The serotonin theory of depression: a systematic umbrella review of the evidence, Moncrieff et al, 2022

[Arvo]

A newspaper article on this review and the Royal College of Psychiatrist's response to it are discussed here.

 

[cassava7]

I’m not sure whether Moncrieff et al touched on this in their article, but a meta-analysis of three large genome-wide association studies (246,363 cases and 561,190 controls in total) did not find evidence for a role of serotonin-associated genes in depression, despite identifying 87 variants after correction for multiple comparisons in both these studies and an independent cohort of 414,055 cases and 892,299 controls:

An intriguing omission among the depression-associated genes identified in our study are genes linked with the serotonergic system, such as the serotonin transporter SLC6A4; the G protein subunit GNB3; the serotonin receptor HTR2A and tryptophan hydroxylase (TPH2). This is surprising, as interaction with the serotonergic system forms the basis of most antidepressant treatments.

Our finding could indicate a functional separation between genetic pathways of depressive disease and pathways of antidepressant treatment. Thus, serotonin-associated genes, while potentially relevant for predicting efficacy and adverse effects of serotonergic antidepressants, may not be directly associated with the aetiology of depression itself (or at least that which is determined by common genetic variation identified in GWAS).

Indeed, a recent review of the genetics studies of depression has remarked upon the failure to demonstrate association with depression for serotonergic and other popular candidate genes 49.

It may also be that the pathways of depression and serotonergic antidepressant effect are separate but entwine through common intermediary genes. One such candidate is NRG1, identified here in depression, and also in a recent meta-analysis of antidepressant response 50.

These findings suggest that there is potentially a need to concurrently model a range of ‘omics data, including genomics, epigenomics, and transcriptomics to gain further understanding of depression pharmacology.

 

[rvallee]

Sure, but it did not validate expectations so what are scientists supposed to do here? The claims have been made, faces have to be saved, careers must be protected, funding must be preserved, history is written by the victors!

 

[rvallee]

The reaction from psychiatrists is interesting, and says a lot about how things are so dysfunctional, how the involvement of psychiatry in chronic illness is toxic at any level, there is simply no safe level because it's too arbitrary. It mostly seems to boil down to: we already knew this, privately, so saying it publicly is not useful. Very similar to how deconditioning has been debunked, but even though it's the basis for GET, GET should still work.

So with the hypothesis debunked publicly, it seems that holding on to trials showing effectiveness is all that's left. Except their evidence is also poor, unreliable, biased and usually restricted to short-term, which is not how it's used in real life. It's also been known that the effectiveness of SSRIs has diminished over time. Not coincidentally: exactly like CBT. And placebo. Because at first you can show big effects, then as you have to do slightly more rigorous studies, bias reduces a bit and that "effectiveness" disappears.

It really seems to boil down to the idea that true or false, the most important thing in medicine is to appear in control, being confidently incorrect is OK, as long as no one is embarrassed. Very political, in a nutshell. There's even the same name-calling and "this person is biased because they disagree with 'common wisdom'" and anti-psychiatry.

This is one opinion but it has all the hits: The serotonin hypothesis of depression: A meaningless debunking.

The serotonin hypothesis of depression, which became popular from the 1990s until now, is false, and has been known to be false for a long time, and never was proven to begin with.
...
The review paper merely documents the absence of much if any scientific evidence for these oversimplified false hypotheses. So it’s not new scientifically at all.
...
The use of SRIs should be based solely on the efficacy data shown for those agents in randomized clinical trials. Those data are indeed weak, and thus, I hold the view that SRIs should be used much less than they are, and for shorter durations, but this view has nothing to do with the already known false concepts of a serotonin theory of depression.
...
“‘Depression’, as commonly conceived, is not a disease; it is a set of symptoms, like fever, chills and night sweats.​

The irony of most physicians believing that CFS is actually depression because CFS is just a set of symptoms, therefore not a real condition, but are OK with the most completely vague definitions of depression and anxiety. Anyway this is one psychiatrist's opinion, there are many different opinions, because basically this is all a set of opinions, rooted in 19th century bigotry and attributing superficial behavior to preferred causes just because.

It's weird to use those symptoms, fever, chills and night sweats. I don't think they have much to do with depression. Chills and night sweats are definitely common side-effects of SSRIs, though. So this is like a vision of cancer that focuses on the side-effects of chemotherapy. So much wrong here.

I do agree that depression is more likely a symptom, not a unique condition, but the idea that it itself has sub-symptoms is the same silliness that made ME into fatigue and subsumed all symptoms as sub-symptoms of fatigue. Symptoms do not have sub-symptoms, this is nonsense. They are simply co-morbid, similar to how flu-like symptoms is a set of symptoms.

It's easy to see how similar this is to arguments being made about why GET is still good even if the lack of evidence for deconditioning were accepted. The problem is not about specific claims or treatments, it's a discipline in crisis, having made empty promises and mislead everyone for too long, just because secrecy can be abused to hide the truth.

 

[Sly Saint]

Merged thread

BBC article: Did we all believe a myth about depression?

A study showing depression isn't caused by low levels of the "happy hormone" serotonin has become one of the most widely shared medical articles.

It has provoked a wave of misleading claims about antidepressant drugs, many of which increase the amount of serotonin in the brain.

This research doesn't show the drugs aren't effective.

But the response to it has also sparked some genuine questions about how people treat, and think about, mental illness.

https://www.bbc.co.uk/news/health-62286093

 

[rvallee]

Happy hormone? That's usually said of dopamine. Even though it does a frackton of things. And serotonin plays many roles, including immunological. Maybe trying to reduce complex biochemical processes to a single output is a bad idea? Just saying.

Because frankly I don't see how this nonsense isn't just a foolish extension of the humours. It's not any smarter to attribute them to small stuff, hormones or some magical "correct" brain "wiring", than it is to big stuff, like whole organ systems.

This whole infantilization thing in medicine is extremely lousy. I don't think myth is the right word, it's been a fraud, a con. Because in mental healthcare, "an" explanation is all that matters. We see this excessively in the whole MUS/FND thing, where they seem obsessed with the idea that the solution is just finding the perfect combination of words that explain all of it away.

It doesn't even have to relate to the issue at all or anything to do with the patient. This is the same problem underneath: standards so low that lies pass through far more easily than the truth. In fact standards where telling the truth is a radical act, especially when the lie has been said too much to admit it was false all along.

 

[rvallee]

CBT Watch: Antidepressants and CBT in The Real World
http://www.cbtwatch.com/antidepressants-and-cbt-in-the-real-world/

Pies and Dawson (2022) have today taken up the cudgel to attack the findings of Moncrieff et al (2002) that were the springboard for the podcast. But they are disingenuous in claiming that no one of academic credibility has ever suggested that low serotonin causes depression. For decades, at least in the UK this has been the dominant message given to patients, with the implication that they need antidepressants to restore the chemical imbalance.

A lot of this is hush, there's probably a lot of discussion happening privately that isn't said publicly, but again the assertion that no one believed it (thus making it a Big Lie), and I guess there will be a general pretense that patients were never told this, even though of course this has long been the primary claim, because "an" explanation is needed. This has long been the general message in Canada, too. All about this unexplained, unevidenced chemical imbalance, all derived from SSRI trials (pragmatic trials, from which cause cannot be inferred, the same sin as with PACE).

I don't even see how this "chemical imbalance" is any more plausible than any nonsense about toxins or karma. Imbalanced how? Caused by what?

Pies and Dawson (2022) have recourse to a biopsychosocial model which posits interactions of thoughts, feelings, social factors and biology, in which will be found some biological factor that is of key importance in the development of depression and through which antidepressants will be found to work.

But none of this explains why perfectly happy people should develop it. Of course the most likely explanation is that it has nothing to do with thoughts, and is probably immunological since when in doubt it usually is, but this has always been brushed aside explicitly using the lie of "chemical imbalance".

In fact this has long been an issue with describing severe clinical depression, how it shows that the chemical imbalance can be significant, even in people who otherwise have ideal psychosocial circumstances, will even say they have no reason to feel this way and this is where the BS explanation played a major role in batting away falsification.

If it's a mix of bio and psychosocial, in circumstances where the psychosocial is ideal, this is where the bio is emphasized, the Big Lie of chemical imbalance. Otherwise the psychosocial is emphasized, and the false bio explanation is added to give more credibility, because to most people it doesn't make any more sense than the imaginary cycle of thoughts and deconditioning makes sense to pwME.

BTW most of the attacks I see are personal attacks about the author, with most of the excuses being about how the trials show it works, even though as we know, those trials are mostly unreliable. That may be fair, but someone can be wrong about some things and right about others, it's just a big tell when the main line of attack is strictly about character, not substance. Especially when the substance is admitted, simply excused away with more BS. Making those attacks even odder.

The combination of this and bungling the pandemic (and probably another if monkeypox is bad) will have massive repercussions in the future. Experts aren't supposed to screw up this badly. It's the excessive arrogance, the need to have "an" explanation and simply flash authority to quell dissent, that did it. The need to be confidently above being correct.

 

[Arnie Pye]

I have been diagnosed as depressed and/or anxious many times throughout my life. Over the course of the last 10 years I have found my own solutions to curing my depression and anxiety, and I wouldn't take a prescribed anti-depressant if you paid me.

One of the things that always puzzles me about the "chemical imbalance" theory of depression is that is that in all the years I was encouraged to take anti-depressants of any kind absolutely nobody suggested my serotonin should be tested.

Also, balance and imbalance bring to mind kitchen scales. There are two things involved - something to be weighed and something to balance it with. So, with serotonin, what is on the other side of the scales? What is imbalanced?

 

[BrightCandle]

I did SSRIs for 6 months and the only thing it did was turn me into an emotional zombie. I had no range I was flat and mellow and docile. What it really did was stop me complaining at my GPs but I was still in wicked amounts of pain I just stopped caring about it. It didn't fix a thing with me it just stopped me taking action about it and was ultimately what let them push exercise into me and caused my body to fail. It doesn't balance a thing it just pushes one transmitter into you enough that all the others get less used and you end up with just one mode of operation. Thankfully I recovered from the impact of the SSRI on my brain but not the damage the doctors did while they had me like that. I consider the use of SSRIs the most evil thing about this, I wasn't depressed I was in agony.

 

[DigitalDrifter]

merged

https://www.ucl.ac.uk/news/2022/jul...not-caused-chemical-imbalance-brain-new-study

Research upon the most commonly investigated serotonin receptor suggested either no difference between people with depression and people without depression, or that serotonin activity was actually increased in people with depression – the opposite of the serotonin theory’s prediction.

Two systematic reviews from 2006 and 2007 and a sample of the ten most recent studies (at the time the current research was conducted) found that lowering serotonin did not produce depression in hundreds of healthy volunteers.

I don't have the URL of the original paper but it's still interesting to read and has great implications if it's true.