Final theory of PSSD etiology. Get in here!
Posted: Mon Nov 29, 2021 10:04 am
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
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