Risk Of Fibrosis With Serotonin Antagonists

[Logan-]

@DaveFoster I know you are experienced with, and knowledgeable about mirtazapine; could you share your opinion of mianserin? Do you have any experience with it? Have you ever considered taking it instead of mirtazapine?

Since mianserin is a 5-ht2b antagonist, I think it might be safer to use for moderate to long term, what do you think? How would their effects on the human mind and the body differ in general, in your opinion?

Also, for long term use (say, for years), which one of these (Cyproheptadine, Lisuride, Metergoline, Mirtazapine, Mianserin) would you choose? I know the purpose of using them would effect the judgement on choice, but lets say that you are using them for the beneficial effects in general. I have also migraine prophylaxis in my mind, and these are all known to be effective in that respect.

How would you rate these agents in terms of their safety in long term use?

As a side note, this article suggests mirtazapine's 5-HT2B "antagonism" is partly responsible for its effectiveness in migraine prophylaxis:

"Decreased frequency of migraines with mirtazapine can be explained by 5-HT2 (especially 5-HT2B) and histamine blockade because migraine initiation is thought to be a consequence of their activation. Furthermore, the activation of 5HT1 receptors (notably 5-HT1B, 5-HT1D and 5-HT1F) by mirtazapine could possibly treat migraine through the contraction of distended meningial and cerebral vessels and the reduction of neurogenic inflammation. The theoretical effect of mirtazapine on migraines is two-fold: (i) prevention of migraine initiation through 5-HT2and histamine inhibition and (ii) treatment of migraine through 5-HT1 activation.

We are unable to fully explain the reoccurrence of migraines at a higher mirtazapine dose in our patient.However, at higher doses, mirtazapine causes less daytime somnolence and sedation, and possibly less histamine blockade. Because histamine is a NO-releasing agent, its presence at higher doses may explain migraine headaches reoccurrence in our patient."
Lévy, E., & Margolese, H. C. (2003). Migraine headache prophylaxis and treatment with low-dose mirtazapine. International Clinical Psychopharmacology, 18(5), 301–303. doi:10.1097/00004850-200309000-00

 

[DaveFoster]

@DaveFoster I know you are experienced with, and knowledgeable about mirtazapine; could you share your opinion of mianserin? Do you have any experience with it? Have you ever considered taking it instead of mirtazapine?

Since mianserin is a 5-ht2b antagonist, I think it might be safer to use for moderate to long term, what do you think? How would their effects on the human mind and the body differ in general, in your opinion?

Also, for long term use (say, for years), which one of these (Cyproheptadine, Lisuride, Metergoline, Mirtazapine, Mianserin) would you choose? I know the purpose of using them would effect the judgement on choice, but lets say that you are using them for the beneficial effects in general. I have also migraine prophylaxis in my mind, and these are all known to be effective in that respect.

How would you rate these agents in terms of their safety in long term use?

As a side note, this article suggests mirtazapine's 5-HT2B "antagonism" is partly responsible for its effectiveness in migraine prophylaxis:

"Decreased frequency of migraines with mirtazapine can be explained by 5-HT2 (especially 5-HT2B) and histamine blockade because migraine initiation is thought to be a consequence of their activation. Furthermore, the activation of 5HT1 receptors (notably 5-HT1B, 5-HT1D and 5-HT1F) by mirtazapine could possibly treat migraine through the contraction of distended meningial and cerebral vessels and the reduction of neurogenic inflammation. The theoretical effect of mirtazapine on migraines is two-fold: (i) prevention of migraine initiation through 5-HT2and histamine inhibition and (ii) treatment of migraine through 5-HT1 activation.

We are unable to fully explain the reoccurrence of migraines at a higher mirtazapine dose in our patient.However, at higher doses, mirtazapine causes less daytime somnolence and sedation, and possibly less histamine blockade. Because histamine is a NO-releasing agent, its presence at higher doses may explain migraine headaches reoccurrence in our patient."
Lévy, E., & Margolese, H. C. (2003). Migraine headache prophylaxis and treatment with low-dose mirtazapine. International Clinical Psychopharmacology, 18(5), 301–303. doi:10.1097/00004850-200309000-00

It's possible that agonism of the 5-HT2B receptor could have some beneficial effects on migraines, but that doesn't disqualify the fibrotic effects.

I've never used mianserin or lisuride, and I didn't find metergoline helpful at all. It increased my performance in the gym but gave me anxiety. Cyproheptadine lacks the fibrotic effects of mirtazapine on the heart mediated through the 5-HT2B, and mianserin does not act as an agonist on that receptor either.

 

[Logan-]

It's possible that antagonism of the 5-HT2B receptor could have some beneficial effects on migraines, but that doesn't disqualify the fibrotic effects.

The fibrotic effects of what? Do you mean that something that antagonizes 5-HT2B can still have fibrotic effects?

What was unexpected for me in the article I posted above is that the authors suggest mirtazapine is an antagonist of the 5-HT2B. I thought it is an agonist of the 5-HT2B?

Mirtazapine acts as an agonist (activator) of 5-HT2B receptors with a binding affinity of around 200 Ki (nM), where a lower binding affinity implies antagonism (deactivation). Mirtazapine has other anti-inflammatory effects that would ameliorate its fibrotic effects to some degree.

 

[DaveFoster]

The fibrotic effects of what? Do you mean that something that antagonizes 5-HT2B can still have fibrotic effects?

What was unexpected for me in the article I posted above is that the authors suggest mirtazapine is an antagonist of the 5-HT2B. I thought it is an agonist of the 5-HT2B?

"Agonist" I mean, but I suppose they're right. There must be some other mechanism of action for mirtazapine's contribution to heart valve disease, as outlined by Lin and others in their 2016 study.

1.Elangbam CS, Job LE, Zadrozny LM, Barton JC, Yoon LW, Gates LD, et al. 5-hydroxytryptamine (5HT)-induced valvulopathy: compositional valvular alterations are associated with 5HT2B receptor and 5HT transporter transcript changes in Sprague-Dawley rats. Exp Toxicol Pathol. 2008 Aug;60(4–5):253–62.
2. Mekontso-Dessap A, Brouri F, Pascal O, Lechat P, Hanoun N, Lanfumey L, et al. Deficiency of the 5-hydroxytryptamine transporter gene leads to cardiac fibrosis and valvulopathy in mice. Circulation. 2006 Jan 3;113(1):81–9.
3. Robiolio PA, Rigolin VH, Wilson JS, Harrison JK, Sanders LL, Bashore TM, et al. Carcinoid heart disease. Correlation of high serotonin levels with valvular abnormalities detected by cardiac catheterization and echocardiography. Circulation. 1995 Aug 15;92(4):790–5.

 

[ecstatichamster]

@DaveFoster can you kindly provide links to works cited

 

[DaveFoster]

@DaveFoster can you kindly provide links to works cited

7. Mekontso-Dessap A, Brouri F, Pascal O, et al. Deficiency of the 5-hydroxytryptamine transporter gene leads to cardiac fibrosis and valvulopathy in mice. Circulation 2006; 113:81–89. [PubMed]
8. Elangbam CS, Job LE, Zadrozny LM, et al. 5-Hydroxytryptamine (5HT)-induced valvulopathy: compositional valvular alterations are associated with 5HT2B receptor and 5HT transporter transcript changes in Sprague–Dawley rats. Exp Toxicol Pathol 2008; 60:253–262. [PubMed]
9. Robiolio PA, Rigolin VH, Wilson JS, et al. Carcinoid heart disease. Correlation of high serotonin levels with valvular abnormalities detected by cardiac catheterization and echocardiography. Circulation 1995; 92:790–795. [PubMed]

 

[ecstatichamster]

thank you so much @DaveFoster

 

[Logan-]

"Agonist" I mean, but I suppose they're right. There must be some other mechanism of action for mirtazapine's contribution to heart valve disease, as outlined by Lin and others in their 2016 study.

1.Elangbam CS, Job LE, Zadrozny LM, Barton JC, Yoon LW, Gates LD, et al. 5-hydroxytryptamine (5HT)-induced valvulopathy: compositional valvular alterations are associated with 5HT2B receptor and 5HT transporter transcript changes in Sprague-Dawley rats. Exp Toxicol Pathol. 2008 Aug;60(4–5):253–62.
2. Mekontso-Dessap A, Brouri F, Pascal O, Lechat P, Hanoun N, Lanfumey L, et al. Deficiency of the 5-hydroxytryptamine transporter gene leads to cardiac fibrosis and valvulopathy in mice. Circulation. 2006 Jan 3;113(1):81–9.
3. Robiolio PA, Rigolin VH, Wilson JS, Harrison JK, Sanders LL, Bashore TM, et al. Carcinoid heart disease. Correlation of high serotonin levels with valvular abnormalities detected by cardiac catheterization and echocardiography. Circulation. 1995 Aug 15;92(4):790–5.

Thank you.

 

[DaveFoster]

thank you so much @DaveFoster

Thank you.

No problem.

 

[No_Energy]

@nwo2012
@DaveFoster

I remember reading multiple times that Mirtazapine is an antagonist on the 5-ht2b receptors. ("While the antagonist actions of mirtazapine at 5-HT2B receptors are of unclear significance (Millan et al. 2000a" , http://www.biblioteca.cij.gob.mx/Ar...nsulta/Drogas_de_Abuso/Articulos/36882760.pdf) , maybe you got this confused because of that other study you posted?. And that study seems vague, given that some people were using multiple antidepressants and Antidepressants with low affinity for the Serotonin transporter could mean a lot of things, bupropion, a bunch of the tricyclics, a NRI, a NSSA.. So, nothing specific about Mirtazapine. I still dont know what the final answer here is.

Did you find Mirtazapine a good antidepressant?. Did it help with energy?
Thanks man.

 

[GutFeeling]

@nwo2012
@DaveFoster

I remember reading multiple times that Mirtazapine is an antagonist on the 5-ht2b receptors. ("While the antagonist actions of mirtazapine at 5-HT2B receptors are of unclear significance (Millan et al. 2000a" , http://www.biblioteca.cij.gob.mx/Ar...nsulta/Drogas_de_Abuso/Articulos/36882760.pdf) , maybe you got this confused because of that other study you posted?. And that study seems vague, given that some people were using multiple antidepressants and Antidepressants with low affinity for the Serotonin transporter could mean a lot of things, bupropion, a bunch of the tricyclics, a NRI, a NSSA.. So, nothing specific about Mirtazapine. I still dont know what the final answer here is.

Did you find Mirtazapine a good antidepressant?. Did it help with energy?
Thanks man.

There are some studies with mice showing antifibrotic effects of mirtazapine I recently made a thread showing that it does not have serotoninergic effect

I've using this drug for 3 months, so I would like to share my experience, it will probably be helpful. Mirtazapine caused my serious and frequent suicidal thoughts to stop almost completely, my perspective in life became much more optimistic and I feel like it make my thoughts go through the correct path, I think this drug also have beneficial effects on ADHD. It's sedating effects are really strong it's like a cyproheptadine without tolerance. My energy levels got better but only if I take the drug at night ofc. It also increase aggression a bit, I think that this is a good thing. I recently started using bupropion (2weeks) and it's effects were positive aswell, but I may be biased since it helps with ADD.

 

[GutFeeling]

Btw bupropion is likely the best antidepressant in regard to energy levels, it caused nausea which can be mtigated by mirtazapine.

 

[No_Energy]

@GutFeeling

Thank you for your input and sharing your experience, that was really helpful!. Yes, it seems mirtazapine is an antagonist on 5ht2b receptors (not an agonist like DaveFoster mentioned), and it is believed that Agonism of those receptors show some risk for heart fibrosis, It is still not clear to me that Antagonism of the same receptor would pose the same kind of risk. Have you used Bupropion by itself? ( long ago experimented w/ buprop. for a few days but thought it was too uncomfortable at night with some anxiety, insomnia.. maybe should have given more time..).. which of the two do you prefer? Are you using them simultaneously?

 

[GutFeeling]

@GutFeeling

Thank you for your input and sharing your experience, that was really helpful!. Yes, it seems mirtazapine is an antagonist on 5ht2b receptors (not an agonist like DaveFoster mentioned), and it is believed that Agonism of those receptors show some risk for heart fibrosis, It is still not clear to me that Antagonism of the same receptor would pose the same kind of risk. Have you used Bupropion by itself? ( long ago experimented w/ buprop. for a few days but thought it was too uncomfortable at night with some anxiety, insomnia.. maybe should have given more time..).. which of the two do you prefer? Are you using them simultaneously?

I've never used bupropion without mirtazapine, I'm currently using both, I think that mirtazapine is a good counter to bup side effects like nausea, restlessness, insomnia and lack of appetite. I like both, since they remember the calming effect of cyproheptadine and a bit of the euphoria that methylphenidate causes, but bupropion nausea is a pain...

5ht2B antagonism prevent fibrosis.

Modulation of TGF-β/Smad and ERK Signaling Pathways Mediates the Anti-Fibrotic Effect of Mirtazapine in Mice - PubMed

 

[SonOfEurope]

Mirtazapine acts as an agonist (activator) of 5-HT2B receptors with a binding affinity of around 200 Ki (nM), where a lower binding affinity implies antagonism (deactivation). Mirtazapine has other anti-inflammatory effects that would ameliorate its fibrotic effects to some degree.

And Dave, sorry if you've addressed this already but at what dose would mirtazapine be best at that? It was the only antidepressant that didn't totally wreck me when I was on them until I replaced them with P4.

Mirtazapine's effects are very dose-dependent no?