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Let's talk the mechanisms behind SSRI sexual dysfunction

J

jaiho

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Jan 14, 2015
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So we know SSRIs increase extracellular serotonin, activating the various 5HT receptors.
There's 5HT1A, which when activated, facilitates erection & sexuality. This is something we want more activity at, and SSRIs should be doing this by default.
5HT2A / C are dopamine inhibiting receptors. We want these blocked.
Most SSRIs do not block the 5HT2 receptors.

For me, adding a potent 5ht2 antagonist to an SSRI is enough to reduce, but not eliminate sexual side effects. Therés other peices to the puzzle.

Considering buspar, a 5ht1a agonist, also seems to reduce them, im confused why this would be the case. SSRIs increase activity at 5HT1A, is it possible that agonist activity here is enough to reduce serotonin activity at 5HT2?

Would love a discussion on this, for possibilities of eliminating sexual & emotional side effects entirely (i believe they are connected), from SSRIs, as some of us have to be on them for life.
 
jaiho said:
So we know SSRIs increase extracellular serotonin, activating the various 5HT receptors.
There's 5HT1A, which when activated, facilitates erection & sexuality. This is something we want more activity at, and SSRIs should be doing this by default.
5HT2A / C are dopamine inhibiting receptors. We want these blocked.
Most SSRIs do not block the 5HT2 receptors.
Click to expand...

The mechanism is thought to be downregulation of 5-HT2A receptors. 5-HT2A receptors are known to regulate sexual behavior. SSRIs do not block 5-HT2 receptors, but they do gradually increase synaptic 5-HT levels, which would in turn desensitize and downregulate 5-HT2A.


jaiho said:
For me, adding a potent 5ht2 antagonist to an SSRI is enough to reduce, but not eliminate sexual side effects. Therés other peices to the puzzle.
Click to expand...

How can you possibly know this? Until this year, there were no selective 5-HT2 antagonists available for use in humans. Any other 5-HT2 blocking drug you could have taken also blocked (at the very least) adrenergic and histamine receptors.
 
I use Nortriptyline, which reduces sexual side effects drastically. It's an inverse agonist at 5ht2a & c. Not selective, but it has various properties that are good provided the doses aren't too high for mACH to become a problem.
I think an addition of a 5ht1a agonist would complete the puzzle.

Dr Stahl explains that to get the full benefit of 5ht2a/c antagonism, 5ht1a agonist is required.
 
jaiho said:
I use Nortriptyline, which reduces sexual side effects drastically. It's an inverse agonist at 5ht2a & c. Not selective, but it has various properties that are good provided the doses aren't too high for mACH to become a problem.
I think an addition of a 5ht1a agonist would complete the puzzle.

Dr Stahl explains that to get the full benefit of 5ht2a/c antagonism, 5ht1a agonist is required.
Click to expand...
Bupropion can also reduce the sexual dysfunction but doesn't block 5-HT2A. The most reasonable interpretation is that both bupropion and nortriptyline reduce SSRI-induced sexual dysfunction by reducing catecholamine re-uptake.
 
jaiho said:
I use Nortriptyline, which reduces sexual side effects drastically. It's an inverse agonist at 5ht2a & c. Not selective, but it has various properties that are good provided the doses aren't too high for mACH to become a problem.
I think an addition of a 5ht1a agonist would complete the puzzle.

Dr Stahl explains that to get the full benefit of 5ht2a/c antagonism, 5ht1a agonist is required.
Click to expand...

Where
Where did Dr Stahl explain that?
i.e. what book, and chapter?

I second bupropion, not only as a dysfunction relief provider, but overal sexual enhancher.
Cialis, levetra etc - are nothing compared to wellbutrin.
It's quite incredible.
 
serotonin2A said:
Bupropion can also reduce the sexual dysfunction but doesn't block 5-HT2A. The most reasonable interpretation is that both bupropion and nortriptyline reduce SSRI-induced sexual dysfunction by reducing catecholamine re-uptake.
Click to expand...

Does
Does nortriptyline have the property of enhancing sexual function also, aside from just dysfunction relief?

If that were true, wouldn't atomoxetine and reboxetine also enhance sexual function?
 
For me, Bupropion causes worse sexual dysfunction on its own than Fluoxetine (SSRI)
Looking at the literature that confuses me, so maybe my brain is just different to most.

Nortriptyline on its own had zero sexual side effects for me, and did enhance sexual function but maybe not libido. I felt i had to wipe the depression away to get that back.

Also, I didn't read it in one of Stahl's books but referenced on this post:
http://www.dr-bob.org/babble/neuro/20090701/msgs/904542.html
 
Are the androgens at all involved in this syndrome in some way? Like with SSRIs messing up the HPTA?
 
serotonin2A said:
The mechanism is thought to be downregulation of 5-HT2A receptors. 5-HT2A receptors are known to regulate sexual behavior. SSRIs do not block 5-HT2 receptors, but they do gradually increase synaptic 5-HT levels, which would in turn desensitize and downregulate 5-HT2A.
Click to expand...

Might this mean that post SSRI sexual dysfunction has something to do with 5-HT2A underactivity related neuroplasticity?

Also, unless more morphological changes are playing a bigger role, it seems like a short acting 5-HT2A agonist could help with sexual dysfunction. Although seeing faces come out of the walls isn't always a turn on.
 
Cotcha Yankinov said:
Might this mean that post SSRI sexual dysfunction has something to do with 5-HT2A underactivity related neuroplasticity?

Also, unless more morphological changes are playing a bigger role, it seems like a short acting 5-HT2A agonist could help with sexual dysfunction. Although seeing faces come out of the walls isn't always a turn on.
Click to expand...
I probably should have described the mechanism better. The sexual dysfunction is directly caused by 5-HT2A receptor activation, as opposed to desensitization.
 
Ohhh okay, so then I guess I'll propose the opposite, post SSRI sexual dysfunction could be related to 5-HT2A overactivation related neuroplasticity, and in theory both the sexual dysfunction and post SSRI dysfunction could be prevented by 5-HT2A antagonists? I can't tell you how many times I've heard people turn down SSRIs that might have otherwise been effective because of the sexual side effects, and if the insomnia is at least partially related to 5-HT2A activation then for both those reasons (and others, seems like 5-HT2A overactivation at the start of therapy is generally bad) it seems like selective 5-HT2A antagonists/inverse agonists would make great adjuncts to SSRI therapy.

https://www.ncbi.nlm.nih.gov/m/pubmed/16336034/ - "blocking 5-HT2A receptors in the presence of serotonin reuptake inhibition using the experimental compound YM992 enhances both serotonin and norepinephrine release"

I still haven't been able to find anything about selective 5-HT2A antagonists being used as adjuncts though, just AAPs...
 
Cotcha Yankinov said:
Ohhh okay, so then I guess I'll propose the opposite, post SSRI sexual dysfunction could be related to 5-HT2A overactivation related neuroplasticity, and in theory both the sexual dysfunction and post SSRI dysfunction could be prevented by 5-HT2A antagonists? I can't tell you how many times I've heard people turn down SSRIs that might have otherwise been effective because of the sexual side effects, and if the insomnia is at least partially related to 5-HT2A activation then for both those reasons (and others, seems like 5-HT2A overactivation at the start of therapy is generally bad) it seems like selective 5-HT2A antagonists/inverse agonists would make great adjuncts to SSRI therapy.

https://www.ncbi.nlm.nih.gov/m/pubmed/16336034/ - "blocking 5-HT2A receptors in the presence of serotonin reuptake inhibition using the experimental compound YM992 enhances both serotonin and norepinephrine release"

I still haven't been able to find anything about selective 5-HT2A antagonists being used as adjuncts though, just AAPs...
Click to expand...

Acute administration of a 5-HT2A agonist to rodents inhibits sexual performance.

http://www.sciencedirect.com/science/article/pii/0024320589901288

The same thing happens in people who take MDMA or serotonergic hallucinogens.
 
Interesting. Do you think we can conclude SSRI induced sexual dysfunction is from 5-HT2A overactivation from studies using 5-HT2A agonists that may achieve a higher degree of activation of 5-HT2A than SSRIs with functional selectivity possibly playing a role?

I guess I'm curious if overactivation of other serotonin receptors could possibly play a role (thinking 5-HT2C, although I'm hoping that study''s antagonists are more selective for 2A). Because if it's really 5-HT2A to blame, well then I guess I'm really surprised we haven't seen selective 5-HT2A antagonists used as adjuncts. The sexual side effects and insomnia seem to be huge complaints.
 
Cotcha Yankinov said:
Interesting. Do you think we can conclude SSRI induced sexual dysfunction is from 5-HT2A overactivation from studies using 5-HT2A agonists that may achieve a higher degree of activation of 5-HT2A than SSRIs with functional selectivity possibly playing a role?
Click to expand...
It is a reasonable conclusion because the same problems can happen with MDMA and other serotonin releasers.
Cotcha Yankinov said:
I guess I'm curious if overactivation of other serotonin receptors could possibly play a role (thinking 5-HT2C, although I'm hoping that study''s antagonists are more selective for 2A).
Click to expand...
If anything, 5-HT2C activation would probably have the opposite effect because 5-HT2A and 5-HT2C activation tend to produce antagonistic effects.
Cotcha Yankinov said:
Because if it's really 5-HT2A to blame, well then I guess I'm really surprised we haven't seen selective 5-HT2A antagonists used as adjuncts. The sexual side effects and insomnia seem to be huge complaints.
Click to expand...
Drug companies have been trying to get 5-HT2A antagonists approved for primary indications like insomnia, psychosis, etc. I don't think SSRI-induced sexual side-effects is viewed as a lucrative indication.
 
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Just playing devils advocate - I suppose SSRIs/SRAs don't have the functional selectivity issue but it still seems like SRAs could be affecting the other serotonin receptors and that could be causing some of the dysfunction. Essentially that you might see improvement of dysfunction with 5-HT2A blockade but maybe some other receptor subtypes are still contributing? I don't actually think that's the case but just contemplating that it may not have been ruled out completely to my understanding.

I suppose the key would be seeing that reducing SSRI induced 5-HT2A activation back to baseline with 5-HT2A blockade brought the sexual performance back to baseline (or I suppose above baseline if the other serotonin receptors are pro-performance). But it would take a much greater mind than I to interpret the relevant data if it's available, to see to what degree the 5-HT2A receptors are mediating the dysfunction.
 
serotonin2A said:
Drug companies have been trying to get 5-HT2A antagonists approved for primary indications like insomnia, psychosis, etc. I don't think SSRI-induced sexual side-effects is viewed as a lucrative indication.
Click to expand...

Maybe with Pimavanserin now in play it is more financially feasible for a 5-HT2A antagonist to be approved for other uses or as an adjunct? Although I wonder how much it costs with no generic and all that.
 
I dont think 5HT2A is the sole culprit here, considering i get enhanced sexual function on psychedelics, which are 5HT2A agonists.
New class of drugs like Viibryd & Trintellix, report a significant reduction in sexual side effects compared to other SSRIs. This is likely because they are 5ht1a agonists.
Psychedelics are also 5ht1a agonists.

I suspect it's a mix of both. 5ht1a post synaptic underactivation due to presynaptic being desensitised due to the SSRI.
Then the increased amount of serotonin floating around activating 5ht2a / c, causing a reduction in DA firing rates. as here:
https://www.ncbi.nlm.nih.gov/pubmed/19448853
 
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