Attempting to cure/reverse my own PSSD
Posted: Thu May 02, 2019 5:55 am
I've been very stressed out in life recently due to an unforeseen financial trouble. I probably won't be able to afford the symptomatic regimen I'm currently on for more than a couple of months until I get my financial situation sorted out. So, I'm left with no choice but to attempt a cure/reversal in case the situation doesn't improve. I was thinking of taking a break from the forum and try to relax, but maybe it would be better to document my journey here, for better or for worse.
Now, my hypothesis is that SRI intake has caused 3 main deficits I named the "trial of evil". I discussed this in several other threads:
1- Glutamate release dysregulation leading to mesocorticolimbic pathway dysfunction and cognitive dysfunction, due to blunting of HPA axis and cortisol release (GR upregulation) as well as altered density of several serotonin receptor subtypes.
2- SSRI withdrawal-induced postsynaptic 5HT1A hypoactivation + presynaptic 5HT1A rebound supersensitivity.
3- Androgen (and possibly estrogen) receptor subsensitivity and dysregulation, leading to sex hormone resistance.
Here's how I'll address each point:
1- For GR downregulation, I would need an ACTH releaser or a corticosteroid. Since I'm against the latter, an ACTH releaser would be ideal. For this, I'll use Baclofen which would also cause a glutamate rebound on top of the cortisol release, potentially restoring long-term potentiation for the duration. As to addressing neurotrophic factors, I'll be taking Metformin which boosts BDNF and upregulates TrkB receptors. It raises SHBG but more on that later.
2- For presynaptic 5HT1A supersensitivity, the only way to "reverse" that would be through desensitization. For this to happen, I need a full agonist with a high intrinsic activity (near 100%). Initially, I thought Buspirone would be ideal but research is showing inconsistent results regarding downregulation. It's also a partial agonist at postsynaptic 5HT1A with low intrinsic activity, which beats the point. The only other full agonist is Vortioxetine, which is also an antagonist of several receptor subtypes (1B, 1D, 3, and 7). This profile would make it one of the most pro-glutamatergic antidepressant, perhaps this is why it's less associated with sexual dysfunction.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4241092/
https://www.ncbi.nlm.nih.gov/pubmed/29269186
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6146203/
Since I no longer believe in the SERT downregulation + presynaptic 5HT1A desensitization/decoupling theory, and I actually believe in the opposite (presynaptic 5HT1A supersensitivity + postsynaptic 5HT1A hypoactivation), for my type of PSSD I feel comfortable taking Vortioxetine for the sake of this experiment.
3. For sex hormone receptor sensitivity, increasing endogenous sex hormones would restore it. For this I'll be taking Mesterolone to bind with SHBG (including the excess from Metformin) and increasing my free testosterone level. If I feel that it's not enough, I may consider taking Clomiphene.
So, initial regimen looks like this:
- Baclofen: 25-50 mg. (ACTH release, GR downregulation, glutamate rebound)
- Vortioxetine: 5 mg. (Presynaptic 5HT1A desensitization, pro-glutamatergic)
- Metformin: 1000 mg XR. (BDNF boosting, TrkB upregulation)
- Mesterolone: 25-50 mg. (SHBG lowering, increasing free testosterone)
I'll be taking this for 3-6 months. Depending on how miserable it will make me feel. These drugs are about 50% cheaper than my symptomatic relief ones, so I can probably see this trial through, unless I need to add Clomiphene or Rasagiline.
As with trial-and-error, I could end up cured, or I could end up much worse than before. It's a risk I'm willing to take at the moment. If it works, I'll need to remain on a single drug to keep presynaptic 5HT1A from sensitizing again. Probably Vortioxetine, or if I find something else that's more selective, would be better, since Vortioxetine upregulates GR and I'm not sure Baclofen's ACTH release would be able to overpower that. We'll see.
Now, my hypothesis is that SRI intake has caused 3 main deficits I named the "trial of evil". I discussed this in several other threads:
1- Glutamate release dysregulation leading to mesocorticolimbic pathway dysfunction and cognitive dysfunction, due to blunting of HPA axis and cortisol release (GR upregulation) as well as altered density of several serotonin receptor subtypes.
2- SSRI withdrawal-induced postsynaptic 5HT1A hypoactivation + presynaptic 5HT1A rebound supersensitivity.
3- Androgen (and possibly estrogen) receptor subsensitivity and dysregulation, leading to sex hormone resistance.
Here's how I'll address each point:
1- For GR downregulation, I would need an ACTH releaser or a corticosteroid. Since I'm against the latter, an ACTH releaser would be ideal. For this, I'll use Baclofen which would also cause a glutamate rebound on top of the cortisol release, potentially restoring long-term potentiation for the duration. As to addressing neurotrophic factors, I'll be taking Metformin which boosts BDNF and upregulates TrkB receptors. It raises SHBG but more on that later.
2- For presynaptic 5HT1A supersensitivity, the only way to "reverse" that would be through desensitization. For this to happen, I need a full agonist with a high intrinsic activity (near 100%). Initially, I thought Buspirone would be ideal but research is showing inconsistent results regarding downregulation. It's also a partial agonist at postsynaptic 5HT1A with low intrinsic activity, which beats the point. The only other full agonist is Vortioxetine, which is also an antagonist of several receptor subtypes (1B, 1D, 3, and 7). This profile would make it one of the most pro-glutamatergic antidepressant, perhaps this is why it's less associated with sexual dysfunction.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4241092/
https://www.ncbi.nlm.nih.gov/pubmed/29269186
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6146203/
Since I no longer believe in the SERT downregulation + presynaptic 5HT1A desensitization/decoupling theory, and I actually believe in the opposite (presynaptic 5HT1A supersensitivity + postsynaptic 5HT1A hypoactivation), for my type of PSSD I feel comfortable taking Vortioxetine for the sake of this experiment.
3. For sex hormone receptor sensitivity, increasing endogenous sex hormones would restore it. For this I'll be taking Mesterolone to bind with SHBG (including the excess from Metformin) and increasing my free testosterone level. If I feel that it's not enough, I may consider taking Clomiphene.
So, initial regimen looks like this:
- Baclofen: 25-50 mg. (ACTH release, GR downregulation, glutamate rebound)
- Vortioxetine: 5 mg. (Presynaptic 5HT1A desensitization, pro-glutamatergic)
- Metformin: 1000 mg XR. (BDNF boosting, TrkB upregulation)
- Mesterolone: 25-50 mg. (SHBG lowering, increasing free testosterone)
I'll be taking this for 3-6 months. Depending on how miserable it will make me feel. These drugs are about 50% cheaper than my symptomatic relief ones, so I can probably see this trial through, unless I need to add Clomiphene or Rasagiline.
As with trial-and-error, I could end up cured, or I could end up much worse than before. It's a risk I'm willing to take at the moment. If it works, I'll need to remain on a single drug to keep presynaptic 5HT1A from sensitizing again. Probably Vortioxetine, or if I find something else that's more selective, would be better, since Vortioxetine upregulates GR and I'm not sure Baclofen's ACTH release would be able to overpower that. We'll see.