[tackem (OP)]

With some doubt on the current chemical hypothesis of depression I would like to offer an alternative biological hypothesis; Worms.
In 2021 the ship 'Ever Given' got stuck in the Suez Canal for a week and created chaos throughout the world for many months. What if worms are getting stuck (maybe deliberately) in the channels between synapses and getting high on the 'free' serotonin in the neighbourhood?
A lack of serotonin has been the current hypothesis for a generation or more but current research casts some doubt on the theory. Most serotonin is protein bound and the only 'free unbound' serotonin is found in the brain where it is a neurotransmitter passing messages by diffusion across the synaptic gap.
Our biome is coming more under scrutiny in all fields of illness. It is important to remember that this includes other organisms as well as bacteria which get most headlines. There are over 300 species of worms known to inhabit the human gut, and, as we have never really looked, no doubt numerous unknown species. Worms use serotonin to aid their motility. (however, I suspect they use it as a drug, get high and dance). As there is little free serotonin in the area they migrate to the brain via the vagus nerve
In the brain they occupy the synapses and bathe in free serotonin. This dilutes the happiness message in the brain and makes the human miserable and depressed.
SSRIs will increase the free serotonin allowing some happiness message to spread as the worms can only absorb a finite amount. Thus, SSRI treatment does have some success.
As the worms die off in their natural cycle the channel blockage will fluctuate naturally.
Worm treatments are cheap and effective. We worm our animals regularly but not ourselves.
 There is no money in this theory for big pharma so do not expect any research, but there is little to stop any GP running a small trial among his depressed patient cohort and all the drugs needed are well known so can be used freely.
Thoughts please?

[Bored chemist]

Worms use serotonin to aid their motility. (however, I suspect they use it as a drug, get high and dance). As there is little free serotonin in the area they migrate to the brain via the vagus nerve

If that was true we would see worms in the brains of depressed people.
We don't.

[tackem (OP)]

Good point Bored Chemist
But what if the 'worm' was 1 nanometer in width and the synaptic gap was also 1 nanometer?
Obviously when we think of worms we think of wriggly creatures we can see, but what if the organisms doing the damage are microscopical and porbably translucent? Could we see them, have we looked for them?

[Bored chemist]

But what if the 'worm' was 1 nanometer

[alancalverd]

There is a reasonable cohort of people self-administering dog worming powders to slow and apparently in some cases reverse the growth of otherwise-intractable intestinal tumors. The underlying biochemistry is sound and well published and dose tolerances have been established by various internet groups.

Whilst you might encounter problems running a controlled clinical trial on an established veterinary pharmaceutical that is not licensed for human use, plus the problem of evaluating  the effect on a weakly-defined psychological state that is subject to a lot of external influences, there  is nothing to prevent anyone giving it a try. The drugs that really work (aspirin, alcohol, penicillin, curare, quinine, morphine....) were discovered, not invented.

[Bored chemist]

The underlying biochemistry is sound and well published.

That's interesting; have you a reference?

[tackem (OP)]

Interesting use of wormers in cancer therapy.
Worms in general reduce the immune response, so killing off the worms may increase the immune response?

[tackem (OP)]

Can I throw another bit of 'evidence' into the mix.
Ketamine is getting a good write up when used in depression. It seems to work very quickly in suicidal ideation.
I have two thought trains on this:
First, the ketamine appears to be acting as an opiate in situ. If the worms are addicts maybe they are more attracted to the opiate as opposed to the serotonin. At this point the worms physically migrate out of the synapses to the opiate source. Freed up synapses allow the serotonin to flow in the correct manner and restores a happy state to the human.
Second, ketamine is acting as a worm killer and removing the blockage.
Thoughts?

[alancalverd]

The underlying biochemistry is sound and well published.

That's interesting; have you a reference?

Try this for a summary
https://www.canceractive.com/article/antiworm-drug%20for%20animals%20effective%20at%20killing%20cancer%20cells

or

https://www.nature.com/articles/s41598-018-30158-6 for an authoritative report and

also google for Joe Tippens for a sensible anecdote.

Those references generally  discuss fenbendazole, which is not licensed for human use, but a related compound, mebendazole, is prescribed as a human antiparasitic and is also causing interest in treating cancer.

But this is all tangential to the  hypothesis that depression is caused by worms. What it does suggest as a test of your hypothesis is that mebendazole might relieve depression, and there would be no serious objection  to a trial.

[Bored chemist]

I wish the patients well. I certainly won't blame them for trying, but the drugs concerned are poorly absorbed from the GI tact and I wonder how they might work (even against intestinal tumours).

[alancalverd]

The theory (and AFAIK invitro and invivo histopathology) is that they inhibit the formation of microtubules that develop to supply blood to the tumor.

"Fen" and "meb" are dispensed as tablets so GI absorption seems to be the best (or least worst) route of administration - certainly preferable to having amateurs injecting themselves with home brew. The folk wisdom is to macerate the powder in vegetable oil to improve uptake.The one case I know (an unresectable intestinal tumor) does seem to be responding, or at least not progressing as quickly as was expected.

[tackem (OP)]

RE Mebendazole only acts in the gut and does not enter the bloodstream.
In terms of worms in the brain the worm pool is destroyed in the gut so no more worms travel to the brain via the vagus nerve. The worms already in the brain grow old and die (14 days?) freeing the synapses and allowing the serotonin to flow as normal.
In terms of any anti cancer effect, worms reduce the immune response so they can roam freely in the gut. If the worms are killed off the immune response should rise and any cancers should come under attack with possibly good results.

[paul cotter]

Alancalverd, microtubules are part of a cell's internal cytoskeleton and are not progenitors of angiogenesis. Inhibition of microtubule action prevents mitosis and thus is a common strategy in oncology- it is quite possible that some anthelminics  are acting as antineoplastics but I haven't as yet seen any research.PS to the op, a 1nm object would not be a worm.

[tackem (OP)]

Accepted, Paul
I was just trying to make the case that if it were typical threadworms causing the synapse blockage we would obviously have found worms in post mortems of depressed brains.
If the 'worm' was microscopic, perhaps translucent, it could lodge in the synaptic gap. Upon death, I would suggest that serotonin flow would cease so the worm would maybe migrate elsewhere, or lose momentum and be washed from the synapse by general cleansing brain currents. Thus even if we searched during a post mortem some 24 hours later the evidence has vanished?
How much do we know about our own gut biome?

[paul cotter]

Serotonin is a minor player in terms of synaptic transmitters. In the brain the most common is , by far , glutamate with lesser contributions from acetylcholine, dopamine, noradrenaline, serotonin and one specific synapse that responds to histamine( there most likely are others that  i'm not up to date on ). Serotonin principally occurs in the raphe nucleus( a very small area ) and it's outgoing connections to the  cerebral hemispheres. Most of the body's serotonin occurs in the gut where it is involved in peristalsis.

[Bored chemist]

no more worms travel to the brain via the vagus nerve.

That was only ever some hallucination on your part.
We don't need to explain why it doesn't happen, because it's already impossible.

Do you realise that?

[Bored chemist]

If the 'worm' was microscopic, perhaps translucent,

Do you understand that much of biology is translucent?
That's why they do this
https://www.microscopeworld.com/t-microscope_slide_staining.aspx

[GaryBrownIE]

Can I throw another bit of 'evidence' into the mix.
Ketamine is getting a good write up when used in depression. It seems to work very quickly in suicidal ideation.
I have two thought trains on this:
First, the ketamine appears to be acting as an opiate in situ. If the worms are addicts maybe they are more attracted to the opiate as opposed to the serotonin. At this point the worms physically migrate out of the synapses to the opiate source. Freed up synapses allow the serotonin to flow in the correct manner and restores a happy state to the human.
Second, ketamine is acting as a worm killer and removing the blockage.
Thoughts?

Both ideas are interesting. You need worms + ketamine + popcorn and a lot of research. To my knowledge, recent studies have shown that people who suffer from depression have structural and functional abnormalities in specific brain areas. However, I am more interested in research related to drug abuse. I read in one of the https://studydriver.com/drug-abuse/ [nofollow] research papers that drugs can change brain chemistry and lead to depression. Drug abuse can also lead to changes in the brain's reward system, making it more difficult for individuals to experience pleasure from everyday activities, a common symptom of depression. That's my point of research.

[Kryptid]

But what if the 'worm' was 1 nanometer in width and the synaptic gap was also 1 nanometer?

Even the smallest known viruses aren't that small (which bottom out at around 20 nanometers across): https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7150055/

The synaptic gap is also larger than that, at about between 20 to 50 nanometers: https://www.sciencedirect.com/topics/mathematics/synaptic-cleft#:~:text=The%20width%20of%20the%20synaptic,nm%20at%20the%20neuromuscular%20junction.

The smallest known worm is Greeffiella, which has a size measured in micrometers, not nanometers: https://alexaanswers.amazon.com/question/6OYtJDqXSYohwGGCPb8QH0

So your idea of worms blocking a synaptic gap is implausible.

[Bored chemist]

travel to the brain via the vagus nerve.

Did you think that was credible?