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

[IamJiva]

5HT-2A agonism cause kalirin concentration rising, that initiating grows of so called dendritic spines,
Its shown in secret researches of rats brain under electron microscope, with DOI(a typical scientific research 5HT2A ligand) as initiator of psychotic fenomens

In psychedelic state of conshesness, dynamic establishing of new neurons connections in CNS occurs, in few seconds new dendrite spine bond can grow(about 3mm long easy) transfer signal to some novel(not connected before) neurone, and disappear back naturally, without harmful side effects.

it allow brain to make some fractal zoomout(remember google maps satelite) when you (spiritual soul - particle of God) can understand nature of reality due to its fractal structure
now you have 3-rd eye, and many ears, some neurones that was "mono" became "stereo" e.t.c.

and you can feel like good pianist with such hands

and your lovely cat can also look strange(unfortunately unlike money in your pocket ))

Better to look on Lion - Krishna

 

[Cotcha Yankinov]

[h=1]5-HT2 receptor antagonism and slow-wave sleep in major depression.[/h]"Specific sleep disturbances such as reduced slow-wave sleep (SWS) and decreased serotonergic (5-HT) activity have been observed in depressive disorders. Ritanserin, a specific 5-HT2 receptor antagonist, has been shown to increase SWS in healthy subjects. This study explored the effects of a single dose or ritanserin (5 mg) on sleep electroencephalography in 18 major depressed patients and in 10 control subjects. Ritanserin affected SWS differently in the two groups. Although stage 3 increased significantly in the groups, in contrast to controls, there was no significant effect of ritanserin on stage 4 in depressed patients. In the depressed group, irritability and DSM-III-R melancholic type predicted 40% or the variance of stage 4 increment after ritanserin, as assessed by stepwise multiple regression. These results are in agreement with a potential 5-HT disturbance, particularly at the 5-HT2 receptor level, in some clinical forms of depression."



Some of the benefit depressed people receive from being on 5-HT2A antagonists/inverse agonists is likely from the improved sleep, depression is highly associated with fragmented sleep. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3630942/ -This meta-study is a good introduction to some of the more specific 5-HT2A inverse agonists and also the study talks of depression as well. A lot of the other drugs Seroquel/Mirtazapine/Trazadone etc. just aren't specific enough to draw conclusions I think.

5-HT2A is very strange, it has complex interactions with all the other brain cells. From wiki - "Especially high concentrations of this receptor on the apical dendrites of pyramidal cells in layer V of the cortex may modulate cognitive processes, working memory,and attention^[8][9][10] by enhancing glutamate release followed by a complex range of interactions with the 5-HT_1A,^[11] GABA_A,^[12] adenosine A₁,^[13] AMPA,^[14] mGluR_2/3,^[15] mGlu5,^[16] and OX₂ receptors.<sup>"

Also would just like to throw out there that I remember there being a functional difference between antagonist and inverse agonists at some of the serotonin sites, I'm pretty sure 5-HT2A was one of them. The inverse agonists make very solid sleep drugs though with a big increase in slow wave sleep, I don't know if it would do much for depression on the first day (as opposed to 5-HT2C antagonism increasing dopamine for example) but I could see the improved sleep helping the depression over time. I suppose if you could separate between an acute effect of 5-HT2A antagonist/inverse agonism helping depression the same day and a chronic effect helping over time by improving sleep that would help clear up this mess. If I remember right that anti-depressants work over time by downregulating the 5-HT2A's then I wonder if its over time they help improve sleep architecture through ultimately less 5-HT2A activity and that is really the benefit for some, probably those specifically with sleep interruption though. I also suppose that if we pretend 5-HT2A antagonist is supposed to help with depression by standard "Same-day" effects then by blunt logic a 5-HT2A agonist should cause depression same day. Maybe the reason why this isn't true is because its not the acute effects that matter but the effect on sleep architecture over time that would show benefit for depression.

TL;DR - Maybe the 5-HT2A over-activity doesn't cause depression in and of itself but that it causes sleep problems which cause the depression over the long term for some people. 5-HT2A being the main excitable serotonin receptor it only makes sense that its activity in one day wouldn't cause depression, probably the opposite, but that over-excitation leads to sleep fragmentation and could cause mental problems over time.</sup>

 

[Phenom3]

Look up activity of Pimavanserin, or "Nuplazid". It is in Priority Review status by FDA for potential approval in Parkinson's Disease Psychosis, but IMO will be heavily prescribed off-label, for some conditions brought up in this thread. MOA is clean and precise, very selective inverse-agonist of 5HT2A receptor, which improves upon lack of targeting characteristics current AP drugs possess.

 

[serotonin2A]

^At this point, there isn't evidence to indicate that pimavanserin will be an effective antipsychotic in conditions other than Parkinson's disease. The hallucinations in Parkinson's disease are primarily visual and occur because 5-HT2A is upregulated due to loss of serotonergic neurons. Those conditions do not exist in schizophrenia patients.

 

[Cotcha Yankinov]

I really hope I can convince someone to prescribe it to me for insomnia, that's what all the original 5-HT2A inverse agonists were investigated for

 

[paranoid android]

Some anti-depressants also act as 5-HT2A antagonists namely Mirtazapine and the Tricyclic anti-depressant Trimipramine which due to it's D2 antagonism is also a Atypical anti-psychotic of sorts. Most anti-psychotics both Atypical and most of the Typicals also act as 5-HT2A antagonists. Quetiapine starts acting on the 5-HT2a receptor once you get to around 200mg's a day and this is one proposed mechanism for it's anti-depressant effects. Even really old Typicals like Chlorpromazine among others act as 5-HT2A antagonists and Chlorpromazine in particular has more affinity for the 5-HT2A receptor then the D2 receptor thus in this way it differs from most other typicals especially the higher potency ones such as Haldol, Pimozide, Zuclopenthixol, etc. Loxapine is another Typical anti-psychotic (though some argue that it's actually a atypical anti-psychotic) that binds more strongly to the 5-HT2A receptor then the D2 receptor.

I have found Quetiapine and Olanzapine to work great on their own at treating Bipolar depression and depending on the type of depression i get may be as effective or more so then Bupropion. Quetiapine XR is actually marketed here as a anti-depressant as well as a anti-psychotic. Trimipramine which is a weird Tricyclic anti-depressant with atypical anti-psychotic properties due to it's D2 antagonism and 5-HT2A antagonism also helps my depression without setting off a Manic episode.

 

[Nagelfar]

Sauce? I have never heard anything that suggests that's true.

Funnest typo in BL history. "I find that info hard to swallow without the sauce"

 

[Xzbtya]

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.)

I'd argue the anti-histamine properties of trazodone may have more to do with knocking you out than the 5HT2A antagonism. I was on nefazodone for a good while and the drug would wire me up like crazy and its antagonism of 5HT2A is stronger than that of trazodone.

"Nefazodone acts primarily as a potent antagonist at the 5-HT2A receptors (Kd 26 nM)"

It also has a lower incidence of sexual dysfunction than any other antidepressant out there. The funny thing is it wasn't very anxiolytic at all. It produced some mild euphoria and stimulation for a while (its a weak triple reuptake inhibitor). When I stopped taking it awaiting live test results (rather stupidly forgetting its short half-life) I experienced the worst depression I had ever felt in my life. Up until that point I only had relatively severe anxiety. The withdrawal was so bad I couldn't leave my bed and trying to take another dosage seemed to make the effects worse. Make of that what you will.

5-HT2C is another weird one. Lorcaserin is a potent and selective agonist of 2C with the main effect being decreased appetite. High doses of prozac act as 2C antagonists increasing dopamine levels in the brain. I think its much more complicated than simply concluding an effect based on whether something is an agonist or antagonist and delving into the conformation the receptor takes once bound (which is not particularly easy).

 

[Cotcha Yankinov]

I'd argue the anti-histamine properties of trazodone may have more to do with knocking you out than the 5HT2A antagonism. I was on nefazodone for a good while and the drug would wire me up like crazy and its antagonism of 5HT2A is stronger than that of trazodone.

The adrenergic antagonism contributes to the sedation as well. I imagine an inverse agonist at 5-HT2A (like the typical sleep drugs Ketanserin and such, which by the way apparently Risperdal is very chemically similar to Ketanserin) would be much more effective at sedation.

As for 5-HT2 receptors, apparently they exert a tonic inhibitory effect on the striatal dopaminergic neurons, so it is possible that antagonizing 5-HT2 increases dopaminergic tone even though there is dopaminergic transmission related to 5-HT2A? If antagonizing 5-HT2A increases dopamine in this way then that could be why it helps with depression, and also helps explain why over density of 5-HT2A is a bad thing (less dopamine). That just leaves me wondering why a 5-HT2A antagonist that might be potentially increasing dopamine transmission is a good thing in a disease like schizophrenia that's commonly thought to be from too much dopamine transmission. Maybe the reducing the excess excitatory 5-HT2A/mGlu is more important than keeping dopamine levels low? I don't know if excess dopamine is a big deal in bipolar mania (or if its more glutamate related) but it seems like reducing the excitatory 5-HT2A/Glutamate could be more important there as well.

Although I imagine a lot of it comes down to brain regions and their specific function, thus it might be hard to make generalizations about receptors without knowing the context of where they are and what they're doing in the brain.

 

[edsorow]

I have melancholic depression with severe anhedonia. The various drugs that I've tried have not helped at all, except bupropion and surprisingly, Hydroxyzine. Bupropion increased motivation, but had no affect on anhedonia and mood reactivity. Hydroxyzine caused euphoria and a complete return of all my emotions, but also joint and muscle pain and obviously the intended drowsiness. Hydroxyzine is a 5-ht2a and d2 antagonist, so I thought this might be relevant. As of yet, no good explanation from doctors.