Your kynurenine acid and Quinolinic acid correspond to my results.
If we talk shortly about IDO/TDO and serotonin metabolism, here is a brief description of my thoughts.
1-2% of tryptophan is converted into 5HTP through tryptophan hydroxylase, which is then converted into serotonin through aromatic L-amino-acid decarboxylase.
95% is broken down into kynurenine through IDO and TDO. The primary purpose of IDO/TDO pathway is to produce niacin and NAD.
If we talk about inflammatory predisposition (genetic, viral or bacterial), it would enhance(upregulate) IDO and TDO activity through IFN-gamma (AA->COX-2->PGE2->INF-gamma->IDO and TDO) and JNK (AA->COX-2->PGE2->JNK->IDO and TDO). It was the thing that lead you to start taking SSRIs(anxiety, depression from neuroinflammation).
Kynurenine has two pathways:
1. Kynurenine ->Quinolinic Acid -> NAD through KMO. Quinolinic Acid is a very powerful NMDA agonist
2. Kynurenine -> Kynurenic acid. Kynurenic acid is an NMDA antagonist.
When immune cells in brain (microglia) detect the virus or excessive inflammation (NMDA signaling), they downregulate KMO in order to increase Kynurenic acid or begin to produce antibodies against it or they begin to produce antibodies against NMDA receptor.
All of those lead assentially to increased NMDA inhibition through Kynurenic acid and a blockade in the production of Quinolinic Acid. If there is no Quinolinic Acid -> there is no NAD which the main goal of Kynurenine pathway. NAD takes an important part in ATP production (glycolysis) when it is used as cofactor to convert Glyceraldehyde 3-phospate into 1,3-Bisphosphoglycerate. If there is no NAD, there is no ATP (NAD is created from Quinolinic Acid and niacin). Without ATP, you end up with a lot of symptoms like fatigue. That would also lead to increased production of Kynurenic acid (NMDA inhibitor) and serotonin. It is the opposite to the proposed theory of depression where quinolinic acid inhibits production of serotonin (
https://pubmed.ncbi.nlm.nih.gov/30335249/).
In the meantime excessive kynurenic acid blocks acetylcholine receptor, NMDA and AMPA receptors. SSRIs were shown to increase kynurenic acid with full remission of depression (
https://www.sciencedirect.com/science/a ... 9119306622). Some interesting fact: Levels of neurally produced kynurenic acid are depleted by fasting, leading to activation of NMDA-receptor-expressing interneurons and initiation of a neuropeptide-y-like signaling axis (
https://pubmed.ncbi.nlm.nih.gov/2559417 ... ter%20food.). Some of the members reported great results with fasting as well as me (I trialed fasting with some speical serotogenic drugs and got almost complete recovery for several days).
As levels of inflammation remain high (from serotonin, viruses, bacteria), body continues production of antibodies against NMDA receptor or KMO, as well as possibly other proteins to "protect" body.
Serotonin has a significant impact on immune system.
"HFD-EAE mice exhibited significantly higher MMP-9 activity and lower IL-4 levels than ND-EAE mice and were significantly correlated with brain 5-HT levels. In conclusion, the increased 5-HT levels in the brain significantly correlated with MMP-9 activity and IL-4 levels play an important role in the exacerbation of disease severity in HFD-EAE mice." (
https://pubmed.ncbi.nlm.nih.gov/26820599/).
"IL4 regulates production of serotonin" (
https://journals.plos.org/plosbiology/a ... =printable).
"IL4 suppresses the serotonin production in neurons" (
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6964913/).
"IL-4 reduced IL-1β-induced 5-HT levels by inhibiting tryptophan hydroxylase (TPH) mRNA and activating serotonin transporter (SERT)" (
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4568381/).
"Interleukin-4 restores neurogenic plasticity of the primary human neural stem cells through suppression of Kynurenic acid production upon Amyloid-beta42 toxicity" (
https://www.biorxiv.org/content/10.1101/227306v1).
Excessive inflammation would also lead to leaky gut, which would lead to a disruption of BBB, and a consequentive even more significant increase in serotonin.
I can't continue writing as I do not have a lot of time. The message of this post is to highlight importance of autoimmunity in PSSD, and how it could be brought up by SSRIs. I have a lot more information which I'd like to share, and, in fact, I will be doing that when I have time. Methylation, serotonin receptors, SERT, cAMP, cytokines, gut-brain axis, histamine as well as advanced thoughts on serotonin and IDO/TDO would be the next topics for discussion.
While you do not fix your constant inflammation (gut, viruses, bacteria), you will still be in the infinite loop.