Would Chlorprothixen help or harm in regards to Serotonin syndrome?

[Mude]

Hi!

I've got a pretty simple, or maybe it's not so simple (to me anyway) question:

Can Chlorprothixen treat Serotonin syndrome effectively (since it's a 5-HT2 receptor antagonist), not taking into account it's complex pharmacodynamics at several other completely different receptor sites?

(Excuse my english here, it's my second language, and I'm a little high, so I'm not sure whether that sentence was actually correct: What I mean by "not taking into account" is, that you only consider the serotonin antagonism, and not any of the other (mACh, H1, D1, D2, D3, and alpha-1-adrenergic receptor) antagonistic effects. On the other hand, I'd just generally be happy for answers to this question; the ones that take the other pharmacodynamic actions into account as well!! )

I am asking this question since Chlorprothixen is the only antipsychotic or rather serotonin antagonist I have available, and probably ever will have available. I'm pretty sure I have read somewhere that antipsychotics actually by antagonising Dopamine, cause an increase in Dopamine production by receptor upregulation later on, or down something like that, and I'm wondering whether it may be the same for serotonin antagonists... Or not?

Kind regards,
Mude

 

[Keif' Richards]

I think you'll probably find more appropriate attention in our more advanced drug discussion forum. I'm going to go ahead and move this there. Good luck!

 

[d1nach]

No. I believe the 5 ht2 receptors most influenced by antidepressants namely 5 ht2a and 5ht2c are downregulated in response to both agonism , antagonism or indirect activation by blocking sert.

This is one mechanism by taking antipsychotics or certain antagonists at 5 ht2 receptor older antidepressants can increase responding in nonresponders to ssris alone


My best guess is this would further increase the seritonin syndrome by blocking some of the 5 ht2a and c presynaptic autoreceptors allowi g the sert to cause evem more effects post synaptically by blocking up your bodys "natural" defense buffer which can be good to make drugs work faster but here be potentially very bad

Also the anticholinergic effects would likely further raise your temp and heart potentially dangerously high and dopamine blocking effects certain wouldnt help either you need everything in balance

 

[Mude]

I think you'll probably find more appropriate attention in our more advanced drug discussion forum. I'm going to go ahead and move this there. Good luck!

Thanks a lot!

No. I believe the 5 ht2 receptors most influenced by antidepressants namely 5 ht2a and 5ht2c are downregulated in response to both agonism , antagonism or indirect activation by blocking sert.

This is one mechanism by taking antipsychotics or certain antagonists at 5 ht2 receptor older antidepressants can increase responding in nonresponders to ssris alone


My best guess is this would further increase the seritonin syndrome by blocking some of the 5 ht2a and c presynaptic autoreceptors allowi g the sert to cause evem more effects post synaptically by blocking up your bodys "natural" defense buffer which can be good to make drugs work faster but here be potentially very bad

Also the anticholinergic effects would likely further raise your temp and heart potentially dangerously high and dopamine blocking effects certain wouldnt help either you need everything in balance

Thank you very very much as well for educating me! I've obviously still got a hell of a lot to learn. Wow. The more you learn about the topic, the more you realise, how complex neurobiology/neurochemistry/pharmacology is.

Kind regards,
Mude

 

[Mude]

No. I believe the 5 ht2 receptors most influenced by antidepressants namely 5 ht2a and 5ht2c are downregulated in response to both agonism , antagonism or indirect activation by blocking sert.

This is one mechanism by taking antipsychotics or certain antagonists at 5 ht2 receptor older antidepressants can increase responding in nonresponders to ssris alone


My best guess is this would further increase the seritonin syndrome by blocking some of the 5 ht2a and c presynaptic autoreceptors allowi g the sert to cause evem more effects post synaptically by blocking up your bodys "natural" defense buffer which can be good to make drugs work faster but here be potentially very bad

Also the anticholinergic effects would likely further raise your temp and heart potentially dangerously high and dopamine blocking effects certain wouldnt help either you need everything in balance

Actually, could you please do me a huge favour and elaborate further? I still don't quite understand this 100%.

This part for example:

This is one mechanism by taking antipsychotics or certain antagonists at 5 ht2 receptor older antidepressants can increase responding in nonresponders to ssris alone

As well as the part about the autoreceptors (which, as far as I understand, in this case are located on the membrane of nerve cells, which produce serotonin, which then binds to it's own receptors and activates them)...

Sorry to bother you!

 

[Cotcha Yankinov]

I was under the impression that 5-HT2A are heteroreceptors and contribute to the hyperthermia of serotonin syndrome. They are also located on cerebral arteries and can participate in causing cerebral vasoconstriction in some 5-HT2A agonist overdoes but idk if the arterial 5-HT2A contribute to serotonin syndrome.

 

[d1nach]

Antagonism of the 5-HT2 subfamily of receptors and inverse agonism of the 5-HT2C receptor appears to be in part responsible for mirtazapine's efficacy in the treatment of depressive states.[98][99]

98 Millan MJ (2005). "Serotonin 5-HT2C receptors as a target for the treatment of depressive and anxious states: focus on novel therapeutic strategies". Thérapie. 60 (5): 441–60. doi:10.2515/therapie:2005065. PMID 16433010.
^ Dekeyne A, Millan MJ (April 2009). "Discriminative stimulus properties of the atypical antidepressant, mirtazapine, in rats: a pharmacological characterization". Psychopharmacology. 203 (2): 329–41. doi:10.1007/s00213-008-1259-8. PMID 18709360.

Conversely, many SSRIs (but not fluoxetine, which is a 5-HT2C antagonist[11]) indirectly stimulate 5-HT2C activity by increasing levels of serotonin in the synapse although the delayed mood elevation that is usually typical of SSRIs is usually paralleled by the downregulation of the 5-HT2C receptors.[12] Many atypical antipsychotics block 5-HT2C receptors, but their clinical use is limited by multiple undesirable actions on various neurotransmitters and receptors
Ni YG, Miledi R (March 1997). "Blockage of 5HT2C serotonin receptors by fluoxetine (Prozac)". Proceedings of the National Academy of Sciences of the United States of America. 94 (5): 2036–40. Bibcode:1997PNAS...94.2036N. doi:10.1073/pnas.94.5.2036. PMC 20038Freely accessible. PMID 9050900.
^ a b Berg KA, Harvey JA, Spampinato U, Clarke WP (December 2005). "Physiological relevance of constitutive activity of 5-HT2A and 5-HT2C receptors". Trends in Pharmacological Sciences. 26 (12): 625–30. doi:10.1016/j.tips.2005.10.008. PMID 16269190.



As an example, norepinephrine released from sympathetic neurons may interact with the alpha-2A and alpha-2C adrenoreceptors to inhibit further release of norepinephrine. Similarly, acetylcholine released from parasympathetic neurons may interact with M2 and M4 receptors to inhibit further release of acetylcholine. An atypical example is given by the β-adrenergic autoreceptor in the sympathetic peripheral nervous system, which acts to increase transmitter release.[1]
Siegel GJ, Agranoff BW, Albers RW, et al., eds. (1999). "Catecholamine Receptors". Basic Neurochemistry: Molecular, Cellular and Medical Aspects (6th ed.). Lippincott-Raven.

I think these answer your questions

 

[isaaccain]

I heard a story about a guy who was taking some antipsychotic, the same one I was on although I forget exactly which one, and he thought he had gotten mild seratonin syndrome from combining his meds and cocaine. He took diphenhydramine which fixed his symptoms and made him well again, but I don't know if it would work for more severe cases

 

[Mude]

@d1nach:
So, I'm not sure I understand: The antagonism of the 5-HT2 receptors leads to upregulation of the same receptors, eventually leading to stronger effects of serotonin binding to those receptors?
But isn't serotonin syndrome more of an acute thing, whereas receptor downregulation or upregulation occurs over a longer period of time?

Thanks for taking the time to write these answers!

@isaaccain:
That's strange and interesting. Because I've often come across people saying that Diphenhydramine actually has some action on the SERT (serotonin transporter, i.e. causing serotonin reuptake-inhibition, which should worsen the symptoms of serotonin syndrome ).

 

[d1nach]

Doctors would tell you yes. However i am skeptical
1. Demonstrate that diphenhydramine would be able to significantly inhibit the sert transporter.
2. Demonstrate that inhibition of the sert transporter influences the toxicity of acute serotonin syndrome
3. Assuming the occupancy due to already taking a ssri at sert is at say 80 % that adding diphenhydramine would be able to further inhibit sert beyond this level
4. That a enzyme interaction cant explain the toxicity for example methaamphetamine and prozac is it serotinin syndrome or is prozac strongly inhibiting the enzyme p450 cyp2d6 drastically altering the pharmokinetics of meth making it a overdose by causing abnormal levels in the blood for abnormally longer amounts of time.
5. Dxm and prozac is it seritonin syndrome or is it drastically increased levels of dxo via p450 cyp2d6 causing hyperthermia rapid heart rte hallucinagions dialated pupils due to potent nmda antagonism.
6. Diphenhydramine + prozac is it serotinin syndrome or is abnormal levels of dph causing anticholinergic syndrome marked by confusion agitation restlessness delirium hyperthermia

 

[d1nach]

I believe antagonism of the 5 ht2 receptors leads to a downregulation because they function more like a inverse or silent agonist where they go in occupy the autoreceptors on the presynaptic neuron which your cells sense then thinking has more serotonin than it really does because the 5 ht 2 receptors are silently occupying the presynaptic autoreceptors it can signal the postsynaptic downregulation of 5 ht2 receptors.

 

[Cotcha Yankinov]

I should mention that 5-HT2 are thought to be regulated atypically when it comes to antagonists causing desensitization, although many 5-HT2A antagonists are really inverse agonists rather than silent antagonists

https://www.ncbi.nlm.nih.gov/m/pubmed/12650852/

RE: a serotonin reuptake inhibitor protecting against SS - one scenario where this could be possible is where an SRI inhibits the releasing ability of a serotonin releasing agent by occupying SERT and preventing uptake of e.g. MDMA into the cell via SERT, where it would normally then act to reverse transporters and cause serotonin efflux.

 

[d1nach]

Thank you cotcha yankinov that paper abstract explains it nicely

In contrast to most other receptors, chronic blockade of 5-HT(2A) and 5-HT(2C) receptors leads not to an up- but to a (paradoxical) down-regulation.

 

[Mude]

Thank you

Thanks to you both for your quick replies/contributions!
Now I actually understand. This is really interesting stuff! I used to think it was as simple as "antagonists/inverse agonists lead to downregulation, and agonists lead to upregulation of receptors". This cleared it up for me, and it makes me realise even more, how incredibly complex this field of research is.

Thanks again, and take care!

 

[Mude]

I think you'll probably find more appropriate attention in our more advanced drug discussion forum. I'm going to go ahead and move this there. Good luck!

Sorry, I forgot to thank you too, for moving this thread to the right part of the forum.