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DucksNQuackers t1_iv6g79d wrote

But is it a cause or a symptom?

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dangil t1_iv75nnu wrote

The serotonin model is dead. Probably a symptom.

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dude2dudette t1_iv80mfh wrote

The Serotonin Model is probably only accurate for a subset of those with depression.

Depression itself may be a symptom, with multiple possible causes (a bit like how severe stomach pain could be caused by IBS, Crohn's, Endometriosis etc.)

There might be various neurochemical imbalances that each can cause the behavioural/cognitive outcome of 'Depression' (especially given the different subtypes of depression that exist)

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Able-Emotion4416 t1_ivb0b7k wrote

There are now tons of studies showing that it isn't necessarily an individual problem for the vast majority of people suffering from mental health. But a huge systemic and societal one. Studies after studies demonstrate that air quality is crucial to prevent depression and anxiety, that most homes and buildings have neurotoxic offgasing, that out-door air qualities in cities is even worse. And that the probability to suffer from depression and anxiety in this environment strongly increases. Same thing with artificial lighting, junk food, and lack of physical exercises...

It's time to work and intervene like animal biologists do. It's time to fix our environment and food. And make them suitable for human mental and neurological health, among others.

Time to choose building materials, food ingredients, and artificial lighting that enhance human health, not harm it. And really time to strongly improve outdoor air quality in cities... We can't continue to make individual people carry the costs and burden of grave societal mistakes...

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dude2dudette t1_ivb3d62 wrote

Behavioural/environmental mechanisms are certainly important. However, that doesn't exclude neurotransmitter mechanisms.

It could be that the environment causes neurotransmitter receptor activation changes (e.g., lived environment (work stress/poor living space/lack of exercise, etc.) modifying one's immune system could lead to opioid activation dysfunction, which could then lead to depressive symptoms - see Charles, Farias and Dunbar, 2020)

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dangil t1_iv80u4c wrote

Pro tip. It’s epilepsy

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40ozSmasher t1_iv76651 wrote

Could you elaborate?

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dangil t1_iv76vw5 wrote

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5299662/

https://www.psychologytoday.com/us/blog/charting-the-depths/201007/the-serotonin-theory-depression-is-collapsing

https://science.thewire.in/the-sciences/serotonin-model-depression-repeal/

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Grisward t1_iv7ozfc wrote

These articles are valuable components of the overall research still ongoing to understand mental health and related pharmacotherapies. They have value. They are not showing serotonin is unrelated to depression.

First “major depressive disorder” is substantially stronger diagnosis than more commonly diagnosed depression.

Second, even among this subset of patients, “SSRIs significantly reduced the Hamilton Depression Rating Scale.” Their initial overall finding was significant decrease in depression (on multiple measurement scales).

They also found increase in adverse episodes (30/1000 in treated versus 22/1000 placebo), which is a known risk with serotonin-related treatments. This risk should not be ignored, for sure. However that risk doesn’t erase the benefit of treatment in some patients, it adds a secondary factor. It is certainly valid for the authors (and other scientists and physicians) to have the opinion that the risks do not outweigh the benefits, however that isn’t the subject of the study, nor is that type of opinion factual. The risks of adverse events is higher in “major depressive disorder”, and so their opinion is based upon a very focused study that only includes the stronger depressive disorder.

The serotonin model is not dead, nor is new data showing it to be dead. The serotonin model is as yet incomplete. The benefits of treatment is not fully understood in concert with risks to each patient.

Edit: fixed typo “sowing” to “showing”. Oops.

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ampanmdagaba t1_iv7n1aw wrote

This study: n=37 with p=0.04 turning to something like 0.5 after removal of one outlier.

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IamreallynotaNPC t1_iv6jlsp wrote

If your body doesn't have a proper amount of the materials required to create serotonin will the body limit its release? If so that would be a symptom, but if the body has all it needs and still didn't release much then it would be the cause. Then I wonder how do you figure that out even...

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DucksNQuackers t1_iv6kp6j wrote

To further complicate things- does the body have the proper amount of materials, under the correct conditions, in the right location? Then, what if anything else is going on with depression in addition to the serotonin piece?

And so the rabbit hole goes. Love this stuff

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IamreallynotaNPC t1_iv6l5c7 wrote

Serotonin cannot cross the blood brain barrier either, so what is made in the body is used there, and what's made in the brain is used only there, which adds more pieces. It is good that we have some confirmation on one part though.

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mjbat7 t1_iv6ymuv wrote

Hijackingthe top comment for visibility. Copying comments from last time this was posted.

Probably could just ignore this result unless it's replicated.

"BPND was significantly reduced in the HC group (1.04±0.31 vs 0.87±0.24 , p < 0.001) but not in MDE (0.97 ± 0.25 vs 0.92 ± 0.22, ns)".

Those differences are apparently p-value significant, but the error bars overlap widely in each group.

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Grisward t1_iv7msd6 wrote

Can you describe “error bars” and why they are more important to you than the P-value? What metric would you want to see?

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mjbat7 t1_iv8rky6 wrote

I used the term 'error bars' to describe the +/- values in the listed results. Frustratingly so far I haven't been able to access the original article in full text, so I can't be sure exactly what those 'error bars' represent. Presumably they're quoting the standard error in the samples, in which case, there appears to be a lot of error in their samples, which suggests that each estimate would have wide confidence intervals, which may overlap. Obviously overlapping confidence intervals don't necessarily mean that the difference isn't real, but if they overlap widely you'd certainly be quite skeptical of the results.

More specifically, let's look at some of the data in the abstract.

In the pre-treatment groups, the baseline BPND was 1.04 +/-0.31 vs 0.97 +/- 0.25. Is this a statistically significant difference? I don't know, but my guess would be that it isn't. Post exposure, the two groups' BPND was 0.87 +/- 0.24 vs 0.92 +/- 0.22. is this a statistically significant difference? Once again, I don't know, but my guess would be that it isn't.

If depressed people weren't measurably different from healthy controls in the baseline or post-treatment measures, then the fact that there is a within-group difference in the healthy controls but not in the depressed patients is much less convincing and seems more likely to be a statistical fluke.

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Grisward t1_iv8ubsu wrote

I get what you’re saying, and to be frank I appreciate the skepticism, and the drive to reality-check the numbers. Sometimes the numbers are over- or under-stated, or not reasonable effects.

In this case the abstract actually says it’s a significant change:

> “was significantly reduced in the HC group (1.04±0.31 vs 0.87±0.24 , p < 0.001)”

They include the P-value. You’re right it’s hard to know what the +/- means, typically that’s standard deviation, and not reflective of confidence intervals. Literally the confidence interval at 95% by definition would be smaller than the difference, that is if it used the same model used by the test.

It’s a whole thing about reporting and displaying confidence intervals, versus standard deviations, etc. Sometimes it’s straightforward to report standard deviation, but is not reflective of whatever statistical model was actually used. Frustrating, but not usually an author issue, also a journal guidance issue.

Oh, and the reason standard deviation does not indicate whether effect size is significant is in part that it doesn’t account for the number of individuals, nor the actual statistical model. Standard deviation is a simple university summary.

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doctoreldritch t1_iv6cte0 wrote

So, question for our resident experts: to what extent was this already known? Obviously it's not totally new information since we prescribe SSRIs for depression, but does this tell us anything new or just confirm what we already suspected?

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DjangoUnhinged t1_iv6efbg wrote

It’s more confirmation, but it’s actually wild how little evidence actually exists - especially in humans - for a serotonergic deficiency in depression. Like there must be some link given the relatively decent efficacy or SSRIs, but the hard evidence is way thinner than most people realize.

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tornpentacle t1_iv6hasz wrote

SSRIs tend to have a rather broad binding affinity. Most of them bind not only to serotonin transporters, but also norepinephrine, dopamine, and 2,700 other things to a lesser degree. Especially curious are factors like agonism of the poorly-understood sigma receptors, which now seem heavily implicated in depression, and also the fact that many SSRIs have been demonstrated to affect NGF and/or BDNF, which modulate plasticity. So the action on serotonin may well be completely irrelevant. Since depression is a disorder of the default mode network, wherein (essentially) the channels of communication become so well established that it is very difficult to break free, there is a whole lot of chatter in the research community about how we are all but convinced now that the neuroplastic effects are more responsible for improving depression symptoms than anything to do with serotonin. But there is also a very compelling reason to believe sigma receptors might be involved, because many drugs known to work as rapid antidepressants share sigma agonism in common (and very little/nothing else).

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LysergioXandex t1_iv7ng0u wrote

Though the sigma receptors are unusually promiscuous, binding to a wide variety of chemical classes. So sigma receptor activity may just be a shared off-target.

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[deleted] t1_iv6iop4 wrote

The vast majority of mental health science has been guesswork and trial and error (at great cost to many who ended up more lab rats than patients).

It’s only the past few years that hard science has really entered the mix and we’re starting to understand how and why things work

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charliedontplaydat t1_iv6iqlk wrote

SSRI’s are so hit and miss because of the event observes for this study. If one doesn’t produce or release seratonin, there isn’t a point in making the nonexistent molecules float around longer before being reuptaken.

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westderecho t1_iv75d8g wrote

Serotonin releasing agents(or rather tri-amine releasing agents) were some of the first antidepressants ever made, and were extremely successful. Consequently they had some severe side effects, and also sometimes worked "too well"(causing euphoria) so they had a short lived existence.

Example being a-met

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jgj570s t1_iv6kpl6 wrote

There was a big meta-analysis a few months ago showing that there probably wasn’t a strong connection between decreased serotonin and depression. This study however is very small and questionable. I would bet my house that it was funded by companies that make SSRIs.

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Exact-Swan-3136 t1_iv6joaz wrote

I am trying to understand the mechanism of this experiment. They dosed rats with a dopaminergic substance (amphetamines), and then cut off half of them (to cause depression), and then they measured the differences in serotonin in each group? This would suggest serotonin deficiency is symptomatic. Was there a control group measured without any amping at all? Which brings me to my next question, could dopamine then reverse the depression? Instead of serotonin?

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LysergioXandex t1_iv7q46r wrote

I’ve only read the abstract.

First, this experiment was done in human patients (17 depressed, 20 healthy controls).
They give the amphetamine not to induce “depression” but to simulate dopaminergic stimulation, which activates serotonin-releasing neurons downstream.

They also administer a radioactive ligand for the serotonin 5-HT2a receptor, which is one of the “targets” of released serotonin. By measuring how much radioactivity is displaced after the amphetamine-induced serotonin flood, they can measure approximately how much serotonin must have been released.

I’m not in this field, but some questions this study raises for me include:

  • does depression alter the activity of amphetamine.
  • are 5HT2a receptors and Dopamine Transporters (amphetamine target) differently expressed in depression.
  • are the inhibitory autoreceptors for serotonin (eg 5HT1 a/b/d) expressed in different proportion to 5HT2a receptors in depression?
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TheToyBox t1_iv6mp8t wrote

Serotonin deficiency is actually super easy to research and replicate and has been for a long time with tryptophan depletion so I don't think that's the new part from this study.

Here's one but there's a zillion:

"Acute tryptophan depletion (ATD) is a well-established dietary method in translational brain research used to briefly lower central nervous serotonin (5-hydroxytryptamine (5-HT)) synthesis. A simplified two amino acid ATD formula (ATDPHE/LEU) was developed while reducing the overall amount of amino acids (AAs), with the objective of administration especially in children and adolescents in future studies."

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a_stoic_sage t1_iv6geui wrote

At the same time, haven't there been recent studies suggesting SSRI's may not work as intended and might be placebo effect?

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WilyStylyMethody t1_iv6h1xu wrote

I believe the most recent one I read posited that while it was unclear whether or not Serotonin re-uptake had a meaningful effect on depression, that there was still a change in neuroplasticity that made it easier for the brain to rewire(or repair?) certain neural pathways, which in turn made it easier for the patients to eliminate certain negative patterns associated with their depression.

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a_stoic_sage t1_iv6hp67 wrote

Can't placebo effect rewire or repair certain neural pathways? If you think you are feeling better, you are rewiring your brain?

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westderecho t1_iv76y9b wrote

SSRIs exert a neurogenic effect on the hippocampus and increase the amount of neurotrophic factors there, and also alter the count/ratio of certain serotonin receptors.

To my knowledge this behavior isn't readily found in placebo trials when comparing against SSRIs, and a placebo would not be able to target a certain region.

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WilyStylyMethody t1_iv6js8e wrote

That I'm not sure of. Hopefully someone more knowledgeable can chip in here.

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KaanyeSouth t1_iv6ntqh wrote

I think the study found that depression is not caused by low serotonin levels. So if ssri's do work, they dont know why. So yes it might be placebo, nobody knows atm.

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Possumsurprise t1_iv769hf wrote

I was under the impression that milder cases of depression may not be that responsive to SSRIs but with more severity a benefit becomes apparent.

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[deleted] t1_iv68v3r wrote

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LysergioXandex t1_iv7tl17 wrote

0.5 mg/kg seems like a big dose of amphetamine! A 150 lb person would receive >30 mg of dexamphetamine, which is a ton for a person who doesn’t take stimulants regularly (hopefully, for experimental control, none of the subjects are stimulant users).

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Dsjewell t1_iv76mha wrote

I’m looking for a real world explanation of this? Was it to say that ssri’s aren’t always helpful but methamphetamines are?

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