Final theory of PSSD etiology. Get in here!

This is a place to post research you have done on the topic along with your conclusions.
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guacamo
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Final theory of PSSD etiology. Get in here!

Unread post by guacamo »

This is my final theory of etiology of PSSD, i was working simultaneously on several different possibilities of what PSSD can be, but i consider this the definitive one, it explains gently why people are cured by some of the treatments while others are not, it explains how it happens that people got cured, taking care of SSRIs mechanism of action and shed a light on possible cure in the future. This topic will contain a lot of information, but i advice everyone to read it fully and to try to understand the concepts i lecture here.

First we must start on with explaining in what part of the brain SSRIs work on. SSRIs works by inhibiting SERT, serotonin transporter that takes serotonin molecule and recycles it back to the neuron to be used again or be terminated by MAO-A enzyme. The highest expression of SERT is in the raphe nuclei in the midbrain. This part of the brain is responsible for synthesis of serotonin via tryptophan hydroxylase 2 and projection of serotonin to the other parts of the brain. This is where 5-HT1A autoreceptors are located at. SSRIs work by downregulating this receptor and after 2 week lag phase they stop inhibiting serotonin, and thus serotonin levels increase and depression lifts, at least in theory. The reality is much more complex as i will explain later on.

What you need to take from it is that raphe nuclei is the part of the brain where PSSD happens.

Next thing to explain is G protein coupled receptor term. GPCR are receptors activated by G proteins (basically all serotonin receptors are GPCR except 5-HT3), to not make things complicated i will just say when ligand (like serotonin), bind to GPCR (like 5-HT1A receptor) it causes it to change conformation and causes activation of nearby G protein, which consist of αβγ subunits, to dissociate α subunit from the βγ subunits. α subunit and βγ dimer later go to activate different cellular mechanisms. Alpha subunit stays while βγ subunit go and do other things depending on the type of GPCR. It is important, why i will explain later on.

Next thing to explain is the term heterodimer and monodimer receptors. Basically these are complex of 2 receptors that when it forms it affects their signal transduction. Homodimer is complex of the same receptors, for example 5-HT1A-5HT1A, where heterodimer is complex of 2 different receptors, like 5HT1A-5HT7. Both of these dimers are existent in the raphe nuclei in large numbers, but 5HT1A-5HT7 heterodimer is more numerous and is more important for us.

The next thing to understand is that when receptors are activated they stimulate certain signal transductions. For example 5-HT2A receptor activation leads to hydrolysis of PIP2 to create IP3 and DAG, which then go on and do other things.
5-HT1A autoreceptor and post-synaptic 5-HT1A heteroreceptor stimulate different pathways. 5-HT1A autoreceptor when activated and βγ subunit dissociates it activates GIRK channels (GIRK3). GIRK3 to be activated it needs βγ subunit and PIP2 (Phosphatidylinositol 4,5-bisphosphate, sounds familiar doesn't it?). This mechanism is responsible for 5-HT1A autoreceptor mediated 5-HT inhibition. This is very, very important part.

SSRIs desensitization of 5-HT1A autoreceptor mediated 5-HT (serotonin) inhibition works by internalization of 5HT1A-5HT7 heterodimer https://onlinelibrary.wiley.com/cms/ass ... 0001-m.jpg. Internalization is basically endocytosis, in layman terms it is swallowing of the receptor by the neuron to procect it's function against too much stimulation. The thing is internalized 5-HT1A-5HT7 heterodimer desensitizes 5-HT1A receptor for activating GIRK3 by PIP2 and dissociated G protein βγ subunits. In result 5-HT1A autoreceptor no longer controls 5-HT flow in the brain. It is not about the amount of serotonin but it distribution, imagine your blood does not provide oxigen to the cells anymore, no amount of holding breath or hyperventilating will change that. Thus, PSSD is born. Links to every paper necessary to connect the dots is below, i placed them somewhat from the most imporant to the least, so if u want to educate yourself u can start from the most upward links. 5-HT1A-5HT7 dimer is expressed in raphe nuclei neurons in large numbers, since this receptor is internalized by SSRIs and 5-HT1A receptor no longer works by activating GIRKs it causes PSSD.

This explains why some people are cured by St John Wort and inositol. Inositol is direct precursor for PIP2 and St John wort affinity to IP3 receptor, IP3 receptor to be naturally activated needs phospholipase C, which depletes PIP2 in the brain. It also takes part in IMPase cycle of phosphatidylinositols. SJW also inhibits Protein Kinase C that inhibits GIRK channel sensitivity for PIP2. Serotonin stimulation crashes a lot of people maybe because post-synaptic serotonin receptors stimulate PI3K, enzyme that metabolises PIP2 to PIP3, thus depleting PIP2 levels even more. Or it can stimulate 5-HT2 receptors that are coupled to Gqs proteins that activate PKC.
Now this is speculation but the likely cause why people are not cured by these treatments is because of the low amount of uninternalized 5-HT1A receptors. The likely causes are plenty. Over my research i came to the papers where one would come to conclusion that finasteride, isotretinoin and mirtazapine share this mechanism too, but i did not save them and have trouble finding them, when i will find them i will update this post.


https://en.wikipedia.org/wiki/Phosphati ... sphosphate
https://en.wikipedia.org/wiki/Heterotrimeric_G_protein
https://en.wikipedia.org/wiki/G_protein ... um_channel
https://journals.biologists.com/jcs/art ... ors-5-HT1A
https://link.springer.com/article/10.11 ... 3316060108
https://onlinelibrary.wiley.com/doi/10.1111/cns.12247
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4849862/
https://www.northeastern.edu/rise/prese ... alization/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3313237/
https://pubmed.ncbi.nlm.nih.gov/12969265/
https://sci-hub.se/10.1371/journal.pone.0140369
https://hal.archives-ouvertes.fr/hal-01996206/document
https://www.frontiersin.org/articles/10 ... 6/full#B24
https://journals.plos.org/plosone/artic ... ne.0140369
https://www.frontiersin.org/articles/10 ... 72/full#h8
https://journals.plos.org/plosone/artic ... ne.0140369
https://www.sciencedirect.com/science/a ... 4215000458
https://physoc.onlinelibrary.wiley.com/ ... phy2.13141
https://academic.oup.com/ijnp/article/1 ... login=true
https://www.sciencedirect.com/science/a ... 8115000232
https://pubmed.ncbi.nlm.nih.gov/22180838/
https://pubs.acs.org/doi/10.1021/jacs.6b11760
https://www.nature.com/articles/ncb781
https://www.frontiersin.org/articles/10 ... 00035/full
Last edited by guacamo on Fri Dec 17, 2021 8:41 am, edited 12 times in total.
nicopickle
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Re: Final theory of PSSD etiology. Get in here!

Unread post by nicopickle »

i think that you are going way to deep into this. i don’t think the mechanism of PSSD is complicated in any way. my short period of recovery shows that. also i think it’s important to take notice of the other drugs that cause these issues in people. they aren’t related to the mechanisms of SSRIs. i don’t know what is happening but, why could a FMT produce a miraculous physical recovery? it seemed that the recovery started after adding capsules to the regimen. it literally felt like my brain came online for the first time in two years. how can all of these symptoms be changed from a single thing? there is some sort of underlying mechanism leading to the wide assortment of our issues, and i believe it is a very simple one that just needs to be found out to heal us
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guacamo
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Re: Final theory of PSSD etiology. Get in here!

Unread post by guacamo »

It is not complicated at all, it is simple signal transduction explained by the latest research, it does not go to connect several different mechanisms, it just goes straight down one path to the core. Serotonin system is influenced by many factors that often have nothing to do with serotonin at first look, from inflammation, diet, etc. Dissociation of By subunit after GPCR activation and in effect GIRK activation is as basic as it gets when it comes to 5-HT1A function. Literally every paper related to 5-ht1a signal transduction start by describing this mechanism.
Last edited by guacamo on Mon Nov 29, 2021 10:22 am, edited 1 time in total.
nicopickle
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Re: Final theory of PSSD etiology. Get in here!

Unread post by nicopickle »

do you think 5-HT flow could be the cause for the physical issues of PSSD? it’s just so hard to believe how my physical symptoms coming from PSSD almost disappeared in a matter of days
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guacamo
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Re: Final theory of PSSD etiology. Get in here!

Unread post by guacamo »

It's not 5-HT flow that is the cause of PSSD at all, reducing serotonin or increasing serotonin will not help because the problem lies in that signal transduction induced by serotonin is dysfunctional, not the amount of serotonin. You can do all you want but you won't overcome the fact that 5-HT1A autoreceptor do not activate GIRKs. Simply serotonin goes or does not go to the places where it should be or shouldve not been. It's the pathway that is wrong not the amount. For example imagine that your blood does not carry oxygen to the cells anymore, no amount of holding breath or hyperventilating will change that.
Last edited by guacamo on Mon Nov 29, 2021 10:35 am, edited 2 times in total.
nicopickle
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Re: Final theory of PSSD etiology. Get in here!

Unread post by nicopickle »

so if the 5-HT1A receptor isn’t activating GIRK, this is a simple mechanism? i’m not familiar with GIRK. but how could these other drugs like finasteride, or accutane cause these issues? i even seen a girl recently that got these issues from birth control.
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guacamo
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Re: Final theory of PSSD etiology. Get in here!

Unread post by guacamo »

Because they stimulate 5-HT1A autoreceptors just like SSRIs do, there are papers for that but i read them during researching SSRIs and didn't save them, when i will have time to find them i will post it in this thread. They are hard to find because they have low power of showing during research. Basically when you google something first things to pop are sites like youtube etc.
nicopickle
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Re: Final theory of PSSD etiology. Get in here!

Unread post by nicopickle »

i believe you. but to the people who are cured, why do you think these remedies fizzle out for some? like i literally felt like this was going to be all behind me after a few days of FMT. i can’t even explain how good i felt i’m such a short period of time. but these changes basically stopped in an instant
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guacamo
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Re: Final theory of PSSD etiology. Get in here!

Unread post by guacamo »

There would be a lot more to say about 5-HT1A and GIRKs, but the leap i would have to take is from 2+2 to something like linear function. It is possible to grasp with the human mind but it would take rather substantial amount of time and i do not think anyone would really want to dig that much. It would not give definitive answers anyway. There is certainly no irreversible damage as is in neuron apoptosis or something of that naure. For what it seems GIRK activation while maintaining high level of PIP2 may be a path to recovery, but how to do it if internalized receptors do not activate GIRKs anymore.
Last edited by guacamo on Mon Nov 29, 2021 11:03 am, edited 2 times in total.
nicopickle
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Re: Final theory of PSSD etiology. Get in here!

Unread post by nicopickle »

i messaged you on dm. i think that my experience a few days ago is very important in terms of finding a remedy for this, as i am a severe case. i honestly don’t care about understanding the mechanisms as long as we can find a solution this this horrible condition. the fact that there is recoveries out there. and my temporary recovery is very important. now while i felt amazing a few days ago, i just can’t seem to grasp what went on in my body to halt these positive changes


also i would like to explain that it wasn’t just a feeling like i was better, it was literally physical changes. my body started producing things again that it hasn’t been producing since PSSD.
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