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Risk Of Fibrosis With Serotonin Antagonists

  1. We know that drugs with the 5-ht2b agonist effect have been linked with fibrosis risk. Which of the serotonin antagonists are safe to use for long term in this regard? I have read that cyproheptadine, pizotifen, lisuride, metergoline, ritanserin, ketanserin are safe. Any more?
  2. I thought mirtazapine blocks all the 5-ht2 receptors; why does Ray Peat think it has been associated with fibrosis risk?

  3. 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.
  4. Thanks. I have seen some people (in online health forums) using mirtazapine for more than ten years, do you think it is safe to use for a decade? What would you worry about, if you were to use it for a very long time?
  5. I think ondansetron might be one
  6. In the context of great thyroid function, the body can reverse fibrosis of the heart, and thyroid has anxiolytic (anxiety-lowering) and anti-depressant effects, so much so as to completely eliminate mood disorders in the majority of cases.

    Sub-optimal thyroid function, which includes low levels of T3, (liothyronine, the active thyroid hormone) and subsequent elevations in estrogen and cortisol all appear in major depressive disorder (MDD), anxiety disorders, both type I and type II bipolar disorder, schizophrenia, obsessive-compulsive disorder (OCD), attention-deficit disorder (ADD) and attention-deficit hyperactivity disorder (ADHD).

    Low thyroid function presents itself alongside symptoms of other mental disorders that involve a sensitization to a given stimulus, such as the following; 1) post-traumatic stress disorder (PTSD) with elevated cortisol and depressed DHEA levels; 2) autism spectrum disorder (ASD) and its variants including Asperger syndrome with high circulating serotonin levels, where thyroid hormone blocks serotonin synthesis; 3) migraine, nausea, irritability and sensitivity to light and sound, all involving elevated serotonin levels; 4) personality disorders including borderline personality disorder (BPD) with depressed free T3 and DHEA levels in particular; 5) histrionic personality disorder (HPD), also known more broadly as hysteria, which includes excessive sociability and reliance on others, and which appears in the context of elevated norepinephrine (the brain's type of adrenaline), itself lowered in the presence of thyroid hormone; 6) anti-social personality disorder (ASPD) and narcicisstic personality disorder (NPD), which include, irrespectively, a myriad of symptoms such as avoidance, callousness and general psychopathy, and where both of the aforementioned personality disorders exhibit elevated cortisol levels.
  7. At least for number 5, females can have removal of their hysteria with a hysterectomy. :p:
  8. Thanks, but you didn't answer my question. The question was about the safety and risks of using mirtazapine for a very long time.
  9. Using serotonin antagonists increase receptors sensitivity from what I saw, I'm curious what happens weeks/months after one stops using them. For the record I doubt Ray gives much credit to the 'receptor-based' approach of drugs.
  10. I wonder about that too.
  11. Lisuride
  12. You asked whether the risks of mirtazapine, which I named as fibrosis of the heart would present long-term risks or not. I stated that thyroid hormone can reverse the effects. Thyroid hormone can also prevent fibrosis of the heart, but it's uncertain whether or not it can prevent fibrosis in the context of a 45 mg dosage of mirtazapine, but it certainly can help. People have taken mirtazapine for several decades without developing valvular heart disease (another term for cardiac valve fibrosis,) whereas others do.

    Chia-Hui Lin et al. investigated patients with prescriptions of least three antidepressants simultaneously, who had higher rates of cardiac fibrosis after only nine years on such drugs with higher rates of cardiac fibrosis increasing with both the dosage and time taking the drug. I partly answered your question on another thread on mirtazapine.

    "We identified a cohort of patients aged 20 years and older who had received at least 3 prescriptions of antidepressants between January 1, 2002, and December 31, 2010...

    Exposure to antidepressants was categorized by the type of antidepressant, affinity for the 5-HT transporter and individual antidepressant. The antidepressants were classified into the following 3 categories according to their affinities for the 5-HT transporter: a high-affinity group (fluoxetine, paroxetine, sertraline, and clomipramine), a moderate-affinity group (citalopram, fluvoxamine, imipramine, venlafaxine, and amitriptyline), and a low-affinity group (trazodone, bupropion, maprotiline, mirtazapine, and dothiepin)28,29 (Appendix 1)."

    "We found a 1.4-fold increase in the risk of VHD among current users of antidepressants. Among current users, a dose–response effect was found in patients with cumulative DDDs [defined daily dose, indicating a higher dosage resulting in increased fibrosis.] Moreover, the users who were currently taking TCAs and antidepressants with moderate and low affinities for the 5-HT transporter were at significant higher risks of VHD [valvular heart disease]."

    The last column in the table from the aforementioned study, that is the column with the aOR heading, shows the rates of cardiac fibrosis for each category of antidepressants. A value of "1.49" implies a 49% increase in the rate for users.

    Since mirtazapine would be considered as having a "low-affinity" for the serotonin transporter, it would fall in the last row of the table (the "LA group").

    If you have continuously taken mirtazapine for nine years alongside two other antidepressants, then you would have a 49% increase in the likelihood that you will develop cardiac fibrosis.

    If you recently took three antidepressants including mirtazapine, as in for less than nine years continuously, then you would have a 29% increase in the likelihood that you will develop cardiac fibrosis.

    If you took three antidepressants including mirtazapine in the distant past, as in for significantly less than nine years continuously, then you would have a 16% increase in the incidence of cardiac fibrosis.
  13. With this, do you mean there are other no risks involved with the long term usage of mirtazapine in your opinion?
  14. Mirtazapine likely has severe negative health risks if used for a decade or longer.
  15. Thanks.
  16. It may be the case but you can not say likely or deduce it from that study of people using at least 3 prescription antidepressants. Jeez at least different ones. And I wonder what other drugs these zombies were using. You have no way of knowing if mirtazipine will act the same as the others LA group because they are different drugs regardless of 'receptor affinity'(if receptors even exist). And also if it's the combination causing the increased fibrosis.
    And I highly doubt mirtazipine taken in lower dosages such as 7.5mg would have any such risk, especially when not combined with those other crap drugs listed.
    So you are merely speculating, nothing more.
  17. The study showed that the development of heart valve disease (cardiac fibrosis) increased in proportion to both the length of use and total dosage taken for all groups of antidepressants.

    It's certainly possible that only one or two antidepressants taken simultaneously would not predispose patients to heart valve disease, but the data suggests that the likelihood increases over a longer time horizon and with a greater dosage for each antidepressant within the study's categories. There's a far lower likelihood that a single of the antidepressants listed in Chia-Hun Lin et al. study, when taken at a low dosage (say 7.5 mg mirtazapine), will cause an increase in the likelihood of fibrosis at a staggering rate of around 40%.

    Dr. Peat has also said that mirtazapine's structure suggests its superior safety compared to that of tricyclic anti-depressants (TCAs).

    It's also interesting to note that the risk of heart valve disease increased in patients with other chronic diseases, which suggests the general health of the patient as a primary determinant for the development of heart valve disease. In other words, a vibrant younger person with a strong metabolism would oppose serotonin's fibrotic effects on the heart, which falls right in line with Dr. Peat's article, Leakiness, aging, and cancer

    "Thyroid hormone protects against excess estrogen, and can prevent or reverse fibrosis of the heart."
    Thyroid opposes serotonin synthesis, as well as the actions of estrogen, the former of which has direct fibrotic effects on the heart, and the latter of which has a negative effect on cardiac output. Thyroid and other things that inhibit serotonin synthesis would protect from the effects of the antidepressants listed in the Chia-Hun Lin et al. study, and a 5-HT2B receptor antagonist, such as terguride would oppose the development of cardiac fibrosis.
  18. Completely agree.
  19. What, if any, would be your opinion of this stuff SELANK®, 0.15%, 3ml in this context, Dave? They claim it normalizes serotonin.
  20. In the brain, Selank has power anti-inflammatory effects, as well as neuroregenerative properties mediated through brain-derived neurotrophic factor. Semax has been studied more extensively and appears safe.

    I planned on taking Selank many years ago in high school, but the cost prohibited its use. Other neurosteroids have a lower cost and can have similar effects.
  21. @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
  22. 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.
  23. 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?

  24. "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.
  25. @DaveFoster can you kindly provide links to works cited
  26. 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]
  27. Thank you.
  28. No problem.