Excess Serotonin Induce Neuronal Apoptosis(Kills Brain Cells)

[Bravoncius Roxford]

Once again you link the cancer cell line study and now a liver cell study, you're not showing any appreciable apoptosis in neuronal cell lines, much less that this has meaningful in vivo implications

The title of one paper you linked
"Sertraline, an Antidepressant, Induces Apoptosis in Hepatic CellsThrough the Mitogen-Activated Protein Kinase Pathway"


I just posted evidence that TCAs actually lead to decreased risk of neurodegenerative disease earlier, so I don't know why you're claiming TCAs are worse. Also, anticholinergics are not causing their deleterious effects on the brain through NMDA antagonism/olney's lesions, and olney's lesions are very unlikely to occur in humans.


The issue at hand for you is not whether or not SSRIs lead to apoptosis of neurons in vivo, but rather whether they can cause adverse effects (why would you limit the adverse effects of psychiatric meds to apoptosis?)

The other issue is the actual pathology of depression and neuropsychiatric disease from which you suffer - don't tunnel vision on apoptosis. Especially not SSRI induced apoptosis in cancer/hepatic/yeast cell lines.

Also, the burden of proof is not on me here, you're the one making the truth claim (that SSRIs cause appreciable apoptosis)

Rumination is a big part of depression that is both a symptom and a causal factor. Try mindfulness to stay in the present, learn mindfulness through an app like Headspace.

Several of the papers I posted dfiscussed that SSRIs induce apoptosis in *neuroblastomas*. Yes, those are cancerous cells, but nerve ones. Also, what does it matter if it is hepatic cells, or heart cells or any other kind of cell? All cells work the same. They all have mitochondria and they are all succeptible to the same toxicicity. Poisons are toxic to pretty much all cells in the body. Alcohol, for instance, poisons brain cells and hepatic cells and all other kinds of cells. I don't understand why you bring this up. The studies I posted clearly indicate an increase in inflammation in *healthy nerve tissue*. The apioptic markers were weaker than in cancerous cells, granted, but the SSRIs do increase markers of apoptosis in healthy nerve tissue as well.

As for why I don't focus on other adverse effects, it is because obviously destruction of brain tissue is a much more serious side effect than any other except for maybe serotonin syndrome which can be fatal.This is why I focus on apoptosis.

Also, my original claim is that the SSRIs *probably* are neurotoxic. I posted evidence of increased inflammatory markers in healthy brain tissue as evidence that they potentially harm the brain. You, conversely, flat out stated that these drugs are 100% safew to the brain in therapeutic doses. Well, what evidence do you have? You still haven't posted *one* study where the SSRIs are proven to be hamrless to human nerve cells in therapeutic doses.

 

[Bravoncius Roxford]

And yes, I do suffer from depression. Some people are naturally anxious and obsess over negative things(angsty). I am fascinated by people that are easy going and content, and I wouldf give up my left testicle to be like that. I have given up trying to figure out how to cure this, because there is no cure. 90% of antidepressants don't work, and the only 10% work "moderately" with a lot of side effects and then stop working after 3 months. One of the things that work is to hold my breathe until I pass out. Snaping my own fingers also work as the intense physical pain takes my focus away from my recurrent and overwhelming negative thoughts. The last time I broke my pinky with a hammer. For about 3 hours I couldn't focus on my negative thoughts. I was free. Then, it was back straight to hell as the pain diminished.

 

[Cotcha Yankinov]

what does it matter if it is hepatic cells, or heart cells or any other kind of cell? All cells work the same. They all have mitochondria and they are all succeptible to the same toxicicity. Poisons are toxic to pretty much all cells in the body. Alcohol, for instance, poisons brain cells and hepatic cells and all other kinds of cells. I don't understand why you bring this up. The studies I posted clearly indicate an increase in inflammation in *healthy nerve tissue*. The apioptic markers were weaker than in cancerous cells, granted, but the SSRIs do increase markers of apoptosis in healthy nerve tissue as well.

All cells are not the same. Even a paper you cited refutes this...

"Assessment of paroxetine cytotoxicity in primary mouse brain and neuronal cultures showed significantly lower sensitivity to the drug's proapoptotic activity.

The high sensitivity to these drugs of the cancer cell, compared with primary brain tissue, suggests the potential use of these agents in the treatment of brain-derived tumors."


Drugs that are abstractly labeled neurotoxins do not affect all cells equally as well, see for example the drugs that gain access to the neuron via their respective reuptake transporters - so MDMA is a major substrate for SERT and thus is fairly selectively neurotoxic to 5-HT neurons.

Also, my original claim is that the SSRIs *probably* are neurotoxic. I posted evidence of increased inflammatory markers in healthy brain tissue as evidence that they potentially harm the brain. You, conversely, flat out stated that these drugs are 100% safew to the brain in therapeutic doses. Well, what evidence do you have? You still haven't posted *one* study where the SSRIs are proven to be hamrless to human nerve cells in therapeutic doses.

I'd like to see my exact quote where I say "these drugs are 100% safe to the brain in therapeutic doses".

I have said that SSRIs are non-neurotoxic because they are not considered neurotoxins like METH/MDMA are. I'm not saying that there isn't a dosage at which SSRIs can cause neurodegeneration through whatever mechanism, but I just don't think its appreciable at therapeutic dosages - you're tunnel visioning pretty hard.

If you limit yourself to "SSRIs can only cause adverse effects via destruction of brain tissue" then you show an extremely poor understanding of neuroscience.

Increased inflammatory markers in healthy brain tissue is not something that you've specifically brought before us very clearly, so please post it plain and clear so we can see (we are not going to dig through the "SSRIs induce some apoptosis in cancer cell lines" papers to find it, link it for us), but even increased inflammatory markers wouldn't necessarily mean the SSRIs are killing neurons left and right.

An inflammatory marker like GFAP is more indicative of degeneration but other markers of inflammation wouldn't necessarily mean cell death. Serotonin has a lot of communications with the immune system, and in many senses SSRIs are thought to work for MDD by decreasing inflammation, but I wouldn't be surprised if the opposite could happen in some instances.

 

[Cotcha Yankinov]

And yes, I do suffer from depression. Some people are naturally anxious and obsess over negative things(angsty). I am fascinated by people that are easy going and content, and I wouldf give up my left testicle to be like that. I have given up trying to figure out how to cure this, because there is no cure. 90% of antidepressants don't work, and the only 10% work "moderately" with a lot of side effects and then stop working after 3 months. One of the things that work is to hold my breathe until I pass out. Snaping my own fingers also work as the intense physical pain takes my focus away from my recurrent and overwhelming negative thoughts. The last time I broke my pinky with a hammer. For about 3 hours I couldn't focus on my negative thoughts. I was free. Then, it was back straight to hell as the pain diminished.

Medications are not the only efficacious treatments for mental illness.

More research is showing that mindfulness meditation (vipassana) can be effective for depression and other mental illness - if you ask me, mindfulness will be able to do things for some people that medications never will. Same with CBT, or mindfulness based CBT.

Mindfulness is essentially antithetical to the behavior/thinking you've displayed to us so far.

 

[Bravoncius Roxford]

All cells are not the same. Even a paper you cited refutes this...

"Assessment of paroxetine cytotoxicity in primary mouse brain and neuronal cultures showed significantly lower sensitivity to the drug's proapoptotic activity.

The high sensitivity to these drugs of the cancer cell, compared with primary brain tissue, suggests the potential use of these agents in the treatment of brain-derived tumors."


Drugs that are abstractly labeled neurotoxins do not affect all cells equally as well, see for example the drugs that gain access to the neuron via their respective reuptake transporters - so MDMA is a major substrate for SERT and thus is fairly selectively neurotoxic to 5-HT neurons.




I'd like to see my exact quote where I say "these drugs are 100% safe to the brain in therapeutic doses".

I have said that SSRIs are non-neurotoxic because they are not considered neurotoxins like METH/MDMA are. I'm not saying that there isn't a dosage at which SSRIs can cause neurodegeneration through whatever mechanism, but I just don't think its appreciable at therapeutic dosages - you're tunnel visioning pretty hard.

If you limit yourself to "SSRIs can only cause adverse effects via destruction of brain tissue" then you show an extremely poor understanding of neuroscience.

Increased inflammatory markers in healthy brain tissue is not something that you've specifically brought before us very clearly, so please post it plain and clear so we can see (we are not going to dig through the "SSRIs induce some apoptosis in cancer cell lines" papers to find it, link it for us), but even increased inflammatory markers wouldn't necessarily mean the SSRIs are killing neurons left and right.

An inflammatory marker like GFAP is more indicative of degeneration but other markers of inflammation wouldn't necessarily mean cell death. Serotonin has a lot of communications with the immune system, and in many senses SSRIs are thought to work for MDD by decreasing inflammation, but I wouldn't be surprised if the opposite could happen in some instances.

You know what I find amazing? That you have written literally dozens of paragraphs of text so far, and yet you haven't posted a single study that proves that the SSRIs are not neurotoxic at therapeutic dosages. Sorry to say, but talk is cheap.

 

[Cotcha Yankinov]

The burden of proof is on you, the one making the truth claim. Mind you that you also haven't provided evidence that SSRIs are clearly neurotoxic at therapeutic doses, while you seem to be hedging an agenda with your own mental illness and issues with SSRIs (that certainly don't need to be due to neurotoxicity or SSRI induced apoptosis)

Why would you think that your issues are to do with neurotoxicity?

The body of literature indicates that SSRIs often exert a protective and neurotrophic effect on the brain.

See for example

http://www.nature.com/mp/journal/v6/n6/full/4000947a.html?foxtrotcallback=true

"Finally, to determine whether fluoxetine affects programmed cell death, reflected morphologically as apoptosis, a TUNEL assay,17 which is intended to detect DNA fragmentation, one of the hallmarks of apoptosis, was carried out (Figure 2).

In the separation group, the number of TUNEL-positive cells per mm2 in the dentate gyrus was 220% higher than in the control group (Figure 3). In the fluoxetine-treated group, the number of TUNEL-positive cells per mm2 was decreased compared to the separation group, and it was close to that in the control (Figure 3).

A similar pattern was observed from supplemental caspase-3 immunostaining (data not shown). These results showed that fluoxetine might exert a preventive effect against apoptosis on neurons during maternal separation."

 

[Bravoncius Roxford]

QUOTE=Cotcha Yankinov;14095617]The burden of proof is on you, the one making the truth claim.[/QUOTE]

The burden of proof is on you. If you had read what I wrote, I merely suggested that the SSRIs are pro-apoptotic, and I provided studies done on nerve cells(not only hepatic or cancer cells) that indicated that the SSRIs have pro-apoptic effects. I also posted studies showing increased markers of brain inflammation. You, on the other hand, flat out stated that the SSRIs are safe to the brain at therapeutic doses. You are the one making the claim, not me.

Mind you that you also haven't provided evidence that SSRIs are clearly neurotoxic at therapeutic doses

I don't have to: I provided studies indicating the possibility that they are, which was my original claim.

while you seem to be hedging an agenda with your own mental illness and issues with SSRIs (that certainly don't need to be due to neurotoxicity or SSRI induced apoptosis)

First of all, I resent you stating that I have "mentall illness". That can almost be interpreted as ad hominem. Not quite, but alomost. Also, I don't have any "agenda" here. I suffer from depression, and I have to take medication. Consiidering the huge blunders the pharmaceutical industry has committed in the past(thalidomide, anyone?)you need to be extra-cautious. The FDA has a budget of only a billion Dollars or so, and it's not like they can do thorough in-depth research on all the thousands of drugs that are forwarded to them for approval every year.

Why would you think that your issues are to do with neurotoxicity?

I never claimned my issues are due to neurotoxicity. I had issues before taking any drug. The point is, SSRIs shouyld be taken only by the severely depressed as they have many side effects including very serious ones such as destruction of brain tissue. They are not toys. If you feel like blowing your brains out, then it is best to take them. After all, it's best to lose several million brain cells rather than all of them which is what would happen if you shot yourself in the head. But these are not candy like many peoploe think. The cost are high, so the benefit needs to be really high to make for a good cost-benefit.

The body of literature indicates that SSRIs often exert a protective and neurotrophic effect on the brain.

You seem to gloss over the fact that the neurotrophic effect of the SSRIs come as a result of the brain trying to protect itself from their neurotoxic effects. Like I said, they increase brain inflammation which is a sign of neurotoxicity.

See for example

http://www.nature.com/mp/journal/v6/n6/full/4000947a.html?foxtrotcallback=true

"Finally, to determine whether fluoxetine affects programmed cell death, reflected morphologically as apoptosis, a TUNEL assay,17 which is intended to detect DNA fragmentation, one of the hallmarks of apoptosis, was carried out (Figure 2).

In the separation group, the number of TUNEL-positive cells per mm2 in the dentate gyrus was 220% higher than in the control group (Figure 3). In the fluoxetine-treated group, the number of TUNEL-positive cells per mm2 was decreased compared to the separation group, and it was close to that in the control (Figure 3).

A similar pattern was observed from supplemental caspase-3 immunostaining (data not shown). These results showed that fluoxetine might exert a preventive effect against apoptosis on neurons during maternal separation."

Interesting study, but the doses given were too low.

 

[Cotcha Yankinov]

You, on the other hand, flat out stated that the SSRIs are safe to the brain at therapeutic doses. You are the one making the claim, not me.

You misquote me. I said that SSRIs aren't neurotoxins, which they aren't. Who cares if they produce apoptosis or neurotoxicity at extremely high doses in vitro, in vivo they don't function as neurotoxins. That isn't to say that they don't cause any neurodegeneration or apoptosis at all, but rather that any of those effects are not appreciable enough for scientists to have labeled it a neurotoxin.

I provided studies indicating the possibility that they are, which was my original claim.

I really only see the one study, which seems to imply that SSRI's deleterious effects in vitro are very weak on neurons compared to the target cancer cells. So I really haven't seen any evidence so far.


"Assessment of paroxetine cytotoxicity in primary mouse brain and neuronal cultures showed significantly lower sensitivity to the drug's pro apoptotic activity.

The high sensitivity to these drugs of the cancer cell, compared with primary brain tissue, suggests the potential use of these agents in the treatment of brain-derived tumors."

First of all, I resent you stating that I have "mentall illness". That can almost be interpreted as ad hominem. Not quite, but alomost. Also, I don't have any "agenda" here. I suffer from depression, and I have to take medication. Consiidering the huge blunders the pharmaceutical industry has committed in the past(thalidomide, anyone?)you need to be extra-cautious. The FDA has a budget of only a billion Dollars or so, and it's not like they can do thorough in-depth research on all the thousands of drugs that are forwarded to them for approval every year.

Whats wrong with admitting that depression is a mental illness?

For the record, there are a lot of (now) pharmacophobics who have had adverse reactions to meds. They typically grow very angry with pharma and tunnel vision on some molecular explanation for how the drug caused the adverse effects.

But it never does them any good.

I never claimned my issues are due to neurotoxicity. I had issues before taking any drug. The point is, SSRIs shouyld be taken only by the severely depressed as they have many side effects including very serious ones such as destruction of brain tissue. They are not toys. If you feel like blowing your brains out, then it is best to take them. After all, it's best to lose several million brain cells rather than all of them which is what would happen if you shot yourself in the head. But these are not candy like many peoploe think. The cost are high, so the benefit needs to be really high to make for a good cost-benefit.

Well I agree that SSRIs are mainly for the severely depressed but to go around worrying everyone about apoptosis might scare off some of the depressives who could benefit. I still don't get why you're so worried about apoptosis. You talk about "Destruction of brain tissue" like we're talking about meth or something.

In reality, SSRIs tend to reverse depression related atrophy of brain regions.

You seem to gloss over the fact that the neurotrophic effect of the SSRIs come as a result of the brain trying to protect itself from their neurotoxic effects. Like I said, they increase brain inflammation which is a sign of neurotoxicity.

Once again, completely outlandish claims with zero evidence..

SSRI's neurotrophic effects are mediated in different ways, but for example mediated through increased serotonin receptor activation that triggers downstream signaling cascades, resulting in release of neurotrophic factors like BDNF and sensitization of BDNF's receptor. Block the BDNF, block the antidepressant effect.

Even cardio increases BDNF and you wouldn't warn everybody about inducing apoptosis with cardio.

SSRIs tend to be anti-inflammatory. I personally don't recall much evidence that SSRIs are pro-inflammatory in the CNS in animals, I've mostly read the opposite. So if you'd like to post those studies, that would be great. The main concern would be activation of microglia, but SSRIs are microglial inhibitors. As a caveat, SSRIs aren't going to be anti-inflammatory 100% of the time, but it would be incorrect to label them as pro-inflammatory substances.

Interesting study, but the doses given were too low.

You don't seem concerned with dosages in your studies running high. We should aim to reflect the in vivo condition, so in vivo studies would be best.

I would encourage you to remember that brain cells die all the time and you trim away a crap ton all the time, especially during development even into the 20s. Its the ability of our brains to grow new connections and trim old faulty ones, so called neuroplasticity, that is the key to the brain's success. Boosting neuroplasticity and promoting synaptic remodeling is a lot of how antidepressants are supposed to work.

 

[Scrofula]

I thought that was a great paper, fwiw. This is the one with the evolution of serotonin receptors in mammalian brain, right, posted by our argumentative OP?

OP, please remember that programmed cell death (apoptosis) is necessary for things like existing. You know, having fingers and not flippers.

Likewise, sprouting neurons, or dendrites and axons all over the place, probably just causes seizures.


And, you know, OP you claim to "have depression" but not a mental illness? Disclosure: I've been taking an SSRI for far too long now (off an on for nearly twenty years, mostly off, solid run the last seven years). They are not ideal treatments, and I wish I was on something else. But by now, any apoptosis of swaths of brain tissue would be pretty apparent.

As for use only on the clinically depressed, is that a cohort SSRIs work on? More and more I've had the impression that they're given to folks like me, you know, just "sad" or anxious. Almost like placebo. I agree they're overprescribed by the millions. Really, I'd expect them to fade out totally as the monoamine theory of depression gets more and more retooled and more effective drugs come along.

Really, the idea you can dial your mood up and down with the concentration of a single transmitter was nuts to begin with.

 

[Vastness]

OP - the reason SSRIs are approved drugs, despite being obvious neurotoxins is because the government wants to keep us under control and docile by inducing minor brain damage in large swaths of the population. Happy now?

In case it's not obvious, I am being sarcastic. You admitted in your original post that you need help interpreting the "highly technical data", implying that you recognise that your own understanding of the science is not complete, and yet, since then, several people have tried to give you the help you asked for, and all you've done is try to tell them why their interpretation is not correct. If you are so sure already of the accuracy of your own understanding of the data, then why did you even bother to post?

 

[cr33py]

Id worry about the effects of depression on the brain before Id worry about the SSRIs.

 

[Scrofula]

^true. These things may be over-prescribed, but they aren't handing out samples to random people. Unwell people get them.

OP, I scanned this review again, and it just doesn't relate to SSRIs (also, I like it a lot less now). The whole point of the review was the yin yang function of the serotonin 1 and 2 receptors. He magically goes from tryptophan in chlorophyll to serotonin signalling in vertebrates. Then he magically goes from the pro-differentiation v. pro-division roles in development, to a pro- v anti-apoptosis role in human brains.

If you accept his hypothesis and take the simplest view of SSRI action, you'd see a modest increase in serotonin concentrations at both the 1 and 2 receptors. This should, in his model, result in nothing. He shows evidence that HT-1a is protective, and less evidence that HT-2a is pro-apoptotic (which is also protective, but in a different way), meaning that the two should balance and nothing happens.

What about MDMA blowing your brains right out of your skull, by activating HT-2a? I don't know, he doesn't say. Why wouldn't MDMA trigger all the other receptors, including the protective HT-1a? I didn't bother to look up the citations. His diagram mentions MDMA itself triggering HT-2a, but he then points out it's low affinity there, and in the ocean of released serotonin his model should predict it would have very little impact. He makes clear this only works in some parts of the brain anyway.

Relating the developmental role of serotonin in somatic cells (body cells as a fetus) to mature neuroplasticity is interesting, but not incredibly convincing, and a long way from being persuasive.

Really, I enjoyed going from chlorophyll to club drugs, until I really looked at what he had. Which turns out to be retconning or cramming his MDMA work into this overarching model. He's too ambitious. Plus his style is bad, including too much experimental detail in a review is annoying. You can breeze through 90% of his paper.

So OP, you're on a crusade anyway, but I wouldn't use anything from this paper to support your SSRIs kill brain cells stance. The serotonin-apoptosis connection is the weakest in there.

But I did go pretty fast, feel free to point out what I missed.