Neurosteroids - PFS, PSSD and PAS

[Shadow]

Background

Various antidepressants, including the SSRIs fluoxetine, fluvoxamine, sertraline, and paroxetine, the SNRI venlafaxine, and mirtazapine, have been found to activate certain 3α-HSD enzymes, resulting in a selective facilitation of 5α-dihydroprogesterone conversion into allopregnanolone. This action has been implicated in their effectiveness in affective disorders, and has resulted in them being described as selective brain steroidogenic stimulants (SBSSs).

Selective serotonin reuptake inhibitors directly alter activity of neurosteroidogenic enzymes

In a mouse model relevant for PTSD, selective brain steroidogenic stimulants (SBSSs) improve behavioral deficits by normalizing allopregnanolone biosynthesis

-> Small doses (1/20 to 1/50 of the therapeutic dose) still affects neurosteroidogenesis.
-> Short term use increase Allopregnanolone production.
-> Long term use reduces Allopregnanolone production by a lot.

Digested info: SSRIs lower testosterone and raise prolactin in men


SSRI Affected Pathway

Progesterone ----- 5aR1 ------> 5a-DHP ----- 3a-HSD -----> Allopregnanolone

The bold part, is the one stimulated by SSRIs, the conversion of 5a-DHP into ALLO, is greatly enhanced.

Allopregnanolone is a potent positive allosteric modulator of GABA action on the GABAA receptor. Allopregnanolone slows the rate of recovery of the GABAA receptor from desensitization and possibly increases the rate of entry into fast desensitized states. Allopregnanolone exerts neurogenetic, neuroprotective, antidepressant, and anxiolytic effects. Reduced levels of allopregnanolone are found to be associated with major depression, anxiety disorders, premenstrual dysphoric disorder, and Alzheimer’s disease.

Allopregnanolone - an overview | ScienceDirect Topics


Low Dosing Effects

One of the most amazing effect of low dosing an SSRI was pete's PSSD recovery, it was like pressing a button that reverted all the crap. His log can be found here: pete (Low-Dose SSRI)

Recently on @Ghost forum, another guy claimed to be recovered, and some other guys reported worsening, not only from the sexual symptoms but others too like tinnitus and visual snow.

From anecdotes that Ive read, some people reported "withdrawal" effects starting to occur on very low doses, I talked to one of them whos trying to taper Cymbalta, he is taking 3 beads(Cymbalta have ~200 beads/capsule), when he try to take less, bad things start to happen. At this dose theres no effect on SERT thus no effect on serotonin.

Others reported worsening of symptoms while trying to reinstate, this one I can confirm, because it happened to me, when I could turkeyd I was left with ED and a obnoxious nerve sensation on the right side of my pelvic area, after the reinstatement, I started to have the neurological problems, tinnitus and hyperacusis included, while tapering my body started to numb more every time I dropped the dose.

My Thoughts

I think that pete's recovery is a key element on understanding PSSD/Withdrawal, and it points to another mechanism, neurosteroids. I think that is too much evidence to just ignore, a low dose who doesnt affect SERT induced recoveries AND worsenings, theres something here!

I think that neurosteroids imbalance are the culprits for the symptoms(not only for Post-SSRI, but PFS and Post-Accutane too), but what its keeping them from being rebalanced is the question to be answerd.

Some additional and interesting articles:

Fluoxetine elevates allopregnanolone in female rat brain but inhibits a steroid microsomal dehydrogenase rather than activating an aldo-keto reductase

SSRIs and the female brain--potential for utilizing steroid-stimulating properties to treat menstrual cycle-linked dysphorias.

Chronic Escitalopram Treatment Induces Erectile Dysfunction by Decreasing Nitric Oxide Bioavailability Mediated by Increased Nicotinamide Adenine Dinucleotide Phosphate Oxidase Activity and Reactive Oxygen Species Production

Effects of Two Selective Serotonin Reuptake Inhibitor Antidepressants, Sertraline and Escitalopram, on Aldosterone/Renin Ratio in Normotensive Depressed Male Patients

This one is very interesting:
Effects of Fungicides on Rat's Neurosteroid Synthetic Enzymes

Take a look at this quote, look at the cascading effects:

The homeostasis of neurosteroids including ALLO and DIOL depends on the catalysis of their biosynthetic enzymes, 5α-Red1 and 3α-HSD, as well as the metabolizing enzyme RDH2. Since 5α-Red1 is the rate-limiting step for neurosteroid formation, this inhibition by TEB and TRI is critical for the production of neurosteroids. Indeed, evidence shows that these fungicides can affect brain function. Rats after exposure to triadimefon developed a deficit in spatial learning and reference memory [21]. Rats after perinatal exposure to tebuconazole produced neurobehavioral deficits and neuropathology [22]. Triadimefon also disrupted the transporter of extracellular dopamine, dihydroxyphenylacetic acid, homovanillic acid, and 5-hydroxyindoleacetic acid in adult rat's striatum [23]. Goldfish after acute and chronic exposure to VCZ developed dysfunction of neuroendocrine regulation of reproduction [24]. Therefore, the disruption of neurosteroid biosynthesis by these fungicides could lead to neurological dysfunction.

@gbolduev this is why I dont think that post-ssri is caused by problems in the serotonergic system.

 

[Shadow]

Ok, Im repurposing this thread.

This is a topic that dont get attention, and I honestly dont know why. Since:
-> Neurosteroids are powerful.
-> They act at CNS level, which seems to be where our problems lay. Serum levels are useless, thus no biomarker was found.
-> Finasteride messes with neurosteroids and Melcangi showed that neurosteroid levels on PFS sufferers are messed up in the cerebrospinal fluid.
-> SSRIs are well know for altering steroidogenesis as I showed above.
-> As far as I know Accutane messes with them too.

So Im trying again to draw attention to this subject.
Please PFS and PAS sufferes, if you read a study about Finasteride and Accutane affecting neurosteroids, post here!

I posted a nice booklet about neurosteroids here: Neurosteroids and the Nervous System

 

[Shadow]

NEUROACTIVE STEROID LEVELS AND PSYCHIATRIC AND ANDROLOGICAL FEATURES IN POST-FINASTERIDE PATIENTS

CSF
Increased: DHEA, TESTOSTERONE and 3α-DIOL
Decreased: PREGNENOLONE, PROGESTERONE, DIHYDROPROGESTERONE(DHP), ISOPREGNANOLONE, TETRAHYDROPROGESTERONE(THP), DIHYDROTESTOSTERONE(DHT) and 17β-ESTRADIOL.
Unchanged: 3β-DIOL.

PLASMA
Increased: PREGNANOLONE, PROGESTERONE, DHEA, TESTOSTERONE and 3α-DIOL.
Decreased: DIHYDROPROGESTERONE(DHP), ISOPREGNANOLONE, TETRAHYDROPROGESTERONE(THP), DIHYDROTESTOSTERONE(DHT) and 3β-DIOL.
Unchanged: 17β-ESTRADIOL.

Increased in both: DHEA and 3α-DIOL.
Decreased in both: DIHYDROPROGESTERONE(DHP), ISOPREGNANOLONE, TETRAHYDROPROGESTERONE(THP), DIHYDROTESTOSTERONE(DHT).

Looks like all the involved enzymes are CYP17A1 members.

PS: Wasnt someone here crashed due to Ketoconazole?

 

[wuf]

NEUROACTIVE STEROID LEVELS AND PSYCHIATRIC AND ANDROLOGICAL FEATURES IN POST-FINASTERIDE PATIENTS

CSF
Increased: DHEA, TESTOSTERONE and 3α-DIOL
Decreased: PREGNENOLONE, PROGESTERONE, DIHYDROPROGESTERONE(DHP), ISOPREGNANOLONE, TETRAHYDROPROGESTERONE(THP), DIHYDROTESTOSTERONE(DHT) and 17β-ESTRADIOL.
Unchanged: 3β-DIOL.

PLASMA
Increased: PREGNANOLONE, PROGESTERONE, DHEA, TESTOSTERONE and 3α-DIOL.
Decreased: DIHYDROPROGESTERONE(DHP), ISOPREGNANOLONE, TETRAHYDROPROGESTERONE(THP), DIHYDROTESTOSTERONE(DHT) and 3β-DIOL.
Unchanged: 17β-ESTRADIOL.

Increased in both: DHEA and 3α-DIOL.
Decreased in both: DIHYDROPROGESTERONE(DHP), ISOPREGNANOLONE, TETRAHYDROPROGESTERONE(THP), DIHYDROTESTOSTERONE(DHT).

Looks like all the involved enzymes are CYP17A1 members.

PS: Wasnt someone here crashed due to Ketoconazole?

Have you ever considered a run with Randro?
That has its most effect on the neurosteroids... I guess that's the reason people feels better by using it.

 

[Area-1255]

Have you ever considered a run with Randro?
That has its most effect on the neurosteroids... I guess that's the reason people feels better by using it.

Its a good call.

 

[johnsmith]

I suppose it totally depends on what neurosteroid is in question, but whats the counter argument for supplementing them?

 

[Area-1255]

I suppose it totally depends on what neurosteroid is in question, but whats the counter argument for supplementing them?

Really nothing. Symptoms of Low Pregnenolone Levels (Signs of Pregnenolone Deficiency Men & Women)
Pregnenolone is VERY safe and one of the best (if not the best) neurosteroids around; it improves ALL ASPECTS of Cognition [1].
It dramatically Improves Cognitive & Negative Symptoms in Schizophrenia [2].
It also has Immense Anti-Aging Benefits [3].
Let's not forget Pregnenolone Protects the Brain from Cannabis Intoxication; can act as a CB1-Negative Allosteric Modulator.
This can facilitate cAMP-Nitric Oxide Synthesis [4] and this is consistent with Pregnenolone ALSO activating the NMDA-Nitric Oxide-cGMP Pathway to "restore Cognitive Function" [5]. Not sure what Benefits Pregnenolone Sulfate DOESN'T have.

 

[vkn1]

I agree that neurosteroids, and perhaps allopregnanolone especially, are extremely interesting for PSSD, PAS, and PFS (which should all be unified under a single new name IMHO).

Maybe the issue is that there doesn't seem to be a good way of increasing ALLO in the brain. You don't want to take an SSRI because that might give you PSSD and it also causes sexual dysfunction, which is exactly what patients are trying to recover from.

But I'm not aware of any other way to increase it. Maybe that's what we should all be focused on.

How can we increase the neurosteroids in our brains? We know low levels are associated with these syndromes as well as PTSD and sexual behavior in rats (https://onlinelibrary.wiley.com/doi/full/10.2164/jandrol.108.005660). So what can we do with this information?

 

[bruschi11]

I like thought of mirtazapine/ remeron. It’s not an ssri. Opposite really.

Lots of pfs stories (like myself) who got a lot better while on mirtazapine. Heck I was going nuts working on my gut, Lyme etc while I was on the drug, but immediately when I went on it, night erections improved immensely. Ability to get erection, ejaculation load... these increased too. But brain stuff was where it did it’s best work.

I know that part of its job is increasing allo, 5ar2. I felt a sense of just normality completely unlike any antidepressant I tried when I was going through hell 18 months ago.

I think combo of mirtazapine and R-Andro would be interesting. As @Helen mentioned R-Andro with gaba agonist.

Also @vkn1, good to see you hear man. Been a long time since solvepfs days.