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What does 5-HT2a antagonism do? (more specifically, for depression.)

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JackiesBabyy

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5-HT2a antagonists are mostly antipsychotics, and I can see how that'd help psychosis seeing as agonists cause hallucinations and panic attacks sometimes. But apparently it's pretty common to add abilify, an AP, to SSRIs when they don't work. I looked up what it does to help depression, and most sources say it's the 5-HT2a antagonism. My question is, how exactly does that help depression?
 
SSRIs downregulate 5HT2A and 5HT2C. I believe the mechanism is through continued exposure from serotonin to them. I'm not sure why these receptors downregulate when others don't.

5HT2A activation upregulates D2 receptors which cause paranoia and psychosis. 5HT2C blocks dopamine and norepinephrine release.

I suspect the "afterglow" from psychedelics is actually 5HT2A downregulation.
 
cannibalsnail said:
SSRIs downregulate 5HT2A and 5HT2C. I believe the mechanism is through continued exposure from serotonin to them. I'm not sure why these receptors downregulate when others don't.

5HT2A activation upregulates D2 receptors which cause paranoia and psychosis. 5HT2C blocks dopamine and norepinephrine release.

I suspect the "afterglow" from psychedelics is actually 5HT2A downregulation.
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So do antagonists also downregulate 5-HT2a? If not, your post really doesn't answer my question at all, I didn't ask how SSRIs work for depression, I asked what 5-HT2a antagonists do for depression, either alone or working hand in hand with the SSRI.

Oh, and if 5-HT2a agonists upregulate d2 receptors, doesn't that mean they should lower tolerance to DA-releasers?
 
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Antagonists down regulate 5ht2a, post questions like this in the big and banging thread unless you want to foster a large discussion.
 
Epsilon Alpha said:
Antagonists down regulate 5ht2a, post questions like this in the big and banging thread unless you want to foster a large discussion.
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What do you mean by "foster a large discussion"?

So, how does downregulation of 5-HT2a aid depression? Cannibal's post explains why it aids anxiety and psychosis, but I don't think less upregulation of D2 would do anything to help depression, if anything it seems like that would worsen it. If it does, how?
 
cannibalsnail said:
Because a higher percentage of dopamine receptor activation is the "good" receptors and not D2.
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That makes sense. I'm not sure what the four dopamine receptors do and I can't find much info on it. Which DA receptor is responsible for dopamine's good functions, such as motivation/alertness/euphoria?
 
2A antagonism alone doesn't seem to do a whole lot. Most of the trials of selective antagonists I've seen are for insomnia, they seem to reduce sleep latency a bit.

The explanation I've seen for the use of abilify is that at low doses it seems to block mostly dopamine autoreceptors. A few people here have said low doses are pretty stimulating.
 
skillet said:
2A antagonism alone doesn't seem to do a whole lot. Most of the trials of selective antagonists I've seen are for insomnia, they seem to reduce sleep latency a bit.

The explanation I've seen for the use of abilify is that at low doses it seems to block mostly dopamine autoreceptors. A few people here have said low doses are pretty stimulating.
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Because it's a weak d2 partial agonist rather than antagonist like all other APs, which is why it doesn't make people as tired and anhedonic. But according to most sources the d2 partial agonism isn't why it helps depression, it's the 5-HT2a antagonism. But I can't find ANY explanation as to how that's true, no matter how hard I look. Best explanation I can find is "5-HT2a antagonism makes SSRIs more effective", but no one explains how.
 
I´m not sure but I think it is because the abilify binds to the 5HT-2A receptor, which leaves more serotonin to bind to the 5HT-1A receptor. 5HT-1A activation is theorized to be the main mechanism of SSRIs antidepressant activity. 5HT-2A agonism is also why SSRI's cause sexual dysfunction, so this antipsychotic might actually help you get your dick hard!

Of course, mirtazapine will also work, less risk imo.
 
Wizzle said:
I´m not sure but I think it is because the abilify binds to the 5HT-2A receptor, which leaves more serotonin to bind to the 5HT-1A receptor. 5HT-1A activation is theorized to be the main mechanism of SSRIs antidepressant activity. 5HT-2A agonism is also why SSRI's cause sexual dysfunction, so this antipsychotic might actually help you get your dick hard!

Of course, mirtazapine will also work, less risk imo.
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But if 5-HT1a activation was the main mechanism of SSRI antidepressant activity, then wouldn't a 5-HT1a agonist like buspirone be an awesome antidepressant by itself when, in reality, only helps SOME people with anxiety and does fuck all for others?

Also, d2 partial agonism also probably makes abilify good for downstairs. Salvia is a d2 agonist and at low, oral doses it can make you incredibly horny, and one of the side effects of ropinirole (d2 agonist) is hypersexuality.
 
2A antagonism alone doesn't seem to do a whole lot. Most of the trials of selective antagonists I've seen are for insomnia, they seem to reduce sleep latency a bit.
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+1

Of course, mirtazapine will also work, less risk imo.
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Exactly. And, at any rate, all the speculative theory-spinning re. the serotonin receptors in this thread is no less systematic (!) than what these glorified phrenologists get up to with their lab rats and aripiprazole on a daily basis (presumably in some strained attempt to retroactively justify the off-label marketing of dangerous metabolic toxins to depressive patients). From what I've seen, the actual effect-sizes and mechanistic findings alike are pretty underwhelming w.r.t. the whole "neuroleptics for [insert condition that is not psychosis]" thing, especially when one considers the sheer volume of clinicians that are writing scripts for this shit. For what it's worth, I've yet to meet a single person who took Abilify for longer than a few weeks without ditching it due to the predictably horrendous side-effect profile, or wondering why they were being prescribed an antipsychotic for a mood disorder in the first place, then finding out a few months later when the drug still had yet to do anything for their depression.
 
P A said:
+1



Exactly. And, at any rate, all the speculative theory-spinning re. the serotonin receptors in this thread is no less systematic (!) than what these glorified phrenologists get up to with their lab rats and aripiprazole on a daily basis (presumably in some strained attempt to retroactively justify the off-label marketing of dangerous metabolic toxins to depressive patients). From what I've seen, the actual effect-sizes and mechanistic findings alike are pretty underwhelming w.r.t. the whole "neuroleptics for [insert condition that is not psychosis]" thing, especially when one considers the sheer volume of clinicians that are writing scripts for this shit. For what it's worth, I've yet to meet a single person who took Abilify for longer than a few weeks without ditching it due to the predictably horrendous side-effect profile, or wondering why they were being prescribed an antipsychotic for a mood disorder in the first place, then finding out a few months later when the drug still had yet to do anything for their depression.
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Yeah, APs aren't fun drugs to be on. I tried my friend's risperdal just to see what it was like one day and I can describe it best as how I feel when WDing from stimulants. I agree they really only should be used for psychosis and bipolar mania, because of the side effects and the fact that Tardative Dyskinesia (spelling?) looks fucking horrible. That's why I'm so curious how in the hell combining atypicals(5-ht2a antagonists) with SSRIs does anything for major depression. It seems like a great combo for bipolar people who get psychotic mania, but how it'd help plain old depression, I just can't figure out. I figure if abilify got approved as a SSRI add on there must have been a clinical trial showing it helped. (Unless researchers are in cahoots with the pharma companies and botched the trial results to make it look not useless, and these days something like this wouldn't surprise me.) Though if I ever did need APs, I'd want to try abilify first because no matter what side effects it gave, at least there's less anhedonia, which is more unbearable to me than physical side effects.

But either way, is what that one person said true about an antagonist blocking a receptor allows for more of the receptor's respective neurotransmitter to bind to other receptors true? Or just a theory? Also, I do think what someone said about 5-HT2c downregulation was correct. Agomelatine is a 5-HT2c antagonist and I've heard good things about it's effectiveness in depression.

(And to add, 5-HT2a antagonists ARE great for insomnia, I take trazodone and it knocks me the hell out.)
 
But either way, is what that one person said true about an antagonist blocking a receptor allows for more of the receptor's respective neurotransmitter to bind to other receptors true? Or just a theory?
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Given the sheer volume and number of serotonin receptors, I think it's very unlikely that selective displacement plays a role at all.

A lot of these antidepressants are still kind of magic black boxes... there's still all sorts of competing theories on how SSRI's work (or don't). Sometimes in medicine drugs are used in practice before they are totally understood, because they produce the desired outcome most of the time. (ex: some anticonvulsants)

The other thing to remember is lots of these drugs are much less selective than you'd like. very few antipsychotics are totally selective 5-ht2a/c antagonists.

My gut wants to say that 5-ht2a/c receptor antagonism is considered to be antipsychotic because activation of the same receptors (esp. 2c) produces psycholeptic effects and sense distortions typical of psilocin, LSD etc.
 
sekio said:
Given the sheer volume and number of serotonin receptors, I think it's very unlikely that selective displacement plays a role at all.

A lot of these antidepressants are still kind of magic black boxes... there's still all sorts of competing theories on how SSRI's work (or don't). Sometimes in medicine drugs are used in practice before they are totally understood, because they produce the desired outcome most of the time. (ex: some anticonvulsants)

The other thing to remember is lots of these drugs are much less selective than you'd like. very few antipsychotics are totally selective 5-ht2a/c antagonists.

My gut wants to say that 5-ht2a/c receptor antagonism is considered to be antipsychotic because activation of the same receptors (esp. 2c) produces psycholeptic effects and sense distortions typical of psilocin, LSD etc.
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That makes the most sense, and how psychedelics are infamous for causing panic attacks too. 5-HT2c activation inhibits the release of DA and NE, so antagonism lets more DA and NE be released.

Anyway, two questions.

1. If 5-HT1a agonism is arguably the main antidepressant mechanism of SSRIs, then why don't selective 5-HT1a agonists do anything for depression? It may explain how they do something for anxiety, but the one mostly selective 1a agonist we have, buspirone, seems to do fuck all for most people while helping anxiety in the rest.

2. Activation of which serotonin receptor(s) are responsible for the empathogenic effects of MDMA and the like, and how does that activation suddenly make you fall in love with the world and want to be close with people?
 
Buspirone is only a partial agonist at 5HT1A.

This is because of the massive activation of 5HT1A receptors (and by extension Oxytocin release). I believe, for whatever reasons, induces 5-HT release more selectively in 1A dense areas.
 
cannibalsnail said:
Buspirone is only a partial agonist at 5HT1A.

This is because of the massive activation of 5HT1A receptors (and by extension Oxytocin release). I believe, for whatever reasons, induces 5-HT release more selectively in 1A dense areas.
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That's kind of funny. So if 5-HT2c downregulation and 5-HT1a activation are really what's behind the efficacy of SSRIs, then SSRIs are basically DA/NE disinhibitors/oxytocin releasers. Interesting.
 
JackiesBabyy said:
2. Activation of which serotonin receptor(s) are responsible for the empathogenic effects of MDMA and the like, and how does that activation suddenly make you fall in love with the world and want to be close with people?
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MDMA requires equal parts of both isomers which have rather different action to get the "magic"
 
bolinas said:
MDMA requires equal parts of both isomers which have rather different action to get the "magic"
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What would this mechanism of action be? I'm interested in really detailed, in-depth explanations, which are unfortunately hard to find on the internet. Like if you look up how SSRIs work they just say "more serotonin gets rid of depression" when if that were true SSRIs would work a lot faster.
 
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