“No Convincing Evidence That Depression Is Associated With, Or Caused By, Lower Serotonin Concentrations Or Activity”

“No Convincing Evidence That Depression Is Associated With, Or Caused By, Lower Serotonin Concentrations Or Activity”

That lack of, or low, serotonin drives “depression” is a medial truism, say many. Those who say it most strongly are those companies manufacturing chemicals to boost serotonin levels (or prevent its “reuptake” in the brain).

Yet is it true? A new paper in Molecular Psychiatry says, in effect, no. The paper is “The serotonin theory of depression: a systematic umbrella review of the evidence” by Moncrieff and others.

The paper is, more or less, a meta-meta-analysis, without, thank the Lord, its own p-values. They do it the old-fashioned way: by thinking about the observations. That is, it is primarily a meta-analysis of various other meta-analyses.

Here are the basic findings, from their Abstract, with my paragraphifications:

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.

The main areas of serotonin research provide no consistent evidence of there being an association between serotonin and depression, and no support for the hypothesis that depression is caused by lowered serotonin activity or concentrations.

Some evidence was consistent with the possibility that long-term antidepressant use reduces serotonin concentration.

You have to laugh at the last line. It’s sort of a confirmation of those drug commercials—Ask your doctor is profitol is right for you!—which list the very condition they are supposed to cure as a potential side effect. By the way, if you took profitol, call the law offices of Howard, Fine and Howard. You may be entitled to substantial compensation.

Like I said, the authors don’t attempt to quantify things unduly, though authors of the papers they reviewed did. For example, Border et al. 2019, which examined “Association between 5-HTTLPR polymorphism and depression”, and which found “No relationship between 5-HTTLPR polymorphism and estimated lifetime MDD diagnosis OR = 1.000, p = 0.994 (N = 115,257)”. We don’t need the p-value here. The odds ratio is 1 is sufficient.

Also, something went horribly right in this paper. The authors wrote in plain English, larding sentences with medical terms only when needed. This is rare.

Their conclusion is clear:

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….

This review suggests that the huge research effort based on the serotonin hypothesis has not produced convincing evidence of a biochemical basis to depression…We suggest it is time to acknowledge that the serotonin theory of depression is not empirically substantiated.

They have also thought through the consequences (my paras.):

The general public widely believes that depression has been convincingly demonstrated to be the result of serotonin or other chemical abnormalities, and this belief shapes how people understand their moods, leading to a pessimistic outlook on the outcome of depression and negative expectancies about the possibility of self-regulation of mood.

The idea that depression is the result of a chemical imbalance also influences decisions about whether to take or continue antidepressant medication and may discourage people from discontinuing treatment, potentially leading to lifelong dependence on these drugs.

Nailed it, I think. By which I mean, it is unlikely the multitude of nervous women (and it’s mostly women) who pop these pills will stop.

CDC pic:

CDC also says “From 2009–2010 through 2017–2018, the percentage of adults who used antidepressants increased among women, but not men.” And it’s educated women who pop the most.

There’s bound to be a huge fight from Eli Lilly (Prozac), Pfizer (Zoloft), Glaxo Smith Kline (Paxil), Forest Labs (Lexapro, Celexa), and others. This is why: “Fortune Business Insights says that the global market size was USD 11.67 billion in 2019 and is projected to reach USD 18.29 billion by 2027.”

That’s too much to give up easily. Bound to be a lot of The Science thrown at Moncrieff. And not just by pharmaceuticals. We all know what Mark Twain said about the patients of quacks. We haven’t had any time to see how the older educated women will take these results, but we do know their behavior in other medical areas. E.g.:

Honestly, now. Do you believe this kind of woman is going to give up her happy pills based on evidence and argument?

One last thing: the authors did not discuss the side effects of SSRIs, including those deleterious effects from stopping taking them. So it’s not only that the pills might not work, they might do more harm than any good. And it certainly seems that way.

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  1. JDaveF

    As a medical doctor, I am sick and tired of meta-analyses. Here’s a tip: lumping a bunch of bad studies together doesn’t produce a good study. If you want to get published, get off your behind and do some real research, like they did in the old days!

  2. Joey Zamboni


    You mean to say that companies misrepresent studies of their products for financial gain…?

    My, how utterly progressively democratic of them…

  3. bruce g charlton

    I spent a couple of decades researching, writing and teaching against the nonsensical, always-unsubstantiated, idea that SSRIs are ‘antidepressants’.

    In fact; they have never in any trial (or in real life) been shown to be effective in genuine (endogenous, melancholic) depression, nor in depressed ‘in-patients’ (a condition only found in about 0.1 percent of the population). SSRIs cannot therefore honestly be called real ‘antidepressants’ in the same sense as eg imipramine, electroconvulsive therapy, or ketamine infusion.

    The only positive trials of SSRIs are in out-patients with milder and mixed symptoms including (but not dominated by) low mood – and then only by calling such patients ‘depression’ (such patients, and there are plenty – used instead to be called anxious, nervous, neurotic etc). Big Pharma have always known this, but instead of marketing SSRIs as anxiolytics (which has a bad reputation of addiction in the 1980s/ 90s), BP re-defined ‘depression’ to make it something diagnosable in approx 10 percent of the population, or more.

    SSRIs are as bad, or worse, at creating drug dependence as anxiolytics such as Valium, or Librium – but SSRI dependence is more negative than ‘addictive’, in the sense of not-being-able-to stop the SSRI without severe side-effects.

    By contrast, many people positively like the feeling of taking benzodiazepine anxiolytics like Valium – and will seek them out. But SSRIs usually make people feel unpleasant (unemotional, demotivated etc) – yet stopping them feels Even Worse.

    What SSRIs actually do to someone’s feelings (when they work) is to ‘blunt’ extremes of emotion (both pleasant and unpleasant emotions), that is to make people less emotionally-responsive to the environment/ more ‘serene’/ ‘harden’ the personality – and in people who are already too ‘flat’, to demotivate.

    The SSRIs can make people feel better *if* the problem is being overemotional, moody, over-reactive; and when unpleasant anxiety and worry are dominant. However, there are significant side effects – including long-term impaired sexual enjoyment, and much-increased rate of deaths by violent suicide especially in younger people (relating to a rare but dangerous sense of inner turmoil akin to the akathisia of antipsychotics). https://charltonteaching.blogspot.com/2014/08/hidden-in-plain-sight-epidemic-of.html

    And the herb St Johns Wort (available cheaply and without prescription) has outperformed SSRIs in effectiveness and safety in all the trails I have seen (mostly done in Germany).

    Also – SSRIs were already known in 1969, when Nobel Laureate Arvid Carlsson discovered the effect in already available antihistamines such as diphenhydramine (a type of Benylin) or chlorpheniramine (Piriton). But Big Pharma wanted new, patentable drugs – and so the finding was kept quiet until these eventually came to market 15-plus years later.


  4. Hagfish Bagpipe

    “A new paper in Molecular Psychiatry…”

    Even the molecules have gone insane.

  5. Hagfish Bagpipe

    ”…potentially leading to lifelong dependence on these drugs.”

    That gives me a great idea for a new business model: make people sick then sell them an addictive “cure” which makes them even sicker so they need more “cures” and “treatments” until you’ve extracted all their wealth and sent them to an early grave! Just pay for some P.R. to buff it up, pay for some Docs to endorse the pills, hire some politicians, capture the regulators, and voilà — vampire gravy train!

  6. Terrence Allen

    Prozac made me feel better, but it could not give my life transcendent meaning.
    My “depression” went away after I converted to the Catholic Church, in ’98.
    Reading Chesterton helped a lot, too.

  7. Screwtape

    The drug companies will land on their feet. They’ll simply relabel depression meds as anxiety meds.

  8. JohnK

    I’m only hijacking this thread because the ladies are getting the once-over here for the drugs that “help” them, and we guys are being unfairly neglected.

    Speaking of X causes Y (but X actually does not cause Y) can we briefly note that lipids (cholesterol) do not cause cardiovascular disease, though there is a multi-billion dollar industry behind the idea that they do?

    I’m a big fan of Scottish GP Dr Malcolm Kendrick (read his book, “The Clot Thickens”), who has been thinking this through, mostly tilting at windmills, for decades.

    (If you are on statins, just skip the rest of this. It might make you sick. Sorry, guys.)

    Statins are drugs that lower cholesterol. Lowering cholesterol, we are informed by maybe an actual million studies, decreases cardiovascular disease (CVD). Millions and millions of people are permanently put on statins because of this.

    But hey! maybe let’s look, not at whether it is even biologically possible for cholesterol to ’cause’ CVD — because an intact, healthy endothelial layer physically prevents LDL (low density lipids) and a ton of other inflammatory agents, from ever touching, let alone accumulating on, an inner artery wall.

    And let’s look, not at Matt’s favorite, “epidemiological” studies, the published versions of which always seen to show “an association”.

    And let’s look, not on whether statins lower cholesterol levels — they do that — but instead, let’s look at actual cardiovascular mortality. This from an unrefuted 2014 analysis:

    Five years on statins prolongs life by 3-4 *days*.

    [ The effect of statins on average survival in randomised trials, an analysis of end point postponement. Kristensen ML, et al. https://bmjopen.bmj.com/content/5/9/e007118 ]

  9. Robin

    In the UK, during the 60s and much of the 70s, almost the entire adult married female population was on Valium. Read somewhere there is a possible connection between long term Valium (benzos) use and Alzheimer’s. Scary.

    @Hagfish: Bad move for Pharma to extract the wealth of the sick individual. Under their new model; that is direct to government, they will instead extract the wealth of the entire hive while the individuals linger forever in declining health and sickness. Now that’s a business model a psychopathic CEO can really be proud of!

    Molecular Psychopathy! LOL.

  10. PhilH

    I don’t mean to be a total lame brain here, but what the heck is a P value? Why do people even use it, and why does Briggs say it’s dumb?

  11. Robin


    P-Value has to do with a comparison of the statistical properties, mean, variance of two groups of data. It was first used by Fisher around about 1932.

    Here is a statement, from 2016, on the usage of P Values from the American Statistical Association:


    Basically is doesn’t mean anything in terms of repeatability, reproduceability or predictability. But investment houses look for Wee-Pees before they invest in new therapeutics and vaccines. This is one of the problems.

    There’s a great deal more excellent material on this subject on Briggs’ website, do a search for ‘P Value,. Very rich technical information.

  12. Cary Cotterman

    I never experienced any benefit from antidepressant drugs, only unwanted side effects. In my experience and opinion, talk therapy is equally worthless, except possibly for the very tractable. In the end, if you’re depressed, you’re screwed. The only thing you can do is keep on keeping on. Oh well.

  13. The Selective Serotonin Re-uptake Inhibitor (SSRI) name was pseudoscience dreamed up in the marketing department of SmithKline Beecham. The “chemical imbalance in the brain” idea was the brainstorm of a sales copywriter in the 1950s. Knowledge of serotonin and other neurotransmitters was even more sketchy when Prozac was invented than it is now. Today, this seductive but mythical gibberish embarrasses researchers.
    Similarly, “ACE inhibitor” or “angiotensin-converting enzyme” blood pressure medications were gobbledegook names used for branding. Lithium is an old therapy for bipolar illness with no sparkling, pseudo-scientific story associated with it. It is not patented and not a money-maker, so no-one will pay a copywriter to invent a marketing idea for it. Note: lithium causes sedation and occasional tardive dyskinesia. It becomes toxic in doses only slightly higher than the therapeutic ones. This can cause permanent brain damage.
    The marketers said depression was like diabetes, and SSRIs were an “insulin” for brain disease. However, no clear relationship of depression to serotonin or other neurotransmitters was ever established, and the drugs all work about the same, with a similar lack of benefit. Jill Moncrieff in The Bitterest Pills (2013) confirmed this:
    No chemical imbalance or other biological process that might explain drug action in a disease-centered way has been substantiated for any psychiatric disorder … Most authorities now admit that there is no evidence that depression is associated with abnormalities of serotonin or noradrenaline, as used to be believed (Dubovsky et al., 2001). There is also little empirical support for the dopamine hypothesis of schizophrenia.
    Ronald Pies, editor-in-chief emeritus of the Psychiatric Times, agreed: “The ‘chemical imbalance’ notion was always a kind of urban legend—never a theory seriously propounded by well-informed psychiatrists… [it was a] myth.”
    Despite this consensus, nearly everyone still believes the metaphor and parrots the message. The idea is 1) your brain is damaged, 2) the drugs fix something, and 3) you need to take medications indefinitely.

    from my book Butchered by Healthcare, available on Amazon.

  14. BrianH

    My mood and outlook improved tremendously when I finally gave up all simple carbs, refined sugar, HFCS, etc forever. Just my anecdotal 2 cents…

  15. Harry MacDougald

    Relatedly, there seems to be a growing pile of studies showing that inflammation of the brain is associated with depression and other personality disorders, and that resolving inflammation produces substantial improvements. It’s not 100% of the time. It’s more like 60+ % of the time it works every time. Inflammation can be resolved by changing diet and exercise. High carbs cause inflammation all over the place. There’s an argument that the entire benefit of statins – weak as it may be – is from their mild anti-inflammatory effects.

    I would find it grimly amusing if the entire scrap heap of theories of personality and the ensuing stack of crackpot therapies, such as SSRIs, were slain by proof that it was all or largely inflammation.

  16. C-Marie

    Talking with God our Father, with His Son Jesus Christ, and receiving leading and guiding by the Holy Spirit, can always lift one up from feeling down. You are soooo loved by God!!!
    God bless, C-Marie

  17. Somebody needs to revisit Doll’s work on cigarette smoking. People haven’t been self-medicating with tobacco for no reason for thousands of years. I smoked on and off when I was younger, I found it very beneficial in situations of stress. Second hand and third hand smoke effects are clearly purely in pursuit of an authoritarian agenda not public health.

  18. anon

    Tom Cruise was ahead of the curve. Who knew he was a prophet?

  19. vince

    healthy cholesterol for 50+ 250-300
    cholesterol levels are directly related to
    manufacture of testosterone
    getting men to take statins to reduce cholesterol
    = emasculation = eugenics

  20. PaulH

    My late sister suffered from chronic health issues based on a life-long battle with diabetes. One of her doctors prescribed an anti-depressant (I don’t remember which one). The doctor eventually cancelled the prescription, saying the “happy pills” weren’t doing any good, and that my sister was who she was… grumpy, opinionated, etc.

    It seems these anti-depressants simply make you think you feel better.

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