The Low Serotonin Cause Of Depression Is Finally Discredited

haidut

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We have know this for a while, but it is nice to see that after thousands of suicides caused by SSRI somebody finally decided enough is enough and used modern medicine's favorite tool (genetics) to discredit the idea that low serotonin is a cause of depression. I think the fact that drugs like tianeptine, which act in a manner directly opposite to SSRI, are helpful for depression should have discredited the low serotonin hypothesis long ago. But I guess unless genes get involved somehow medicine will just not take notice. Some notable quotes from the study:

http://www.medicalnewstoday.com/releases/281645.php

"...New evidence puts into doubt the long-standing belief that a deficiency in serotonin - a chemical messenger in the brain - plays a central role in depression. In the journal ACS Chemical Neuroscience, scientists report that mice lacking the ability to make serotonin in their brains (and thus should have been "depressed" by conventional wisdom) did not show depression-like symptoms."

"...Interestingly, the mice were compulsive and extremely aggressive, but didn't show signs of depression-like symptoms. Another surprising finding is that when put under stress, the knockout mice behaved in the same way most of the normal mice did. Also, a subset of the knockout mice responded therapeutically to antidepressant medications in a similar manner to the normal mice. These findings further suggest that serotonin is not a major player in the condition, and different factors must be involved. These results could dramatically alter how the search for new antidepressants moves forward in the future, the researchers conclude."

So, another key finding of the study was that low serotonin made mice resistant to stress, which is something Ray has mentioned many times - i.e. low serotonin prevents learned helplessness from stress!
 

Wilfrid

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Re: The low serotonin cause of depression is finally discred

@Haidut,

I'm not sure if tianeptine, which is often consider as a SSRE, is acting to a manner directly opposite to SSRI.

"....the first indication that tianeptine possesses a mechanism of action different to that of other classes of antidepressant was the finding that, upon acute and sustained administration, tianeptine decreased the extracellular levels of serotonin (5-HT) (86,87). At that time, this finding was hypothesized to be the consequence of a 5-HT re-uptake enhancement. It has been demonstrated that tianeptine also reduced both the number of transporter sites and their mRNA levels in the dorsal raphe nucleus (88). However, any facilitatory influence of tianeptine upon 5-HT re-uptake may be exerted indirectly rather than directly at 5-HT transporters, for which its affinity is low. Further, the validity of older data has been contested on the basis of technical limitations that could not be circumvented at that time (89). More recent investigations have shown that acute and long-term administration of tianeptine does not elicit any marked alterations (neither increases nor decreases) in extracellular levels of 5-HT in corticolimbic structures of conscious rats (89,90). From an electrophysiological point of view, sustained administration of tianeptine did not modify the spontaneous firing rate of serotonergic neurons in the dorsal raphe, nor did it modify the activity of postsynaptic 5-HT1A receptors nor the effectiveness of the terminal 5-HT autoreceptor antagonist in increasing the efficacy of the stimulation of the 5-HT pathway, despite prolonged treatment (90). Thus, the role of 5-HT in the mechanism of antidepressant efficacy of tianeptine is doubtful."

From: http://www.ncbi.nlm.nih.gov/pmc/article ... po=11.8421

Tianeptine seems to act more like a glutamate modulator according to this study.
And one of " the diiferent factors" could be perhaps the glutamate pathway.
What do you think about it?
 
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haidut

haidut

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Re: The low serotonin cause of depression is finally discred

Wilfrid said:
@Haidut,

I'm not sure if tianeptine, which is often consider as a SSRE, is acting to a manner directly opposite to SSRI.

"....the first indication that tianeptine possesses a mechanism of action different to that of other classes of antidepressant was the finding that, upon acute and sustained administration, tianeptine decreased the extracellular levels of serotonin (5-HT) (86,87). At that time, this finding was hypothesized to be the consequence of a 5-HT re-uptake enhancement. It has been demonstrated that tianeptine also reduced both the number of transporter sites and their mRNA levels in the dorsal raphe nucleus (88). However, any facilitatory influence of tianeptine upon 5-HT re-uptake may be exerted indirectly rather than directly at 5-HT transporters, for which its affinity is low. Further, the validity of older data has been contested on the basis of technical limitations that could not be circumvented at that time (89). More recent investigations have shown that acute and long-term administration of tianeptine does not elicit any marked alterations (neither increases nor decreases) in extracellular levels of 5-HT in corticolimbic structures of conscious rats (89,90). From an electrophysiological point of view, sustained administration of tianeptine did not modify the spontaneous firing rate of serotonergic neurons in the dorsal raphe, nor did it modify the activity of postsynaptic 5-HT1A receptors nor the effectiveness of the terminal 5-HT autoreceptor antagonist in increasing the efficacy of the stimulation of the 5-HT pathway, despite prolonged treatment (90). Thus, the role of 5-HT in the mechanism of antidepressant efficacy of tianeptine is doubtful."

From: http://www.ncbi.nlm.nih.gov/pmc/article ... po=11.8421

Tianeptine seems to act more like a glutamate modulator according to this study.
And one of " the diiferent factors" could be perhaps the glutamate pathway.
What do you think about it?

Yes, I have seen that study. That's why I did not call tianeptine an SSRE, but just said opposite activity to SSRI. There are several studies where tianeptine is compared to SSRI in terms of behavior and the rodents showed opposite reaction to a number of stressful stimulus when given tianeptine or SSRI. So, by opposite effect I meant that tianeptine seems to be a true anti-depressant while SSRI are an actual inducer of depression and helplessness. Ray has written that depression is a classic symptom of hypothyroidism and improving oxidative phosphorylation ameliorates depression. Here is a study that shows tianeptine does exactly that in the brain:

http://www.ncbi.nlm.nih.gov/pubmed/23325329

"...Deprived rats increased the immobility time, but tianeptine reversed this effect and increased the swimming time; the BDNF levels were decreased in the amygdala of the deprived rats treated with saline and the BDNF levels were decreased in the nucleus accumbens within all groups; the NGF was found to have decreased in the hippocampus, amygdala and nucleus accumbens of the deprived rats; citrate synthase was increased in the hippocampus of non-deprived rats treated with tianeptine and the creatine kinase was decreased in the hippocampus and amygdala of the deprived rats; the mitochondrial complex I and II-III were inhibited, and tianeptine increased the mitochondrial complex II and IV in the hippocampus of the non-deprived rats; the succinate dehydrogenase was increased in the hippocampus of non-deprived rats treated with tianeptine. So, tianeptine showed antidepressant effects conducted on maternally deprived rats, and this can be attributed to its action on the neurochemical pathways related to depression."

And here is another study that compares tianeptine to a known SSRI and again tianeptine improved the energetic pathways while the SSRI suppressed it in most of the cases.

http://www.ncbi.nlm.nih.gov/pubmed/22659397

"...The creatine kinase was increased in the prefrontal cortex with tianeptine and in the amygdala with imipramine after acute treatment; chronic treatment increased the creatine kinase activity in the hippocampus with imipramine and tianeptine. The complex I activity was decreased in the prefrontal cortex with imipramine and increased in the hippocampus with tianeptine. The other complexes were increased with imipramine and tianeptine at all doses, but were related to the treatment given and the brain area studied. Chronic treatment increased the malate dehydrogenase activity in the amygdala with tianeptine. Acute treatment decreased the succinate activity in the prefrontal cortex, hippocampus and amygdala with tianeptine; chronic treatment increased the succinate activity in the hippocampus with tianeptine at all doses. In conclusion, tianeptine exerted antidepressant-like behavior which can be attributed to its effects on pathways related to depression, such as BDNF and metabolism energy."

And finally, one study showing beneficial effect of tianeptine on several markers of oxidative stress, especially catalase (CAT).

http://www.ncbi.nlm.nih.gov/pubmed/23036485
 

Wilfrid

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Re: The low serotonin cause of depression is finally discred

Thanks for the reply, Haidut. I misunderstood you in the first place and I'm sorry to being vague in my response too.
The increased level of succinate dehydrogenase probably enhance the ATP synthesis thus providing some relief from depression in rodents.
My point was to outlined that things are confusing as tianeptine doesn't probably act as a SSRE drug in rodents and propably act in a different ways as proved by the studies you posted ( including the one I posted too) but some studies made on humans appear to say that tianeptine work indeed like an SSRE by lowering free plasma serotonin (f-5ht) while enhancing platelets serotonin (p-5ht):

http://libgen.org/scimag/get.php?doi=10 ... 005.10.013
 
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haidut

haidut

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Re: The low serotonin cause of depression is finally discred

Wilfrid said:
Thanks for the reply, Haidut. I misunderstood you in the first place and I'm sorry to being vague in my response too.
The increased level of succinate dehydrogenase probably enhance the ATP synthesis thus providing some relief from depression in rodents.
My point was to outlined that things are confusing as tianeptine doesn't probably act as a SSRE drug in rodents and propably act in a different ways as proved by the studies you posted ( including the one I posted too) but some studies made on humans appear to say that tianeptine work indeed like an SSRE by lowering free plasma serotonin (f-5ht) while enhancing platelets serotonin (p-5ht):

http://libgen.org/scimag/get.php?doi=10 ... 005.10.013

I am beginning to wonder if the lower plasma 5-HT is a cause or a result of relieved depression. If tianeptine boosts oxidative metabolism in the brain that will actually lead to increased serotonin uptake and lower 5-HT levels overall due to increase formation of HIAA and excretion. So the so-called "SSRE" may be a result/symptom of improved metabolism rather than a true mechanism of action for tianeptine. I think a good study would be administering tianeptine and something that inhibits oxidative phorphorylation. If tianeptine still lowers plasma 5-HT then it probably is an SSRE. Otherwise, the SSRE would likely be an effect of better metabolism. However, I doubt that anybody would design such a study in humans since it would be considered highly unethical. Also, if it turns out that tianeptine does lower plasma 5-HT (thus relieving depression) then it would be another heavy blow against the SSRI class of drugs.
 

BingDing

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Re: The low serotonin cause of depression is finally discred

It's interesting that study was reported in a medical context even though the study is from a science journal. I read this today in one of Ray's articles

People have told me that when they looked for articles on fructose in PubMed they couldn't find anything except articles about its bad effects. There are two reasons for that. PubMed, like the earlier Index Medicus, represents the material in the National Library of Medicine, and is a medical, rather than a scientific, database, and there is a large amount of important research that it ignores. And because of the authoritarian and conformist nature of the medical profession, when a researcher observes something that is contrary to majority opinion, the title of the publication is unlikely to focus on that. In too many articles in medical journals, the title and conclusions positively misrepresent the data reported in the article.

And thanks for the discussion about tianeptine. My new doctor had never heard of it so I bought some online. Still researching it before I try.
 

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Re: The low serotonin cause of depression is finally discred

I don't think tianeptine is available in the U.S.. A psychologist at my work had never heard of it either and even though they don't prescribe meds they usually have to know a bit about them to deal with their clientele.
 

Wilfrid

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Re: The low serotonin cause of depression is finally discred

@Haidut,

Thanks again for your response.
Do you think that, for example, aspirin ( probably in a dose dependent manner) could qualify as an oxidative phosphorylation inhibitor?

http://www.ncbi.nlm.nih.gov/pmc/article ... p00344.pdf

I also read that utilization of salycilates inhibit succinate dehydrogenase and alpha-ketoglutarate dehydrogenase among other ATP promoting substances.
Is aspirin by opposing tianeptine's positive effect on brain oxidative metabolism should be avoid?

Then aspirin is working by a completely different and antagonist mechanism (ie by lowering brain capacity of oxidative metabolism) by inhibiting ATP promoting substances like succinate dehydrogenase.
If so, does someone with depression ,or with any sickness involving excess serotonin, should avoid substances like aspirin?


@Blossom and BingDing,

You should be able to order pure tianeptine powder from this retailer:

http://nootropicsdepot.com/other-nootropics/

:D
 
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haidut

haidut

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Re: The low serotonin cause of depression is finally discred

Wilfrid said:
@Haidut,

Thanks again for your response.
Do you think that, for example, aspirin ( probably in a dose dependent manner) could qualify as an oxidative phosphorylation inhibitor?

http://www.ncbi.nlm.nih.gov/pmc/article ... p00344.pdf

I also read that utilization of salycilates inhibit succinate dehydrogenase and alpha-ketoglutarate dehydrogenase among other ATP promoting substances.
Is aspirin by opposing tianeptine's positive effect on brain oxidative metabolism should be avoid?

Then aspirin is working by a completely different and antagonist mechanism (ie by lowering brain capacity of oxidative metabolism) by inhibiting ATP promoting substances like succinate dehydrogenase.
If so, does someone with depression ,or with any sickness involving excess serotonin, should avoid substances like aspirin?


@Blossom and BingDing,

You should be able to order pure tianeptine powder from this retailer:

http://nootropicsdepot.com/other-nootropics/

:D

I think the effects of aspirin are dose-dependent (I know, I have a firm grasp of the obvious). Someone posted a study that showed the optimal dose of aspirin for stimulating metabolism is 1.5g initial dose and then 500mg every 4 hours after that. Higher doses, like Ray wrote, would direct metabolism towards producing heat and not ATP. I think this is the reason people with cancer need to take 6g+ of aspirin a day - i.e. it is toxic to cancer cells mitochondria and since it also inhibits lipolysis, cancer cells starve (if Ray is right that cancer cells prefer to burn PUFAs). Of course there are the effects on prostaglandins and estrogen, and those two are causative in cancer, so my understanding is not complete by any means but I think there is a good reason why cancer prevention requires lower doses of aspirin and cancer "management" needs much higher doses.
Ray wrote that he sometimes takes 500mg of aspirin and other times "just a little", and that for most people taking a little aspirin (probably <500mg a day) every other day is sufficient for cancer prevention. Finally, the antidepressant effects of aspirin in the study were seen at about 500mg daily dose (human). So, yet another data point that shows aspirin megadosing is probably not warranted except in cases of cancer or very serious fibrosis of some tissue.
Just my 2c.
 

jyb

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Re: The low serotonin cause of depression is finally discred

haidut said:
Ray wrote that he sometimes takes 500mg of aspirin and other times "just a little", and that for most people taking a little aspirin (probably <500mg a day) every other day is sufficient for cancer prevention.

Talking about aspirin...what would you do if you catch a cold and sore throat and have fever coming? Assuming aspirin reduces fever and keeps temperatures below fever level.

On one hand, fever in that instance is inflammation that seems useful for healing. On the other hand, it's not intuitive why something fundamentally beneficial like aspirin would not help. And lowered fever means less pain, yet one of Peat's lessons is that healing, raising metabolic rate, health...rarely involves pains, to the contrary.
 
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haidut

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Re: The low serotonin cause of depression is finally discred

jyb said:
haidut said:
Ray wrote that he sometimes takes 500mg of aspirin and other times "just a little", and that for most people taking a little aspirin (probably <500mg a day) every other day is sufficient for cancer prevention.

Talking about aspirin...what would you do if you catch a cold and sore throat and have fever coming? Assuming aspirin reduces fever and keeps temperatures below fever level.

On one hand, fever in that instance is inflammation that seems useful for healing. On the other hand, it's not intuitive why something fundamentally beneficial like aspirin would not help. And lowered fever means less pain, yet one of Peat's lessons is that healing, raising metabolic rate, health...rarely involves pains, to the contrary.

I guess if you take a lot of aspirin, you can replace one fever with another:): If you uncouple the mitochondria you will produce more heat but the fever from the cold would be gone.
I am not sure I understand the last part of your post. You say "And lowered fever means less pain, yet one of Peat's lessons is that healing, raising metabolic rate, health...rarely involves pains, to the contrary." So are you saying Peat is saying healing involves pain or no pain? Or do you mean lowered fever means more pain?
 

SaltGirl

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Re: The low serotonin cause of depression is finally discred

As positive it is to see more research done into serotonin and what it really causes, I believe mainstream will dismiss this with the usual arguments as "Just one study", "These were mice, not humans", etc etc.
 

Wilfrid

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Re: The low serotonin cause of depression is finally discred

SaltGirl said:
As positive it is to see more research done into serotonin and what it really causes, I believe mainstream will dismiss this with the usual arguments as "Just one study", "These were mice, not humans", etc etc.

I think that's an unfair statement.
I was myself very badly treated by mainstream medical treatment for my crohn's and I , in general, have no affinity and no compassion for them.
However, it's a fact that, in general too, rodents are not humans.

«Most in vivo basic research is performed on rodents with the hope that some of it will have a positive impact on human health. Some treatments effective in the mouse model have proven to be ineffective in man. Conversely, those found to be ineffective in mice never get the opportunity to be tested in man.

Man is a diurnally active-nocturnally resting animal. Mice and rats are exactly the opposite, i.e., nocturnally active-diurnally resting. Research commonly is performed by diurnally active humans working during the diurnal phase on rodents. This, however, is when the research subjects are in their resting phase, being nocturnally active animals. In a general sense, it is not logical to expect data obtained from resting animals to be transferable to active humans. A more logical transfer from mouse to man would be expected if the research was carried out during the rodent's active period (nocturnal phase): active to active (even resting to resting) transfers are more scientifically valid than resting to active or active to resting transfers. One way to avoid the common pitfall of obtaining data from resting animals (diurnal phase) is to perform the research during the rodent's nocturnal (active) phase. This means working at night or with the animals synchronized (takes 10–14 days) to a reversed 12:12 L:D (light:dark) cycle so that their nocturnal (active) period coincides with the diurnal period for the researcher. When this is done, one should work in low red light, which is not visible to rodents.

The following scenario indicates some of the problems associated with working on resting animals during their diurnal phase and transferring the data to the diurnally active human. The scenario presented is a general one, but it has its origin in the well-documented field of chronotoxicology/chronopharmacology (Reinberg, 1992). A chemical food additive is tested in a mouse model for carcinogenicity. The test is done when the susceptible biochemical event (e.g., rate of DNA synthesis) happens to be at its lowest (trough) activity, i.e., 1200 (mid-diurnal or resting phase). No cancers are produced. The data are accurate: exposure to the chemical at 1200 did not result in any cancers. The data are used to classify the chemical as non-carcinogenic and it is approved for use as food additive. However, if the same dosage of the same chemical had been tested at 2400 (mid-nocturnal or active phase), a time of maximal susceptibility of the biochemical event involved, 40% of the animals would have developed liver cancer and the compound would be classified as carcinogenic and unsafe. For human safety it becomes extremely important to test for carcinogenicity/toxicity of a compound when the mouse is at its most biochemically susceptible time (could be mid-night, a time of maximal DNA synthesis) to that compound, not when the mouse is at its most resistant time (could be noon, a time of minimal DNA synthesis). Only in this way would the carcinogenic/toxic potential of the compound be discovered. To test a food additive, which in reality is highly carcinogenic/toxic, during a specific point in the host's circadian system when the true carcinogenic/toxic potential of the compound is “hidden” by biological time is inappropriate, misleading, and dangerous.»

Quote from the link below:
http://onlinelibrary.wiley.com/doi/10.1 ... 5(20000815)261:4%3C141::AID-AR3%3E3.0.CO;2-C/full

It sounds reasonable that the same scenario described above apply to any drugs (whatever is it) first tested on rodents and then transfered on humans.
Like we can't ignore the first study/experiment made on human that , few years after the "discovery" of the EFA deficiency ( made on rats ) by Burr, disproved the EFA deficiency mechanism. It can't be one way of thinking.
We should not ignore the work of some scientist, like the one I quoted above, that proved rodent's drugs metabolism ( due to their circadian rythm ) are different from human's metabolism.
And it should not be too surprising that rodent's hormonal secretions and reactions toward human's provocated exogenous stress situation are probably a lot more different than you or me...'
As Haidut said so well in response to the study ( made on humans) I posted: "a good study would be administering tianeptine and something that inhibits oxidative phorphorylation."
And it should apply to humans as well as for rodents. :2cents

Other possibilities for depression are also folate deficiency (it's pretty well documented in humans) and / or B12 deficiency ( particulary the role of Adenosylcobalamin in NO scavenging and dopamine enhancing effect) ect....
Some " mainstream" scientist are still working to disproved that low serotonin is the only cause of depressive disorders.
 

SaltGirl

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Re: The low serotonin cause of depression is finally discred

I am not saying we should ignore it or even discredit it. I am more expressing my utter lack of faith in the medical establishment when faced with evidence like this and what will probably be what the pseudoskeptics will argue. That even if we have a few mainstream scientists fighting for the truth there is an army of inducted people who will scream them away.

Of course, I am still a little embittered after how the masses managed to get TED to screw with Sheldrake's talk. :)
 

Wilfrid

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Re: The low serotonin cause of depression is finally discred

That's true, a lot of ( and ,unfortunately, often the most influent ) scientist in the medical establishment have a gift to screw up ( usually by using mass media communication ) every new hypothesis that will discredite their own knowledge.
But there is sometimes a very good indicator of their ignorance about a specific subject.
I found myself as a patient that when you told them about new therapy and/or treatment ( that they are not aware of), they quickly became angry and/or often disrespectful.
Their ego could sometimes cost a human life...and that's the sadest part of the story.
But I think, and I hope, that a new generation of some young scientist, with a fresher and newer insight on disease management and treatment, are emerging.
And I know that we have at least some of them on this forum that fit the description above.. :D
 

Blossom

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Re: The low serotonin cause of depression is finally discred

Bump for kenobi. :bump
 

burtlancast

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Re: The low serotonin cause of depression is finally discred

Wilfrid said:
I found myself as a patient that when you told them about new therapy and/or treatment ( that they are not aware of), they quickly became angry and/or often disrespectful.
Their ego could sometimes cost a human life...and that's the sadest part of the story.

That's a good observation, and sadly, it's very common in all fields of the medical profession.
 

Mito

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Here is another one...
Serotonin and Depression: A Disconnect between the Advertisements and the Scientific Literature

"Research has demonstrated that class-wide SSRI advertising has expanded the size of the antidepressant market [3], and SSRIs are now among the best-selling drugs in medical practice [2]."

Attempts were also made to induce depression by depleting serotonin levels, but these experiments reaped no consistent results [9]. Likewise, researchers found that huge increases in brain serotonin, arrived at by administering high-dose L-tryptophan, were ineffective at relieving depression [10].

Serotonin researchers from the US National Institute of Mental Health Laboratory of Clinical Science clearly state, “[T]he demonstrated efficacy of selective serotonin reputation ke inhibitors…cannot be used as primary evidence for serotonergic dysfunction in the pathophysiology of these disorders” [12].

The incongruence between the scientific literature and the claims made in FDA-regulated SSRI advertisements is remarkable, and possibly unparalleled.
 
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haidut

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possibly unparalleled

...and possibly criminal. I think Pfizer is currently getting sued in class action type for its SSRI for "permanent sexual dysfunction".
 

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