PSSD Forum

Tree wrote: ↑Mon Sep 26, 2022 6:12 am fluvoxamine increases Akt-phosphorylation through sigma1-receptors [180,181], while sertraline decreases it [182].

Sertraline inhibition of Akt leads to more gsk3b expression which causes less canonical wnt activation and decrease sert expression through changes in microrna. It probably explains why some ssris cause worse symptoms than others.

Sertraline is the drug that gave me terrible pssd so sigma 1 agonism might provide some relief. I'll be trialing dhea, it's a sigma 1 agonist. I'm starting to connect the dots.

"Fluoxetine increases miR-16 levels in raphe by antagonizing canonical Wnt signaling"

doesn't using an antagonist for a period of time result in upregulation? taking setraline for long time which antagoniszes the receptor might resulted in upreglating the sigma1 receptors?
and also agonising a receptor for a period of time result in downregulation?

"Our findings indicate that GSK3B expression was upregulated by the continuous treatment with sertraline"

"However, after 12 months of treatment we found a significant increase in the expression of total GSK3B"

Lithium is used in many studies to mitigate induced gsk3b expression by ssris.

Gsk3b -> inhibits canonical wnt -> mir-16 -> decreases sert expression -> 5ht receptor desensitization -> pssd

LeaveMeAlone wrote: ↑Tue Sep 27, 2022 5:55 am

Tree wrote: ↑Mon Sep 26, 2022 6:12 am fluvoxamine increases Akt-phosphorylation through sigma1-receptors [180,181], while sertraline decreases it [182].

Sertraline inhibition of Akt leads to more gsk3b expression which causes less canonical wnt activation and decrease sert expression through changes in microrna. It probably explains why some ssris cause worse symptoms than others.

Sertraline is the drug that gave me terrible pssd so sigma 1 agonism might provide some relief. I'll be trialing dhea, it's a sigma 1 agonist. I'm starting to connect the dots.

"Fluoxetine increases miR-16 levels in raphe by antagonizing canonical Wnt signaling"

doesn't using an antagonist for a period of time result in upregulation? taking setraline for long time which antagoniszes the receptor might resulted in upreglating the sigma1 receptors?
and also agonising a receptor for a period of time result in downregulation?

Possibly not all receptors behave the same to stimulus ex. 5ht1a and 5ht2a. I have to do more research.

"The authors found that fluoxetine infusion into the raphe increased the rate of miR-16 maturation from its precursor, which was blocked by WNT3A."

https://www.nature.com/articles/nrn2941

This suggests WNT3A might block the mir16 directed effects on SERT.
The only thing I have found to increase WNT3A is asiaticoside which is a triterpene in gotu kola.

link11 wrote: ↑Tue Sep 27, 2022 8:57 pm "The authors found that fluoxetine infusion into the raphe increased the rate of miR-16 maturation from its precursor, which was blocked by WNT3A."

https://www.nature.com/articles/nrn2941

This suggests WNT3A might block the mir16 directed effects on SERT.
The only thing I have found to increase WNT3A is asiaticoside which is a triterpene in gotu kola.

Excellent, I'll see if I can find any wnt3a activators.

Information I have confirms what you found "Wnt3A- binds to the receptor Fzd and its coreceptor LRP5/6, leading to activation of the canonical Wnt/β-catenin pathway and downregulation of GSK-3β".

Dkk1 can decrease LRP6 expression which leads to canonical wnt suppresion but I don't think ssris target this pathway. Stress however has been shown to activate dkk1. Stress has always made my symptoms noticeably worse.

"Wnt7a and Wnt7b specifically have been identified as canonical Wnt pathway activators" let me know if any of these wnt proteins are targeted by ssris.

Both Curcumin and Valproic acid increase wnt3a expression in the brain. I'm going to microdose Curcumin extract and see what happens.

"In the hippocampus, curcumin enhanced the expression of Wnt3a, Dvl, FZD1 and LRP5/6, and the Wnt target genes Ngn2 and NeuroD1"

"Here, we determined that VPA treatment increased the expression of β-catenin protein, Wnt3a, and NeuroD1 which is Wnt target gene and needed for the survival and maturation of adult-born neurons"

Any update on this? @Tree

ytho wrote: ↑Fri Oct 21, 2022 5:09 am Any update on this? @Tree

It's too early to tell. The only noticeable symptom is increased insomnia to the point I can't sleep at all. I'm extremely sensitive to anything that raises serotonin even at small doses. My approach with Curcumin is small doses a couple times a week to see if over time symptoms get better gradually.

For anyone who believes pssd is caused by a loss of sert function, we might be getting some relief soon. Chinese researchers have developed an antidepressant compound called ZZL-7. It supposedly increases the serotonin transporter expression, which decreases serotonin in the dorsal raphe, through decoupling nnos from sert.

https://www.mentaldaily.com/article/202 ... nt-effects

https://www.science.org/doi/10.1126/science.abo3566

How can we get this medication?