess of what happens to the rest of the human race during intense stress.
Kind of annyoning for people like me who were not traumatized or distressed in childhood and had an unremarkable flu resulting in the illness. I suppose there is the possibility of a genetic element somewhere in there. But I also wonder if there aren't more elements that decouple this cycle, such as increasing gaba directly in the raphe nucleus.
All that being said, the drug may help because the HPA axis is probably involved in some capacity. So I do expect positive results from the smaller studies, trending to less impressive ones over time. If the drug can actually cause a reset.
) they are using objective measures and a decent clinical team.