Breakthrough Study - Depression NOT treated by Serotonin-based Drug Regimen


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https://www.nature.com/articles/s41380-022-01661-0

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Despite the fact that the serotonin theory of depression has been so influential, no comprehensive review has yet synthesised the relevant evidence. We conducted an ‘umbrella’ review of the principal areas of relevant research, following the model of a similar review examining prospective biomarkers of major depressive disorder. We sought to establish whether the current evidence supports a role for serotonin in the aetiology of depression, and specifically whether depression is associated with indications of lowered serotonin concentrations or activity.

They did this study because someone finally realized that the serotonin based treatment had never produced any studies which verified any beneficial results from such treatment.  It was all theoretical based on chemistry alone, not actual observations of test subjects.  It is important to understand that the chemistry needs to be backed up by actual patient studies because of how complex the human body is -- especially the brain.  Offsetting mechanisms, system backups, chemical filters, reactionary operations of the body, drug tolerance, human behavior, etc. all contribute to how effective, ineffective, or counter-effective a chemical reaction may be.

The results say that they cannot confirm whether serotonin-based anti-depressants can actually treat depression.  Some studies show that they tend to have an opposite effect.

While it is preliminary, the findings are extremely surprising to the medical field.  More studies are required for confirmation and thorough understanding of the "why".  We'll see how this runs the course as the profession begins to wake up about this.

Edited by Carborendum
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  • Carborendum changed the title to Breakthrough Study - Depression NOT treated by Serotonin-based Drug Regimen
1 hour ago, Carborendum said:

They did this study because someone finally realized that the serotonin based treatment had never actually been studied.  It was all theoretical based on chemistry alone, not actual observations of test subjects.  

I'm wondering - can you quote anything from that link to support any of your three claims?

Because when I read through it, I see stuff like:

Quote

17 studies were included: 12 systematic reviews and meta-analyses, 1 collaborative meta-analysis, 1 meta-analysis of large cohort studies, 1 systematic review and narrative synthesis, 1 genetic association study and 1 umbrella review.

I mean, there are an awful lot of big words in the study that I don't understand, but I do know what the word "cohort" means.  It means 'a bunch of people'. 

Quote

Two meta-analyses of overlapping studies examining the serotonin metabolite, 5-HIAA, showed no association with depression (largest n = 1002). One meta-analysis of cohort studies of plasma serotonin showed no relationship with depression, and evidence that lowered serotonin concentration was associated with antidepressant use (n = 1869). Two meta-analyses of overlapping studies examining the 5-HT1A receptor (largest n = 561), and three meta-analyses of overlapping studies examining SERT binding (largest n = 1845) showed weak and inconsistent evidence of reduced binding in some areas, which would be consistent with increased synaptic availability of serotonin in people with depression, if this was the original, causal abnormaly. However, effects of prior antidepressant use were not reliably excluded. One meta-analysis of tryptophan depletion studies found no effect in most healthy volunteers (n = 566), but weak evidence of an effect in those with a family history of depression (n = 75). Another systematic review (n = 342) and a sample of ten subsequent studies (n = 407) found no effect in volunteers. No systematic review of tryptophan depletion studies has been performed since 2007. The two largest and highest quality studies of the SERT gene, one genetic association study (n = 115,257) and one collaborative meta-analysis (n = 43,165), revealed no evidence of an association with depression, or of an interaction between genotype, stress and depression. 

[bolding mine] I mean, all those N numbers refer to the number of individual humans involved in those studies.  

I'm failing to see how anyone could possibly think serotonin based treatment has never been studied.  Or that it was all theoretical based on chemistry alone, not actual observations of test subjects.

 

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no comprehensive review has yet synthesised the relevant evidence.

What this means, is that while we've been studying the holy living crap out of depression and brain chemistry, in and out of the lab, with a never ending tsunami of individual and group studies;  While we've even been doing meta-analyses of the studies, lumping many studies together and doing studies of the studies; while we've been doing all that for decades, nobody has made the effort to do a meta analysis  in order to "synthesise and evaluate evidence on whether depression is associated with lowered serotonin concentration or activity in a systematic umbrella review of the principal relevant areas of research". 

 

Edited by NeuroTypical
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4 hours ago, Carborendum said:

They did this study because someone finally realized that the serotonin based treatment had never actually been studied.

From a recent article

“Notwithstanding their key roles in therapy and as biological probes, 7% of approved drugs are purported to have no known primary target, and up to 18% lack a well-defined mechanism of action.“

The following is a screenshot of a medical app for the drug Colchicine, a well known and frequently used gout medication.  We know how some of it works, but not the EXACT mechanism.

2A6AEE4A-EC1E-4B3A-B3C3-60619C75FFA0.thumb.png.7310b59178c0a8ed2666a1d60713a612.png

For most drugs we don't know the exact mechanism.

 I see patients all the time that are on 10+ medications.  No one knows the chemical interactions that are occurring when multiple medications are floating around the system.

And then you add in pollution, genetic modification of our food products, etc…

I remember 20 years ago in med school when we were told that we needed to do a better job treating pain.  That nobody should ever be in pain. And that a patient’s perceived pain should be a vital statistic.  - Guess who started the current Narcotic epidemic.  Pain is no longer a vital statistic.  ( I never bought into that garbage anyway).

Be careful out there folks.

Edited by mikbone
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I guess if I were going to write something about this article, it would say something like "We all seem to believe that depression involves a chemical imbalance in the brain, but we aren't finding much support for that theory.  The jury is pretty much out that SSRIs and other serotonin-impacting drugs can and do have measurable impacts in mood, but we're now even at a greater loss to understand why."

4 minutes ago, mikbone said:

I see patients all the time that are on 10+ medications.  No one knows the chemical interactions that are occurring when multiple medications are floating around the system.

Yep, I'm a big fan of taking the absolute lowest number of meds you can.   My family just got over COVID last month.  One of us is still having some (minor) lingering side effects.  The doctor leveled with us, there's no way to be sure if it's leftover COVID symptoms, or symptoms resulting from the antiviral meds.  And while he's sure the symptoms aren't due to overtaking OTC cold medicines in our case, he's had no shortage of patients that keep drinking cough syrup like soda, and then come to him asking for help with the impacts of that decision.

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42 minutes ago, NeuroTypical said:

I'm wondering - can you quote anything from that link to support any of your three claims?

Because when I read through it, I see stuff like:

I mean, there are an awful lot of big words in the study that I don't understand, but I do know what the word "cohort" means.  It means 'a bunch of people'. 

I probably worded that poorly (I'll fix it).  Apologies.  Here are the interesting findings.  It wasn't that there has never been any study.  But that no studies conclusively determined that this was an effective treatment.

Quote

Two meta-analyses of overlapping studies examining the serotonin metabolite, 5-HIAA, showed no association with depression

One meta-analysis of cohort studies of plasma serotonin showed no relationship with depression, and evidence that lowered serotonin concentration was associated with antidepressant use.

Two meta-analyses of overlapping studies examining ...and three meta-analyses of overlapping studies examining ... showed weak and inconsistent evidence of reduced binding

One meta-analysis of tryptophan depletion studies found no effect in most healthy volunteers

Another systematic review (n = 342) and a sample of ten subsequent studies (n = 407) found no effect in volunteers. 

Quote

The two largest and highest quality studies of the SERT gene, one genetic association study (n = 115,257) and one collaborative meta-analysis (n = 43,165), revealed no evidence of an association with depression, or of an interaction between genotype, stress and depression. 

The conclusion:

Quote

Our comprehensive review of the major strands of research on serotonin shows there is no convincing evidence that depression is associated with, or caused by, lower serotonin concentrations or activity. Most studies found no evidence of reduced serotonin activity in people with depression compared to people without, and methods to reduce serotonin availability using tryptophan depletion do not consistently lower mood in volunteers. 

So, whatever it does or does not do, treatment using anti-depressants that are based on serotonin levels doesn't seem to work.

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Posted (edited)
36 minutes ago, mikbone said:

For most drugs we don't know the exact mechanism.

I've heard that before.  It kind of makes you wonder how much of modern medications are just snake oil. (No offense).

Admittedly, I know from personal experience that ibuprofen, aspirin, acetaminophen, and naproxen sodium all work wonders on my headaches.  But no one knows how that works either.

But this "study of studies" shows that no studies seem to indicate that the seratonin based treatment works at all.

Edited by Carborendum
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When I was younger, I had frequent depressive periods as well as occasional manic periods. 

When I was a teenager, my parents and several other adults in my life made it clear that I wasn't measuring up. People wanted to know what was "wrong" with me that I wasn't as they always expected me to be, and I was told that I needed to "get over" myself. I was constantly compared to Eeyore and told I just needed to "smile" more. 

It wasn't until a few years ago that relatives on my dad's side of the family explained that autism spectrum disorders ran in the family, and that only came out after *all* of my nieces and nephews were found to have spectrum-related disorders. 

As of two weeks ago, I myself... have officially been diagnosed as having been on the spectrum this entire time. I'm so high-functioning that I don't have any of the stereotypical behaviors, which is why quirks like "I get tired after long periods of social interaction", "I sometimes get overwhelmed in high stress situations and need to back away before I lock up", and "I've learned through trial-and-error that this is the best way to do something" were mistaken as something else or otherwise dismissed by people around me. 

In other words, all of the issues I was going through were the result of my having been on the spectrum and having never been tested because my parents didn't know what to look for. If I had been tested, I likely would have been pinged early (I was already pretty weird by the time I started school, and the head trauma from various misadventures didn't help any) and so I could have gotten the training and instruction I needed when I was a child. This would have helped me during junior high and high school when a lot of things were going wrong all at once, and likely would have better informed my choices as a young adult. 

Without that vital piece of information about the family history, I could have easily been doped up on Ritalin or some sort of other drug meant to make me "normal" but which didn't actually get to the root of the matter. As it is, the fact that I never got the diagnosis at an early age and never got the intervention meant that I basically lived my own personal hell, and it negatively impacted the way my life has turned out. 

So yeah, family history, environmental factors, head trauma, and so on... all of these need to be looked at in regards to mental health treatment. Just giving people drugs isn't always going to do it, and could make things worse. 

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10 hours ago, Carborendum said:
Quote

Most studies found no evidence of reduced serotonin activity in people with depression compared to people without, and methods to reduce serotonin availability using tryptophan depletion do not consistently lower mood in volunteers. 

So, whatever it does or does not do, treatment using anti-depressants that are based on serotonin levels doesn't seem to work.

Again, it's literally not saying what you are claiming.  I think you're totally missing the point of everything you're quoting. 

I can see nothing in this paper saying anything like "using anti-depressants that are based on serotonin levels doesn't seem to work".  There's nothing here looking at the effectiveness of various forms of treatment.  This isn't a paper about what happens when we try to treat depression.   There's nothing here looking at treatment effectiveness.  

This is a paper that looks at what we thought we knew about the biochemical causes of depression.   It talks about "whether tryptophan depletion (which lowers available serotonin) can induce depression".   Tryptophan depletion isn't a treatment for depression.   It's something they tried to see if it made people depressed.

It talks about how "there is no convincing evidence that depression is associated with, or caused by, lower serotonin concentrations or activity".   That's talking about depressed folks' serotonin levels.  It's not about what happens when we give depressed people a serotonin boost. 

It talks about how there is little "evidence of reduced serotonin activity in people with depression".   That's looking at the biochemistry of depressed people.  It's not talking about what happens when we try to treat depressed people to make them less depressed. 

There's some stuff indicating how depression treatment actually lowered serotonin levels, but again, it's not measuring effectiveness of treatment.  It's measuring serotonin levels.

Again, the jury has been pretty firmly out for a number of decades: Yes indeedily-doodilly, antidepressants that boost serotonin levels, clearly, unambiguously, proven in study after study, do indeed have an overall positive impact on mood.  Perfect?  Nope.  Always?  Nope.  100% reliable? Nope.  The best choice every time?  Nope.  Side-effect free?  Nope.  Never ever harmful? Nope.  But overall positive impact on mood? - you bet. 

 

Literally 10 seconds of googling:

1999 - NIH - Efficacy of SSRIs and newer antidepressants in severe depression: comparison with TCAs

2015 - Psychiatry Advisor - New Analysis Reconfirms Effectiveness of SSRI Antidepressants

2018 - The Lancet - Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis

2019 - Mayo Clinic: Selective serotonin reuptake inhibitors (SSRIs)

 

And another 10 seconds of searching the church website:

https://www.churchofjesuschrist.org/study/ensign/1989/02/mental-illness-in-search-of-understanding-and-hope?lang=eng
"Perhaps 90 percent of depression victims can be helped. Therapy that teaches the patient to modify negative thought patterns to change his emotions is very helpful. Antidepressant medications are also quite effective. Priesthood blessings and prayer can lend spiritual power and aid healing."

Elder Holland: https://www.churchofjesuschrist.org/study/general-conference/2013/10/like-a-broken-vessel?lang=eng 
"If things continue to be debilitating, seek the advice of reputable people with certified training, professional skills, and good values. Be honest with them about your history and your struggles. Prayerfully and responsibly consider the counsel they give and the solutions they prescribe. If you had appendicitis, God would expect you to seek a priesthood blessing and get the best medical care available. So too with emotional disorders. Our Father in Heaven expects us to use all of the marvelous gifts He has provided in this glorious dispensation."

https://www.churchofjesuschrist.org/study/ensign/2020/09/young-adults/i-finally-admitted-that-i-had-depression-jesus-christ-helped-me-out-of-the-darkness?lang=eng
"I have felt strength and hope and light come from both spiritual and temporal tools. Here are a few practices that bring light into my life each day that you can try too:
7. Don’t be ashamed to see a doctor or of taking antidepressant medications—these are tools Heavenly Father has provided for us to heal."

 

Edited by NeuroTypical
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4 hours ago, Ironhold said:

So yeah, family history, environmental factors, head trauma, and so on... all of these need to be looked at in regards to mental health treatment. Just giving people drugs isn't always going to do it, and could make things worse. 

Absolutely.  Please nobody mistake my posts as pushing antidepressants as a cure-all or critical component to dealing with mental illness.   They've been shown to be handy in some cases, critical in others, and overprescribed to fix normal life in others.

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8 minutes ago, NeuroTypical said:

Again, it's literally not saying what you are claiming.  I think you're totally missing the point of everything you're quoting. 

I think it is saying exactly what I quoted... because... I quoted it.

If there is a different point you think it is making I am not getting it from the study or your post.  Could you clarify?

8 minutes ago, NeuroTypical said:

I can see nothing in this paper saying anything like "using anti-depressants that are based on serotonin levels doesn't seem to work". 

Then what does this mean?

Quote

One meta-analysis of cohort studies of plasma serotonin showed no relationship with depression, and evidence that lowered serotonin concentration was associated with antidepressant use.

-----

8 minutes ago, NeuroTypical said:

This is a paper that looks at what we thought we knew about the biochemical causes of depression.   It talks about "whether tryptophan depletion (which lowers available serotonin) can induce depression".   Tryptophan depletion isn't a treatment for depression.   It's something they tried to see if it made people depressed.

I didn't say it was a "treatment".  I agree it was a method to see if it made people depressed.  But why?

Acute Tryptophan depletion has been shown to reduce serotonin levels in otherwise emotionally normal humans.  When they did so, they found (Just as you said) that it didn't result in any increase in depression symptoms.  So, if the method used was supposed to reduce serotonin levels.  And that condition didn't result in more depressed people, the conclusion was that lower levels of serotonin do not result in depression.

That is what the finding was.

8 minutes ago, NeuroTypical said:

It talks about how "there is no convincing evidence that depression is associated with, or caused by, lower serotonin concentrations or activity".   That's talking about depressed folks' serotonin levels.  It's not about what happens when we give depressed people a serotonin boost. 

It talks about how there is little "evidence of reduced serotonin activity in people with depression".   That's looking at the biochemistry of depressed people.  It's not talking about what happens when we try to treat depressed people to make them less depressed. 

There's some stuff indicating how depression treatment actually lowered serotonin levels, but again, it's not measuring effectiveness of treatment.  It's measuring serotonin levels.

These statements imply that this only works in one direction.  But the theory behind serotonin based therapy is that it works in both directions. 

  • Too little = depression
  • Increase it = cure depression

So, this study essentially shows that lower levels don't seem to be indicative of depression.  So, why do we think increasing the levels would cure it?

8 minutes ago, NeuroTypical said:

Again, the jury has been pretty firmly out for a number of decades: Yes indeedily-doodilly, antidepressants that boost serotonin levels, clearly, unambiguously, proven in study after study, do indeed have an overall positive impact on mood.  Perfect?  Nope.  Always?  Nope.  100% reliable? Nope.  The best choice every time?  Nope.  But overall positive impact on mood? - you bet. 

 As I said, this is preliminary.  We'll see how the medical field treats this.  Scientific truth must always be open to scrutiny.  If this is met with outright rejection without actually addressing the facts of these findings, we know something is up.  If it is met with "a healthy skepticism" then that would be a reasonable response when other studies (as you linked to below) show other findings.

8 minutes ago, NeuroTypical said:

The interesting thing I see here is that these also deal with just one side (i.e. the up, but not the down - as you alluded to before).  If there is a particular reason that this is a valid method of determining the validity of the treatment, I'd be interested in hearing what it is.

8 minutes ago, NeuroTypical said:

And another 10 seconds of searching the church website:

https://www.churchofjesuschrist.org/study/ensign/1989/02/mental-illness-in-search-of-understanding-and-hope?lang=eng
"Perhaps 90 percent of depression victims can be helped. Therapy that teaches the patient to modify negative thought patterns to change his emotions is very helpful. Antidepressant medications are also quite effective. Priesthood blessings and prayer can lend spiritual power and aid healing."

Elder Holland: https://www.churchofjesuschrist.org/study/general-conference/2013/10/like-a-broken-vessel?lang=eng 
"If things continue to be debilitating, seek the advice of reputable people with certified training, professional skills, and good values. Be honest with them about your history and your struggles. Prayerfully and responsibly consider the counsel they give and the solutions they prescribe. If you had appendicitis, God would expect you to seek a priesthood blessing and get the best medical care available. So too with emotional disorders. Our Father in Heaven expects us to use all of the marvelous gifts He has provided in this glorious dispensation."

https://www.churchofjesuschrist.org/study/ensign/2020/09/young-adults/i-finally-admitted-that-i-had-depression-jesus-christ-helped-me-out-of-the-darkness?lang=eng
"I have felt strength and hope and light come from both spiritual and temporal tools. Here are a few practices that bring light into my life each day that you can try too:
7. Don’t be ashamed to see a doctor or of taking antidepressant medications—these are tools Heavenly Father has provided for us to heal."

I understand your desire to cry foul when someone is saying "STOP TAKING ANTI-DEPRESSANT MEDS!"  I had hoped that my disclaimer about the study being preliminary was enough to attenuate that idea.  But I guess not.

As for the Church website articles, I am very persuaded by the words of wise men saying the best they know how.  But part of that is that they are depending on modern medicine knowing what they are doing.  And usually, I'd agree.  But we all know that medical science has turned on its heel on more than one occasion.

Is this issue one of them?  We'll see.

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So, I just had a discussion with my wife about this topic.  And she's further along the anti-med track than I am.  So, I think it was very easy for people to believe I was as far as her.  I'll try to remedy that by explaining here what I told my wife.  Eventually, she agreed.

The science of medication begins with a theory based on chemistry, biology, & biochemistry.  The theories need to be backed up by studies that show the efficacy of the medication in actual human beings.

There were enough studies that said that these medications provided significant numbers to state that these were valid methods of treatment.  However, with any medication, there are outliers.  Usually, fully approved drugs need to have a very low outlier percentage.  But many of the medications show numbers all over the board.  They are not 1% or 2%.  They range from 8% to 40% failure of these "outliers".

This is one reason why some medications must be prescribed by a competent physician.  If you happen to be one of the outliers, he can make a determination of whether to switch drugs or not... especially if you happen to have an adverse reaction to it.  Any mood altering drug must be carefully monitored to see how any given individual will react to the drug.

The theory behind most modern anti-depressants is that

  • Depression is caused by low serotonin levels.
  • Raising them through drugs will hopefully treat the depression.

The trials show the following:

  • Many people who take drug A show symptoms B.
  • Some outliers are always present.

What they don't show is:

  • Raising the levels of serotonin specifically was the mechanism by which the drug functioned to produce symptoms B.
  • How do we know that symptoms B is a sign of coming out of depression?  i.e. some of the symptoms can only be dependent upon the patient being honest about what they are feeling.  While they do a placebo control group, that is not nearly enough to determine the truthfulness of patients being treated with Drug A.

Even so, obviously SOMEthing is working.  Why else would we have a series of patients that seem to be getting on with their lives when treated with the drug? This one overarching symptom, to me, is the one true result that we can depend on.  Are they getting on with their lives?

The question then becomes, how can we verify that the serotonin was the trigger that helped them?  We only have theories based on our accepted knowledge of biochemistry.  Studies have been done in many cases in many ways to determine if this is really the mechanism.  And many of them seemed to say "no".  This is not what is causing the change.

The study I linked to in the OP was a study of studies.  What were the commonalities?  What were the procedures?  What were the results?  Etc.  The primary thing that they reported on was if we have a theory that X causes Y, then the converse would also be true.  But these studies found that Y is not caused by X in otherwise healthy individuals.  So, why do we still think that getting rid of X will cure Y?

My non-professional opinion is that when we see that these medications do work, there appears to be some other mechanism at work.  This would explain why some meds work on some patients, but not others; and all are at varying levels regardless of the level of depression or the change in serotonin levels of the patients..  The real cause of depression is Q, or R, or S, or T... depending on the patient.  And any individual drug may have a secondary effect that gets rid of Q.  Another has a secondary effect of diminishing R...  You get the idea.

So, while the medication in question may have some good effects that we're measuring, the mechanism of that medication may very well be something other than the current theory.  I'd like to know what the actual mechanism is so that we don't have such a long phase of "trial and error" before we get to the correct medication for the individual case.  If we knew, then we could actually look for the real cause (Q, R, S, T...) instead of assuming everyone is depressed because of X.

That sure would have helped me earlier in life.

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57 minutes ago, Carborendum said:

This is one reason why some medications must be prescribed by a competent physician.  If you happen to be one of the outliers, he can make a determination of whether to switch drugs or not... especially if you happen to have an adverse reaction to it.  Any mood altering drug must be carefully monitored to see how any given individual will react to the drug.
...
So, while the medication in question may have some good effects that we're measuring, the mechanism of that medication may very well be something other than the current theory.  I'd like to know what the actual mechanism is so that we don't have such a long phase of "trial and error" before we get to the correct medication for the individual case.  If we knew, then we could actually look for the real cause (Q, R, S, T...) instead of assuming everyone is depressed because of X.

That sure would have helped me earlier in life.

Makes perfect sense.

My wife was stable on the same med for 20+ years.  But when she and her doctor were trying different things, it was like the fourth thing they tried.  Two of them were "this just doesn't seem to be doing anything", the other one was "ok holy crap not sure who this person is but I'd like my wife back now please".  

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