Long term SSRI use lowers neurosteroid levels

[nasibi]

Post SSRI Syndrom (PSSD) symptoms are somewhat identical to those of Post Finasteride Syndrom (PFS). Particularly in the domain of sexual/erectile dysfunction. It's worthy of note that Finasteride causes a significant decrease in the brain neurosteroid levels. One of the very prominant and significant neurosteroid is Allopregnanolone (ALLO). It works as a potent GabaA receptor positive modulater. This neurosteroid is thought to have a huge impact on depression, anxiety, cognition and sexual behaviour. It is synthesized endogenously by the enzyme 3a-HSD from 5alpha- Dihydroprogesterone (5a-DHP).

Those well researched on this neurosteroid and the Post Finasteride Syndrom might have heared/read about people wanting to use long term low dose SSRIs (like 2.5 mg/day Fluoxetine) in an effort to increase brain Allopregnanolone levels. They do it because there are some studies showing that low dose Fluoxetine increases Allopregnanolone levels.

I am also intersted in increasing my Allopregnanolone. I have come up with a protocol for this. At first I wanted to add low dose Fluoxetine in my routine. However just recently I found two very interesting studies. The following studies show that long term use of SSRIs actually lower neurosteroid levels, something contradictory to the common held belief on forums.

Opposite effects of short- versus long-term administration of fluoxetine on the concentrations of neuroactive steroids in rat plasma and brain.

RESULTS:
A single dose of fluoxetine (20 mg/kg, i.p.) induced in 20 min significant increases in the cerebral cortical and plasma concentrations of 3alpha,5alpha-TH PROG (+96% and +13%, respectively), 3alpha,5alpha-TH DOC (+129 and +31%, respectively), progesterone (+111 and +58%, respectively), and pregnenolone (+151 and +59%, respectively). In addition, the plasma concentration of corticosterone was also significantly increased (+24%) after acute administration of fluoxetine. In contrast, long-term administration of fluoxetine reduced the basal concentrations of these various steroids (ranging from -22 to -43%), measured 48 h after the last drug injection, in both brain and plasma.

https://www.ncbi.nlm.nih.gov/pubmed/11685383

Prevention of the stress-induced increase in the concentration of neuroactive steroids in rat brain by long-term administration of mirtazapine but not of fluoxetine.

In contrast, long-term administration (10 mg/kg i.p., once daily for 2 weeks) of fluoxetine, but not that of mirtazapine, induced marked decreases in the cortical and plasma concentrations of these neuroactive steroids.

https://www.ncbi.nlm.nih.gov/pubmed/12095071

Could this decrease in the neurosteroid levels be the culprit behind the many symptoms of Post SSRI Syndrom?

[fasttrack1982]

Interesting post. My PSSD symptoms didn't start until I was on SSRI for many years, so maybe I at first experienced an increase in neurosteriods and then a decrease over a longer period of time.

[Glitch]

Sure, the neurosteroid theories make the most sense. I believe it starts with epigenetics though.

[Dubya_B]

Good stuff!

Are any of you guys signing up for the University of Milan study of PSSD to see if lowered neurosteroid levels are part of the condition?

[Juvo]

Good stuff!

Are any of you guys signing up for the University of Milan study of PSSD to see if lowered neurosteroid levels are part of the condition?

I was under the impression this was strictly animal based and not with humans?

On a side note, the Ulm Germany study is human and still looking for participants. Contact sulawesi for details.

http://www.pssdforum.com/viewtopic.php?f=5&t=975

[Dubya_B]

I was under the impression there was already an animal study by the University of Milan under way and they were looking for prospective participants for human studies in the event it panned out.
Sorry if there was a misunderstanding on my part.

[raven100]

Topic moved to General forum

[Coraggio]

I am agree. We have also spoken about this somewhere here. Melcangi is going to search nuerosteroid levels in brain PSSD rats.

[Juvo]

I am agree. We have also spoken about this somewhere here. Melcangi is going to search nuerosteroid levels in brain PSSD rats.

This is interesting. I wonder how many rats they need to go through before landing on PSSD, or if PSSD is inevitable when trying to induce it.

[logicalscout]

I was going to create another thread but this thread is close enough. I found this study regarding allopregnanalone and fluoxetine. Has anyone tried a neurosteroid approach to treating PSSD?

One of the reasons I think people do get a slight increase in libido by re-instating SSRI's is that increases the neurosteroids it down regulated in the first place.

https://www.researchgate.net/publicatio ... y_3a5a-THP

Sexual dysfunction, as a result of selective-serotonin reuptake inhibitor (SSRI) treatment among women, is relatively common and is a factor in medication compliance. The mechanisms that underlie these side-effects of SSRIs are not well-understood. SSRIs can alter activity of catabolic enzymes that are involved in progesterone's conversion to 5 α-pregnan-3 α-ol-20-one (3 α,5 α-THP). 3 α,5 α-THP plays a key role in female reproductive physiology and behavior. This study aimed to determine whether 3 α,5 α-THP, in the midbrain ventral tegmental area (VTA) may be a potential mechanism for fluoxetine's reduction in sexual responding of female rodents. We hypothesized that if fluoxetine induces decrements in sexual responding in part through actions of 3 α,5 α-THP, then fluoxetine will inhibit sexual receptivity concomitant with reducing 3 α,5 α-THP levels, effects which can be reversed by 3 α,5 α-THP administration.   Experiment 1 investigated effects of acute systemic fluoxetine [20 mg/kg intraperitoneal (IP)] and/or 3 α,5 α-THP [500 µg, subcutaneous (SC)] administration on sexual responding of ovariectomized, hormone-primed rats. Experiment 2 examined effects of 3 α,5 α-THP administration to the midbrain VTA (100 ng) on fluoxetine-induced decrements in lordosis of ovariectomized, hormone-primed rats and hamsters. Sexual responding was determined in rats and hamsters. For rats, the percentage of times that the lordosis response occurred following mounting by a sexually-vigorous male (lordosis quotients) was utilized. For hamsters, lateral displacement, the pelvic movement that females will make to facilitate intromissions by a male hamster, was utilized. Fluoxetine significantly reduced lordosis, and this was reversed SC 3 α,5 α-THP. Intra-VTA 3 α,5 α-THP attenuated fluoxetine's detrimental effects on lordosis quotients and lateral displacement of rats and hamsters, respectively. Thus, fluoxetine's effects to disrupt female sexual responses may involve its effects on progestogens in the midbrain VTA.

From what I understand, 3 α,5 α-THP is allopregnanalone. It is also the major metabolite in question for finasteride and isotretinoin related syndromes.