Risk Of Fibrosis With Serotonin Antagonists

Logan-

Member
Joined
May 26, 2018
Messages
1,581
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?
 
Last edited:
OP
L

Logan-

Member
Joined
May 26, 2018
Messages
1,581
I thought mirtazapine blocks all the 5-ht2 receptors; why does Ray Peat think it has been associated with fibrosis risk?

Dr. Peat specifically mentioned that amitriptyline and mirtazapine have been tied with occurrences of fibrosis.

I know you think that anti-serotonin drugs eventually cause problems, but you've said that amitriptyline is relatively safe. Do you think it's safer than mirtazapine for moderate-term use? I've read that mirtazapine's a "successor" to mianserin.

Dr. Peat: "Although the structure suggests that it might be safer, fibrosis has been associated with both of them, and I think it’s best to concentrate on optimizing the metabolism, with thyroid, pregnenolone, progesterone, etc."
 

DaveFoster

Member
Joined
Jul 23, 2015
Messages
5,027
Location
Portland, Oregon
I thought mirtazapine blocks all the 5-ht2 receptors; why does Ray Peat think it has been associated with fibrosis risk?
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.
 
Last edited:
OP
L

Logan-

Member
Joined
May 26, 2018
Messages
1,581
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.

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?
 
Last edited:

DaveFoster

Member
Joined
Jul 23, 2015
Messages
5,027
Location
Portland, Oregon
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?
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.
 
Last edited:

nwo2012

Member
Joined
Aug 28, 2012
Messages
1,107
At least for number 5, females can have removal of their hysteria with a hysterectomy. :p:
 
OP
L

Logan-

Member
Joined
May 26, 2018
Messages
1,581
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.

Thanks, but you didn't answer my question. The question was about the safety and risks of using mirtazapine for a very long time.
 

Wagner83

Member
Joined
Oct 15, 2016
Messages
3,295
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.
 
OP
L

Logan-

Member
Joined
May 26, 2018
Messages
1,581
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.

I wonder about that too.
 

DaveFoster

Member
Joined
Jul 23, 2015
Messages
5,027
Location
Portland, Oregon
Thanks, but you didn't answer my question. The question was about the safety and risks of using mirtazapine for a very long time.
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]."

medi-95-e3172-g005.jpg

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.
 
OP
L

Logan-

Member
Joined
May 26, 2018
Messages
1,581
You asked whether the risks of mirtazapine, which I named as fibrosis of the heart would present long-term risks or not.

With this, do you mean there are other no risks involved with the long term usage of mirtazapine in your opinion?
 
Last edited:

DaveFoster

Member
Joined
Jul 23, 2015
Messages
5,027
Location
Portland, Oregon
With this, do you mean there are other no risks involved with the long term usage of mirtazapine in your opinion?
Mirtazapine likely has severe negative health risks if used for a decade or longer.
 
Last edited:

nwo2012

Member
Joined
Aug 28, 2012
Messages
1,107
Mirtazapine likely has severe negative health risks if used for a decade or longer.

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.
 

DaveFoster

Member
Joined
Jul 23, 2015
Messages
5,027
Location
Portland, Oregon
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.
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.
 

nwo2012

Member
Joined
Aug 28, 2012
Messages
1,107
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.

Completely agree.
 

Ideonaut

Member
Joined
Sep 20, 2015
Messages
499
Location
Seattle
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.

What, if any, would be your opinion of this stuff SELANK®, 0.15%, 3ml in this context, Dave? They claim it normalizes serotonin.
 

DaveFoster

Member
Joined
Jul 23, 2015
Messages
5,027
Location
Portland, Oregon
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.
 

Similar threads

Back
Top Bottom