Serotonin and the Unsubstantiated Chemical Imbalance Theory of Mental Disorders

Yves here. Regular readers have likely learned that the site moderators are not keen about agnotology, which informally we call Making Shit Up. As KLG explains below, the most mainstream approach for treating depression, as in medicating to improve functionally low serotonin levels (supposedly due to poor uptake in the brain), has been built on what could most charitably be described as an unproven intuition.

By KLG, who has held research and academic positions in three US medical schools since 1995 and is currently Professor of Biochemistry and Associate Dean. He has performed and directed research on protein structure, function, and evolution; cell adhesion and motility; the mechanism of viral fusion proteins; and assembly of the vertebrate heart. He has served on national review panels of both public and private funding agencies, and his research and that of his students has been funded by the American Heart Association, American Cancer Society, and National Institutes of Health

To channel our inner Leonard Cohen, the Chemical Imbalance Theory of Mental Disorders is something “everybody knows.” And everybody knows this largely because of direct-to-consumer (sic) advertising that dysregulation of serotonin synapses in the brain causes depression, and other perhaps related disorders.

But is this “something” true?  Current disinterested “science” basically says “No.”

But there is a long history here, and much of it makes perfect sense at the molecular and cellular levels.  The Chemical Imbalance Theory dates back to 1967, when the British psychiatrist Alec Coppen, following upon the 1965 work of Joseph Schildkraut on norepinephrine, published The Biochemistry of Affective Disorders in the British Journal of Psychiatry.

As the field developed, this putative biochemical mechanism of depression fit in well with biomedicine during the rise and subsequent hegemony of modern molecular biology as the dominant, and sensible if reductionist, explanatory framework for biological structure and function.  Causes and effects were to be sought in molecular mechanisms of disease, period.

This strategy has worked increasingly well in oncology, for example, as the molecular mechanisms of transformation from normal cell to cancer cell followed by cancer progression and metastasis were identified.  This spirit of the times led inexorably to the rise of neuropsychiatry, or to be only slightly facetious, “Yes, we have a pill for that!”  This approach has also led to a “disease management-by-pill” approach to other serious disorders that are largely sociogenic (e.g., metabolic syndrome, Type-2 diabetes), which is a subject for another time.

Back to serotonin, also called 5-hydroxy tryptamine (5HT), which is active in platelets and the cardiovascular and gastrointestinal systems.  The action of 5HT/serotonin as a neurotransmitter in the central nervous system[1]concerns us here, where a deficiency of serotonin is hypothesized to cause depression and certain other mental disorders.

Key points:

(1) Serotonin is synthesized from the amino acid tryptophan (long “a” for most biochemists) in two enzymatic steps and then

(2) Packaged into secretory vesicles through VMAT2 (Vesicular Monoamine Transporter-2).  Stimulation in the presynaptic terminal of the seratonergic neuron causes the vesicles to fuse with the presynaptic plasma membrane and

(3) Release serotonin into the synaptic cleft.  Serotonin then diffuses across the cleft and

(4) Interacts with a serotonin receptor on the postsynaptic plasma membrane, and

(5) Signals are transduced as downstream cellular effects that are eventually manifested in behavior(s).  Serotonin is removed from the synapse through

(6) Re-uptake into the presynaptic cell through the serotonin transporter (SERT), after which it is degraded into 5-HIAA (5-hydroxyindole acetic acid) by monoamine oxidase and a dehydrogenase or repackaged into the secretory vesicles.  If the patient being treated for depression is taking a monoamine oxidase inhibitor (MAOI), repackaging of serotonin into secretory vesicles in enhanced, which increases the concentration of serotonin in the seratonergic neuron and thereby maintains putative normal function.

This straightforward biochemistry and molecular cell biology is the foundation upon which the Chemical Imbalance Theory rests, and it led to the perfectly rational pharmaceutical interventions that followed for serious conditions, including depression, social anxiety disorder, generalized anxiety disorder, PTSD, obsessive-compulsive disorder, panic disorder, and bulimia nervosa.  These include the previously mentioned MAOIs and the well-known, and doubly well-advertised selective serotonin reuptake inhibitors SSRIs (e.g., Prozac, Zoloft, Celexa, Lexapro, and Paxil).

An extensive analysis of the serotonin theory of depression was published online on 20 July 2022 in the well-established journal Molecular Psychiatry (SpringerNature): The Serotonin Theory of Depression: A Systematic Umbrella Review of the Evidence.  To state the conclusion at the outset, to be followed by the evidence presented:

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.

But first, what is a systematic “umbrella review”?  An umbrella review is the highest level of systematic review of scientific support for a particular area of evidence-based medicine (EBM).  The umbrella review seeks to (1) Review other systematic reviews on a particular topic, (2) follows a standard/published methodology, (3) Often requires a broader question than is typical for a traditional systematic review, (4) Comprehensive and exhaustive searching is required to find all evidence syntheses on a topic, (5) Conducted in an unbiased and reproducible manner, (6) May or may not include a meta-analysis, (7) Useful when there are competing interventions to consider.

The hierarchy of evidence in evidence-based medicine (Figure 1) can be presented as follows: (1) Foundational studies/primary research by individual research groups ➡️ (2) Systematic reviews ➡️ (3) Meta-analyses➡️ (4) Umbrella reviews.

25% of umbrella reviews through April 2018 were devoted to EBM in psychiatry/clinical neurology, followed by 24% for general internal medicine, and 15% for public/environmental/occupational health, followed by pharmacology, oncology, multidisciplinary sciences, nutrition, and rehabilitation at 5-8% each.

This distribution (Figure 3) makes intuitive sense.  General internal medicine is the largest individual medical specialty, while psychiatry and clinical neurology will have (should have) the longest and most difficult route from primary research to valid clinical interventions.

So, on to the umbrella review of The Serotonin Theory of Depression, which has followed the rules, and given the full year between submission and acceptance, peer review and revision have likely been extensive.  The authors first conducted a scoping review to identify the six areas of support for the serotonin hypothesis: (1) Are there lower levels of serotonin and 5-HIAA in body fluids of depressed individuals; (2) Are serotonin receptor levels altered in people with depression, which would dysregulate the response to serotonin; (3) Do higher levels of SERT, the serotonin transporter, account for lower levels of serotonin in seratonergic synapses; (4) Depletion studies – does depletion of tryptophan, which would lower levels of serotonin, cause depression; (5) SERT gene – are there higher levels of the SERT gene in people with depression; and (6) Is there an interaction between the SERT gene and stress in depression.

Note that these areas are those that should be considered based on the biochemistry and molecular cell biology covered above using this diagram, if, according to the Chemical Imbalance Theory, serotonin levels are related to depression, and other mental disorders.  Inclusion and exclusion criteria were well chosen, and the reviewers worked independently. Disagreement was resolved by the research group as a whole, and authors of studies under consideration were contacted when data were difficult to parse.  Of 360 non-duplicate records screened, 17 studies (5%) met the selection criteria and were included in the analysis but subsumed within these 17 extensive reviews were more than 100 individual studies.  The analysis presented is extensive.

Serotonin and 5-HIAA. Three reviews (2018, 2018, 2020) studies including 27 individual studies comparing people with depression and healthy controls. These revealed “lower levels of plasma 5-HT in (post-menopausal) women with depression,” but this may not have been statistically significant (note that statistically significant and/or insignificant may or may not be biologically relevant).  However, “two meta-analyses (19 studies included) showed no evidence of an association between CSF (cerebrospinal fluid) levels of 5-HIAA, which is the stable breakdown product of serotonin, and depression.

Serotonin Receptors.  Two meta-analyses (both in 2016) that included 24 individual studies comparing depression with healthy controls.  Fourteen serotonin receptors have been identified in the human genome.  Most of the research on serotonin and depression has focused on receptor 5HT-1A.  The results “indicate either no difference in 5HT-1A receptors between people with depression and controls, or a lower level of these inhibitory receptors, which would imply higher concentrations or activity of serotonin in patients with depression.”  These studies included patients who were taking psychiatric medicines, which may have had an influence on the results.

Serotonin Transporter (SERT).  Three overlapping meta-analyses (2014, 2015, 2016) based on 40 individual studies. SSRIs are thought to work by inhibiting SERT, which would increase the concentration and dwell time of serotonin in the synapse.  A reasonable expectation is that patients with depression would have higher levels of SERT protein or activity.  Overall, the data did not show any consistent relationship between SERT and depression. All three reviews cited evidence from animal studies that antidepressant treatment reduces the level of SERT in these animals.  If these results represent a genuine outcome, they suggest that depression is associated with higher serotonin activity or concentration.

Depletion Studies.  One meta-analysis and one systematic review (2006, 2007; >50 individual studies). Tryptophan depletion should reduce the level of serotonin.  This can be accomplished in human subjects by using and amino acid drink that lacks tryptophan, but in my view this would be a stretch in human studies.  There was a slight effect in mood reduction following tryptophan depletion.  However, most of the subjects had been or were taking antidepressant medication, and participant numbers were small.  Eight studies of healthy volunteers showed no connection between tryptophan depletion and mood.

SERT Gene and Gene-Stress Interactions. It was originally thought that a repeat length polymorphism (variation in the size of the promoter, i.e., to a first approximation the regulatory element in the gene responsible for turning the SERT gene off and on) was associated with serotonin levels and depression.  Down-regulating expression of the SERT gene would raise the levels of serotonin in the synapse, however, if this resulted in less SERT protein in the presynaptic cell (a common assumption that is usually correct).  Despite early studies showing a statistically significant association between the polymorphism and depression in some groups, two recent, high-quality meta-analyses found no relationship between the SERT gene polymorphism and depression.

So, this extensive and comprehensive umbrella  “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…no evidence of reduced serotonin activity in people with depression compared to people without, and methods to reduce serotonin availability using tryptophan depletion (remember that tryptophan is the “feed stock” of serotonin) do not consistently lower mood in volunteers…high-quality genetic studies effectively exclude an association between genotypes related to the serotonin system and depression.

Nevertheless, the Chemical Imbalance Theory is still commonly put forward by medical professionals, for example here and here, and the general public remains convinced, largely through direct-to-consumer (sic) advertising and what can be accurately labeled as disease mongering. This may induce patients to take or continue antidepressant medication, which can lead to lifelong dependence on these powerful drugs.  As noted above, the various rationales for a connection between serotonin and other neurotransmitters such as norepinephrine make perfect sense based on the underlying biochemistry and cell biology, and they certainly fit in with the current scientific zeitgeist that the causes and treatments of virtually all disorders are to be found in molecular details.  But scientists and physicians often fail the distinguish between the agent of a disease and the cause of same.

Perhaps more pressing, however, is how medical students are taught to think of the Chemical Imbalance Theory as these excepts from current textbooks show:

Several medications are available to treat depression…MOAIs, SSRIs…These drugs are all thought to work (emphasis added) by altering levels of various neurotransmitters at crucial nerve terminals in the central nervous system (Black and Andreasen, 7thedition, 2021).

The effects of 5HT(serotonin)-active drugs (e.g., buspirone, gepirone, and ipsapirone, which are selective partial agonists of 5HT-1A receptors in anxiety and depressive disorders, like the effects of SSRIs, strongly suggest a role for 5HT (emphasis added) in the neurochemical mediation of these disorders (Goodman & Gilman, 13thEdition, 2017).

Black and Andreasen’s Introductory Textbook of Psychiatry is widely used in medical schools.  Goodman & Gilman’s The Pharmacological Basis of Therapeutics will be released in its 14thedition in November 2022.  It has been the “blue bible” of pharmacology since 1941, which is the year Alfred G. Gilman was born, the son of the pharmacologist Alfred Z. Gilman of Goodman & Gilman.  The younger Gilman edited the blue bible for many years and was awarded a Nobel Prize along with Martin Rodbell in 1994 for the discovery of G-proteins in signal transduction.  

Imagine these statements, which are equivalent to those above: Cisplatin and radiation therapy are thought to be effective in treatment of Oropharyngeal Squamous Cell Carcinoma (OPSCC) because squamous cell carcinoma cells may be susceptible to Cisplatin, which is thought to work by irreversibly crosslinking DNA in cancer cells, and focused ionizing radiation which is thought to damage the same DNA in these cancer cells and kill them.

In real life, squamous cell carcinoma is killed by Cisplatin and radiation exactly by these mechanisms, which lead to programmed cell death (apoptosis) of the cancer cells.  Yes, other cells die too, but the cancer cells go first and faster. One would hope that medical students would notice the conditionals in the statements on these drugs and depression, but it is perhaps too much to expect them to dispute long-standing and deservedly authoritative sources such as Goodman & Gilman.

Still, it would be churlish for a biochemist and molecular cell biologist – who has studied purified proteins in solution and who has used cells cultured in the laboratory, along with an occasional fruit fly, slime mold, mouse, or zebrafish for organismal validation – to demand that something as complex as depression and other associated mental disorders yield to equivalent experimental approaches.  The integrative levels of these two approaches are not remotely congruent.

And this could be one of the problems of Evidence-Based Medicine as currently taught, practiced, required, recommended, and misunderstood.  The underlying validity of EBM depends on scientific research performed as described and prescribed by Karl Popper and others: Disinterested in the outcome, transparent, and carefully performed in a manner so that the conventional statistical significance of a result, if statistical analysis is necessary, means that the result is also biologically and medically meaningful.  A legitimate scientific hypothesis is also falsifiable in the Popperian sense, i.e., rendered meaningless by results that contradict or fail to support the hypothesis.

It seems that if this were how biomedical science, especially research in clinical medicine, including large, well-conceived and conducted, clinical trials that included all relevant results, both positive and negative, much of so-called EBM would be redundant.  There would still be a use for large meta-analyses and systematic reviews of the scientific knowledge behind clinical practice, but they could and would be considered confirmatory (yes, Karl Popper, an experimental result can be reasonably confirmed) rather than the “gold standard” of clinical knowledge (see final note below).

Finally, as Carl Sagan and others before him famously said “extraordinary claims require extraordinary evidence.”  While the Chemical Imbalance Theory is not necessarily an extraordinary claim at the molecular and cellular levels, the hypothesis has not yielded to any number of experimental approaches.  The evidence is just not there, but the hypothesis has nevertheless not been falsified.  The theory has led to the widespread prescription of a host of drugs, with considerable profit to Big Pharma, in adults and children that come with the warning that “the use of certain antidepressants to treat major depressive disorder (MDD) in adolescents may increase the risk of suicidal ideations and behaviors.”

Other less serious consequences are included in warnings to adults.  This would seem to be an extraordinary risk, based on the conclusion of the review that has been the backbone of this post, “that the huge research effort based on the serotonin hypothesis has not produced convincing evidence of a biochemical basis to depression.  This is consistent with research on many other biological markers[2]. We suggest it is time to acknowledge that the serotonin theory of depression is not empirically substantiated.

I see nothing to add to this conclusion.

One last final personal note: When reading the scientific literature, one often comes upon a paper that makes you sit up and take notice.  And laugh. An all-time favorite of mine now is entitled “Fifty psychological and psychiatric terms to avoid: a list of inaccurate, misleading, misused, ambiguous, and logically confused words and phrases.” A mouthful, yes.  Included are “A gene for,” “Antidepressant medication,” “Chemical imbalance,” “Genetically determined,” “Gold Standard,” “Reliable and valid,” “Statistically reliable,” “Underlying biological dysfunction,” “Comorbidity(particularly relevant during our current Pandemia[3])” “Interaction,” “Reductionism,” and “Scientific proof.”  Enjoy! Many of you will find other terms much to your liking.

Thank you to those who emailed the link to The Serotonin Theory of Depression: A Systematic Umbrella Review of the Evidence

___________

[1]This link is to a commercial site, but the diagram is useful for our purposes, if somewhat busy because it is intended for working scientists.  Regarding commercial sources of information, I have never known a molecular biologist who did not have a well-thumbed New England Biolabs catalog on her desk.  The one I use most of the time is from 2001, with the current version available for information on newer techniques.

[2]“A systematic search for prospective studies investigation biomarkers of MDD onset, relapse, and recurrence was performed. Of the 67,464 articles screened only 75 prospective studies were identified that studied biomarkers before MDD onset and relapse/recurrence.  Of those, only 38 studies reported results on participants that were healthy (had no MDD diagnosis) at baseline and are thus unconfounded by disease state.  Prospective evidence for the majority of biomarkers predicting onset, and relapse/recurrence of MDD was scarce (N = 75) and spread over a wide range of topics: Neuroimaging (N = 24), Gastrointestinal factors (N = 1), Immunology (N = 8), Neurotrophic (N = 2), Neurotransmitters (N = 1), Hormones (N = 39), and Oxidative stress (N = 1)…In order to falsify biological theoriesfor MDD better comparisons between or integration of studies is necessary.” Emphasis added.

[3]Thank you to a clinical colleague for this term.

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76 comments

  1. Amfortas the hippie

    well done.

    my long time doc is a true believer in big pharma…but ive known him long enough that he doesn’t press too hard on my reluctance and distrust…no matter how hot the drug reps are.
    depression is, i’d allege, a perfectly natural, and indeed rational, response to certain situations(as in when one rather suddenly cannot walk)
    nevertheless, at doc’s urging, i’ve tried a few of those drugs….and they didn’t work as intended,lol.
    (couldnt sleep, agitated, couldn’t get a stiffy)
    one, welbutrin, induced a mild seizure.
    but its so much cheaper to prescribe a pill than to prescribe talk therapy.
    out here, that’s what church is for.

    and, an observation: i’ve spent a lot of time in the last 4 years or so buried in medical journals, white papers and whatnot….as well as the doctor versions of the literature pertaining to every drug they gave my wife.
    the “well we don’t really know what it does” asscovering is everywhere…even in the stuff on chemo drugs.
    prolly a risk management thing that the lawyers inserted into whatever style manual is used for this kind of writing

    Reply
    1. Rolf

      Hi Amfortas!

      depression is, i’d allege, a perfectly natural, and indeed rational, response to certain situations(as in when one rather suddenly cannot walk)

      Yes, many times over. And I’d enlarge that response pool to include Our Current State of Public Sphere Dysfunction, as represented by the complete capture of elected public officials by “elites” (quotes denoting that there is nothing truly elite —as in ‘best of a class’ — about them) wealthy enough to “pay to play”.

      Reply
  2. Simple John

    This is the type of reporting that I show to people who ask why read another blog.
    Just for the record – I moved to California at age 51 in 1991. Took advantage of Tijuana pharmacies for antibiotics, tranquilizers. Prozac was for sale and in the popular press. I thought: “Why not?”.
    Within five days I was seriously depressed with suicidal thoughts. Not my normal psyche.
    Then as now the rap was “Young people may suffer suicidal ideation.”. How convenient I could claim youth again through the magic of big pharma’s denial that all ages could be affected.

    Reply
  3. John Moffett

    I am a neuroscientist and your readers should know there are two types of neuroscientist, the ones who look for new drugs, and the ones who want to do basic research to find out how the brain works. I am the latter type. We have always doubted the serotonin hypothesis, as it is too simplistic when talking about something as complex as the brain. But because it can slightly improve mood in some people, and thus paper over the underlying depression, it has been the go-to solution for doctors treating depressed patients. I don’t expect any change in behavior from doctors now that this review debunks the hypothesis, because patients really do just want “a pill for that”. I have a friend with depression, and he really wants a pill for it. So until basic science comes up with a more holistic theory of depression and its causes (many of which probably are sociogenic) doctors will continue to prescribe these drugs, which are not good for the patients in the long run.

    Reply
      1. mrsyk

        +1 on this. I highly recommend the Long Solitary Walk and/or the Submerge in Cold Water techniques. More hiking and swimming, less screen time!

        Reply
          1. steve2241

            Have been shown to increase serotonin? The whole point of the piece was to say that increasing serotonin doesn’t do what you think it does!

            Reply
            1. JAC

              That was my point! What you missed was that they also and reduce inflammation. There is a link between low serotonin and inflammation that no one seems to care about. Taking prozac helps a little because it treats the low serotonin but it does not treat the inflammation.

              Reply
        1. Lexx

          Thank you for making the distinction between “exercise” and “outdoor exercise”, where one is likely to get a dose of sunlight even in winter. There is some good science behind the effectiveness of natural lighting on the brain and circadian rhythms. Improved my sleep pattern immediately. I can submerge and stay there for 6+ straight hours. Otherwise, I woke up every two hours and eventually got out of bed exhausted and sleepwalked through my day.

          Poor sleep and fatigue were also the only symptoms I experienced of having low serotonin levels. It didn’t follow that low serotonin = depression. For some folks though, it may.

          Reply
      2. clarky90

        Long long fasts. Only spring water and electrolytes (a pinch of sodium chloride, potassium chloride, magnesium sulphide)

        The following was written in 1974, before the western world was completely taken over by “the hyperactive, incessant fiddlers”. Fiddle, fiddle, fiddle…. with serotonin levels, blood pressure, interest rates, co2 levels, methane levels, money velocity, debt levels, borders, sovereignty, identity …………… Up, no down! More more more, noooooo less less……. no just a bit more. Innovations, break throughs….. Please stop these incessant medieval machinations, involving everybody and everything……..!

        Controlled Fasting Treatment for Schizophrenia
        ALLAN COTT, M.D. 1974

        http://orthomolecular.org/library/jom/1974/pdf/1974-v03n04-p301.pdf

        The fast consists of total abstinence from food for a period of 25-30 days. The large majority of patients request voluntary admission to the unit. A
        small percentage of the patient population is transferred in from other units when all other
        conventional treatments have failed to produce improvement. All patients must agree to adhere to the required routine of the treatment and may leave the treatment on request. If the patient voluntarily breaks the fast, the treatment is ended.

        Hunger diminishes greatly by the end of the second or third day, and appetite is no longer felt by the fifth day. Throughout the fasting period the patients receive as much water as they desire but they must take a minimum of one litre each day. They adhere to a regimen which includes outdoor walks and other exercise, breathing exercises,
        afternoon nap if desired, hydrotherapy procedures (baths and showers), daily cleansing enemas, and general massage. A minimum of three hours of exercise is required, but the patient may have two periods of exercise consisting of three hours each.
        Patients lose 15-20 percent of their total body weight on a 30-day fast, but their clinical
        appearance is not that of a person who is starving. Their skin color is good and muscle and skin tone is healthy. The patients do not express any longing
        or desire for food. Because their prior experiences with treatment have been that of little or no improvement with frequent relapses, many patients request that their fasting period be extended to insure the permanence of their improved state. When patients are discharged from hospital, they are advised to take prophylactic fasts
        of three to five days each month but not to exceed a total of 10 days in the first three months. After this period three-to five-day fasts not to exceed 10 days in any month are recommended. Fasting is terminated when the patient’s appetite is restored, his tongue becomes clean, and symptoms are alleviated. When feeding is begun, the patient remains in hospital for the number of days equal to
        the length of the fast. Feeding is begun with a saltfree fruit, vegetable, and milk diet. The amounts of food and its caloric value are gradually increased. Meat, eggs, and fish are excluded from the diet. Bread is not taken until the sixth or seventh day.
        The treatment has been found to be effective in more than 70 percent of cases of schizophrenia of many years’ duration. Forty-seven percent of
        patients followed for a period of six years maintained their improvement. …..

        Reply
      1. JAC

        Can we please stop with this? Please? These is a difference between sadness and depression that I think you all do not understand. Laying in my bed for 9 months not even able to brush my teeth. No I am sorry, I saw the birds out my windows, and the nature, it did nothing. I felt nothing.

        If birdwatching or nature alone cured your depression you were not depressed or over time it just went away.

        Sadness is not depression!

        Reply
        1. Lexx

          I turned the lamp on for the first time two weeks ago. I have a different reason for not spending more time outdoors. If I had meant ‘SAD’, I’d have said so. My point was that low serotonin levels doesn’t uniformly equate to depression for everyone. We are not equally effected; depression is multi-faceted and so is treatment.

          Reply
    1. QuicksilverMessenger

      This whole thing angers me to no end. I am not sure where to insert this comment so maybe here seems good.
      My wife had been diagnosed with anxiety and panic attacks, periodic bouts with depression, etc. and was on many medications. I don’t know what the cumulative effect was but it came to certain point that she had a serious crisis. She was then convinced that it was all of the dope they were giving her (no doubt true) and that she needed to get off of them. She tried to quit and wean off of them but things started to get worse. Her doctors then put her some other drugs (don’t know the names but were the ones that can cause ‘suicidal ideations’), the culmination being she shot herself in the head, leaving our 4 year old daughter and me.
      I wonder if there is a hell and whether it is populated by pharmaceutical executives, psychiatrists, and ‘neuroscientists’?

      Reply
    2. Craig

      I don’t expect any change in behavior from doctors now that this review debunks the hypothesis, because patients really do just want “a pill for that”.

      It works the other way too. Doctors who are loaded with patients, just don’t care, want to annuity bill insurance, or just who are not smart are lumping what they can under “depression” and prescribing a pill to make the problem (you wanting proper healthcare) go away. Once you have a depression diagnosis, symptoms of almost any ailment can fit under that umbrella and will be stuffed there. If it’s not emergent or acute and treatable with an antibiotic, depression is the go to diagnosis.

      Reply
  4. Henry Moon Pie

    “depression is, i’d allege, a perfectly natural, and indeed rational, response to certain situations(as in when one rather suddenly cannot walk)”

    “We’re all suffering from SSS. Sh|t Society Syndrome.”

    Along those lines, it would be nice to see cross-societal or cross-cultural studies about the prevalence and distribution of depression, anxiety, etc. Which societies produce the most depression? Which cultures are marked by high levels of anxiety? Then we could go about prescribing remedies for societies that were producing problems. Something along the lines of “take some universal, single-payer healthcare and call me in five years,” or “institute a UBI and call me next electoral cycle.”

    Instead, we act like our social structure and the worldview that underlies it are TINA and individuals must pop pills to cope.

    Reply
    1. antidlc

      The World’s Happiest Countries
      https://www.cnn.com/travel/article/worlds-happiest-countries-2022-wellness/index.html

      For the fifth year in a row, Finland is the world’s happiest country, according to World Happiness Report rankings based largely on life evaluations from the Gallup World Poll.
      The Nordic country and its neighbors Denmark, Norway, Sweden and Iceland all score very well on the measures the report uses to explain its findings: healthy life expectancy, GDP per capita, social support in times of trouble, low corruption and high social trust, generosity in a community where people look after each other and freedom to make key life decisions.

      Reply
      1. Terry Flynn

        As recently as 2019 (hate linking to Wikipedia but I’m too ill to go find the official suicide rates) Finland had higher suicide rate than EU average. Plus I’m not the only person on here to be profoundly sceptical when Sweden is clumped together with its neighbours….. IIRC Yves has more robust stats on its neoliberalism run wild…… I merely have anecdata from living there for a while.

        Yes you can certainly score various Nordic countries VERY highly on certain “hard stats” and i don’t argue them. Sooner or later though all these surveys end up giving overall “citizen provided” “happiness scores” on Likert scales…… At which point I just switch off and click to next article…..look up cardinality in mathematics. That’s what these scores must possess to be remotely comparable. I’m not aware of a single mathematician who has proved this (or anything even approaching this).

        Reply
        1. digi_owl

          Because while summers can be really nice, the winters can be really harsh indeed.

          It may also correlate that the Nordics are some of the biggest consumers of coffee.

          Reply
  5. VT Digger

    I sent this to the CMO of my company (Harvard/Columbia/etc). We run a national mental health clinic chain. He said, “Yes they do work, but we need more treatment options”

    Hard to stop selling ‘blockbuster’ drugs, eh doc?

    The tapering phase of an SSRI killed a friend of mine (I’ll never believe he killed himself)

    Reply
  6. Pay the Piper

    Before we all continue to pile on big Pharma, let’s not ignore the fact that these medications do indeed help a great many people. To some, it is literally the difference between life and death. What is a more interesting question than “is the chemical imbalance theory of treatment scientifically valid?” is “why do the drugs work in the first place?” The drugs must be doing something else if the chemical imbalance idea is flawed, no? That is a more interesting area of study which could lead to a better understanding. It is a bit like epilepsy. To this day, researchers and doctors still do not know why seizures occur nor why some drugs are effective and some not. Each medication has a different effect in the brain yet those same meds will not work in one person, but work wonders in another. In this case (as in the case with depression and other mental health conditions), the ends justify the means. Not living with seizures is a better option even if one is taking a drug where no one has a clue why it works. I am all for falsifying hypotheses and creating scientifically-based treatments but it does not seem rational to suggest we stop “enriching big Pharma” just because some doubt the serotonin hypothesis.

    Reply
    1. Yves Smith Post author

      This comment verges on Making Shit Up.

      SSRIs perform on a par with placebos. In clinical trials, participants are told of the possible side effects. Since SSRIs have quite a few, those studies are effectively unblinded. So there is no solid evidence they work any better than faith healing.

      Reply
      1. Deschain

        I’ve been struggling with depression for 30 years. I’m on two different anti depressants – buproprion and trintellix – and they have done wonders for my mood over the last decade+. Fewer lows and better highs. No side effects either.

        The plural of anecdote is not data, I know. But at least for me, they have significantly improved my quality of life, and by extension the quality of my relationships with my family. I’m not one to dismiss that lightly.

        Reply
      2. Katy

        Maybe I can rephrase Pay the Piper’s comment.

        You can observe the phenomenon that a drug seems to work without understanding why it works. As a person with epilepsy, I take medications that seem to prevent my seizures. Nobody has a model that can tell me why.

        To your point Yves—with SSRIs, they start with a model for why a drug should work without actually having evidence that the drug does work. You can’t go from a model to a treatment in this case.

        Reply
      3. JAC

        Because SSRI’s act on par with placebo’s does not mean that for a subset of people they do not work. There is most likely a “many causes” situation for depression where in fact SSRI’s may work for some people and not for others.

        The problem starts when the medical industry sees all diseases as single cause.

        Reply
        1. lambert strether

          Sounds like a better approach would be to go with the side effect-free and cheaper placebos, then. Isn’t the functionality of the placebo effect the most interesting question of all?

          Reply
      4. antidlc

        Back in 2012, Irving Kirsch, associate director of the Harvard Placebo Studies Program went on 60 Minutes.

        https://www.cbsnews.com/news/treating-depression-is-there-a-placebo-effect/

        60 Minutes
        Treating Depression: Is there a placebo effect?
        February 19, 2012 / 7:31 PM / CBS News

        Do antidepressants work? Since the introduction of Prozac in the 1980s, prescriptions for antidepressants have soared 400 percent, with 17 million Americans currently taking some form of the drug. But how much good is the medication itself doing? “The difference between the effect of a placebo and the effect of an antidepressant is minimal for most people,” says Harvard scientist Irving Kirsch. Will Kirsch’s research, and the work of others, change the $11.3 billion antidepressant industry? Lesley Stahl investigates.

        The following script is from “Treating Depression” which aired on Feb. 19, 2012. Lesley Stahl is the correspondent. Richard Bonin, producer.

        The medical community is at war – battling over the scientific research and writings of a psychologist named Irving Kirsch. The fight is about antidepressants, and Kirsch’s questioning of whether they work.

        Kirsch’s views are of vital interest to the 17 million Americans who take the drugs, including children as young as six and to the pharmaceutical industry that brings in $11.3 billion a year selling them.

        Irving Kirsch is the associate director of the Placebo Studies Program at Harvard Medical School, and he says that his research challenges the very effectiveness of antidepressants.

        Irving Kirsch: The difference between the effect of a placebo and the effect of an antidepressant is minimal for most people.

        Lesley Stahl: So you’re saying if they took a sugar pill, they’d have the same effect?

        Irving Kirsch: They’d have almost as large an effect and whatever difference there would be would be clinically insignificant.

        Reply
      5. Joe Renter

        Okay, you win. But I know my son might not be alive if he did not have meds for ADHD and his anxiety and depression. I do agree that working out really helps (I also suffer, like many from depression). I would rather go a natural holistic route for all concerned if possible.

        Reply
        1. Ken in MN

          The study was titled 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, published in The Lancet in 2018, with a rundown given by Dr. Harriet Hall on the Science Based Medicine blog, titled The Debate Is Over: Antidepressants DO Work Better Than Placebo.

          I noticed that another commenter mentioned Irving Kirsch. She had this to say:

          A meme that continues to appear regularly in the media and in the comments section of this blog is “antidepressants are no better than placebo.” It is a false belief based on a faulty interpretation of the evidence. A new study has just come out that should put the final nail in its coffin. Antidepressants are indisputably effective when prescribed appropriately for moderate-to-severe major depression. Part of the confusion is that they have often been prescribed inappropriately for mild depression or sadness, where there is no evidence to support their use. They are serious drugs for a serious illness, not “happy pills.”

          The “antidepressants are placebos” meme may have originated with Irving Kirsch. In a 1998 meta-analysis, he found that 75% of the apparent effects of antidepressants were placebo effects, and he suggested that the other 25% probably were too.

          Reply
    2. Anonymous

      Going anonymous for this one, and yes it’s anecdotal. I struggled with depression for decades, took St. Johns Wort which helped a little. Got into a true crisis months ago (had been building for years…) and was persuaded to try prozac which I did with great trepidation. The 3 week transition from St. Johns Wort to prozac was horrible, filled with beautiful dreams of suicide. But unlike depression, the suicidal moods disappeared after a few hours which made them much easier to bear.

      The prozac allowed a reset of some sort – I have described it as finding myself wandering in an unknown meadow; completely new but totally safe. Biggest downside is I can nap almost anytime, so extra coffee and exercise are needed.

      I’m not suggesting anyone else go this route, only saying it helped me. I’m in month 4, my 90 day supply cost me $10.

      Reply
      1. Amfortas the hippie

        speaking of “reset”…i’ve obtained a bit of Fun Guys for when i feel i’m ready…and likely when it ain’t as hot.
        might seem rather reckless and extreme, but i have lots of experience with Fun Guys.
        they work, if done properly: set and setting…nice meadow, not an industrial wasteland…meditate and center one’s intent beforehand, etc.
        the inexperienced should attempt to have a guide along for the ride.

        Reply
        1. Anonymous

          The idea of using a theraputic psychedelic has also been proposed to me, I have never done anything more active than pot. One friend who had been on anti-depressants for years was able to come off of them after a few psilocybin guided treatments. I’m intrigued, may try at some point. Thanks for your thoughts.

          Reply
      2. Joe Renter

        I have used St Johns work and Kava Kava with some success. Also, CBD and low THC gummies. What really helps though is some soul searching. Ask yourself, why am I in this world? What is the universe about? Do I have a soul? Then explore theories on the above and most importantly try a mediation routine.
        I should also say that service work is quite important. “Take your brothers need as a measure of your own”.
        We are here a short time in one incarnation, but the soul and spirit are timeless (relative).
        The path is a long hard-fought battle to liberation.

        Reply
    3. Bugs

      If it weren’t for citalopram and its friend lorazepam, along with 2x weekly talk therapy, this comment would not be here. These are miracle drugs for a few of us. Perhaps they’ve been overprescribed because certain countries’ health care is basically ‘toss them a pill’ but here in France, I got much more than just the pill. I got a doctor who cared and followed me until I was cured. After about 5 years, the citalopram caused some libido side effects and my GP sent me to a psychiatrist who did Transcranial Magnetic Stimulation, which allowed me to taper off everything over a year’s time. To be clear, he was not agains the SSRI and benzos and still asks me if I think I need them every time I see him. Now I’m drug free. I made it through a major relationship crisis, deaths of loved ones, an unwanted move away from the city…I think I’m finally cured of the deep dark black suicidal melancholy and bile that nearly killed me twice. Oh and music and exercise is great. Pixies and Tori Amos and the Throwing Muses, run a track if you can.

      My takeaway on SSRIs is that if you feel _bad_ on it, call your doctor immediately. I went through a week each of Prozac, Paxil, and Zoloft before hitting on Seropram as the one that worked. Effexor also worked for me but I’m not someone who can dose that much.

      YMMV

      Reply
  7. PlutoniumKun

    The manner in which the scientific-medical establishment clings to outdated science and treatment is genuinely shocking for anyone who believes in ‘following the science’. The irony is of course that EBM was supposed to be the solution, but all too many of them are little more than Big Pharma shills. Its not just a case of getting the science wrong, its the regular misapplication of risk analysis and evidentiary requirements.

    I do have some sympathy for doctors in their day to day work. I’ve raised this question many times with doctors I know and its usually met with a shrug of the shoulders and a response along the line of ‘my patients simply won’t accept being told to eat more veg and take a walk, they want a prescription’ (which is of course true’). And of course there is the liability issue of going off-piste when it comes to standardised recommendations. I think many doctors are willing to work with patients who are knowledgeable and willing to take risks, but the patient needs to know what to ask for. Thats a big ask for many people.

    Reply
  8. Matthew

    Psychologist here, from what I understand of the history this gets the order of inference wrong historically. These medications were not developed based on the serotonin imbalance theory, rather the medications came first,
    were noticed to have an effect on mood, and then the theory was developed based on what could be discerned about the effect the medications seemed to have on the brain. But that is certainly an incomplete picture of what they are doing and they surely interact with many neurochemical systems in ways we do not understand. From what I have heard, though I don’t see this in the literature much, what sparked things off was the obvious effects of LSD on mood that were apparent in the 1940s, and then the use of tricyclics in the 1950s based on similar observations. Modern antidepressants are an attempt to create chemicals that will have some effect on mood without having the unacceptable side effects of LSD and TCAs, which has not been possible to achieve without producing unreliable effects in terms of mood. But in my mind it’s important to get the order of logic right here, and it is not as it is presented above. Nor can it be, speaking of EBM, in medicine when practitioners are faces with the need to treat a person right now with a condition they do not understand well. You find things that seem to do something first, then figure out how later.

    Reply
    1. KLG

      Based on my reading of this history (I am not a historian of psychotropic drugs and defer to their disinterested work on the subject), these SSRIs certainly came after tricyclics, which were discovered and marketed in the 1950s. It is not clear that at the time the mechanism(s) of these drugs were well understood, but I have not read this literature extensively. It seems to me that SSRI development was intentional and followed upon the relevant primary research included in the reviews, by Schildkraut (1965, with the catecholamine norepinephrine as a focus) and Coppen (1967, serotonin added to norepinephrine). Fluoxetine (Prozac) first appears in the biomedical literature (PubMed) in 1974 followed by Celexa and Luvox in 1977, Paxil in 1978, Zoloft in 1983, and Lexapro in 2001. This would imply that the order of logic was to develop drugs that targeting serotonin, because serotonin deficiency/dysregulation had been identified as a likely cause of depression and related disorders.

      In support of this provisional hypothesis, the abstract of the earliest report (PubMed search, sorted by date, earliest first; I have not been able to read the entire paper) on fluvoxamine (Luvox) on states:

      The clinical efficacy of fluvoxamine (DU 23000)–the first selective serotonin re-uptake inhibitor of the new class of 2-aminoethyloximethers of aralkylketones was investigated in endormorphous depressed patients during 5 weeks treatment with mean daily dosages of approximately 150 mg DU 23000. A marked and statistically significant improvement of the overall and detailed psychopathology was noted by means of the Global Clinical Impression and Hamilton Rating Scale as early as in the first week of drug administration. Bipolar patients tended to improve more than unipolar ones, retarded depressions more than agitated ones. An additional anxiolytic medication was occasionally required. The drug was well tolerated. Psychometric and laboratory findings did not show any significant changes. The findings are discussed in the light of the indolamine (note serotonin is an indolamine) hypothesis of depression.

      1977: https://pubmed.ncbi.nlm.nih.gov/335026/

      Reply
    2. Lex

      Thank you. I was well acquainted with LSD (and mushrooms) prior to my first experience with SSRI’s. The first SSRI prescription was during a very serious depressive episode and while it made me feel odd, everything was odd and wrong then. I eventually went off the SSRI and much later in life – being more attuned to my mental health – asked to take them before things got really bad. And that’s when I noticed that in “acclimation period” it really felt like the very beginning of a low dose LSD experience. I told my therapist about this and got dismissed. But from a tiny bit of research I learned that (perhaps mistakenly) the receptor sites are the same for both drugs.

      I can’t say whether the SSRIs really help me or not. Even placebos can be effective medication and I’d assume that’s particularly true for psychiatric medication. At this point though, I think I might prefer microdosing mushrooms (or LSD but high quality LSD is hard to source) to going the SSRI route again.

      Reply
    3. IM Doc

      With respect, I believe KLG has the historical facts correct.

      In the 50s and 60s, the antidepressants that were used had to do with the monoamine neurotransmitters in the brain – MAO inhibitors and tricyclics.

      Then in the late 60s and into the 70s, there was a push into the idea that serotonin could be involved and then all of Big Pharma went through their entire inventory of molecules to specifically look for those which could be utilized to alter serotonin in the brain.

      This history is nicely summarized in this article from Nature – https://www.nature.com/articles/nrd1821

      Interestingly, fluoxetine ( what would later be known as Prozac) was first isolated in 1972 by Eli Lilly. It was later found to have effects on the serotonin receptors and eventually was the first SSRI approved as Prozac in 1986. These companies have literally tens of thousands of molecules in their databases, and when they go through them all to see if any will fit the model they are trying to emulate. Prozac was no different.

      What most people are unaware of – fluoxetine is actually a natural molecule, found in the plant Hordeum vulgare – what we know as barley. This isolation happened during the 60s and early 70s – when lots of experimentation was being done in plant molecules, especially those with psychiatric or hallucinogenic properties.

      Another interesting thing is some of the other modern anti-depressants actually were molecules in the libraries of Big Pharma, Big Ag, and Big Chem and had been created or discovered initially to be used as coloring for shellac or as cleaning products. And only years later found to have serotonin properties.

      The thing that is important to realize is the original papers for drugs like Prozac are some of the best examples we have to teach our students about the hazards of data manipulation and the inappropriate usage of the relative risk ratio.

      One can readily see when looking at the raw data that the drug arms in the protocols were just microscopically better than the placebo arms. But thanks to the data manipulation known as RRR they appear to the non-statistical citizen as breakthroughs. They are not.

      Reply
      1. Matthew

        We are talking past each other here a bit. Serotonin IS a monoamine neurotransmitter. The point is that regardless of the details of the “serotonin imbalance theory,” it was very clear already that serotonin had something at least to do with regulating mood, along with the other monoamine neurotransmitters dopamine and norepinephrine. Recreational drugs generally impact these neurotransmitters, and generally impact mood. And MAOIs, as well as LSD, which impact serotonin and others, were already observed to work in vivo first decades earlier. Modern antidepressants are also in use now that impact the other monoamines dopamine and norepinephrine. That basic relationship is more solid than is being presented here.

        Reply
  9. Matthew

    EBM as a program of research and practice is recent and aspirational. The norm has always been treat now based on the best information available with the obvious understanding that that level of information will vary from condition to condition.

    Reply
  10. Ghost in the Machine

    I have a feeling we might see an impactful umbrella review for statins as well in the future. Another blockbuster Pharma drug. Interesting that we call them blockbusters eh?

    Reply
    1. amur

      I second the call for a similar review of statins. I recently tried a statin for the first time based on my doctor’s recommendation. Within a week of starting, I had strong, negative mood changes that caused me to stop taking the meds immediately.

      When I asked my doctor about the effect, she said it wasn’t one she was aware of. I’m not taking a statin at this time and wonder how many people end up on anti-depressants after beginning statins.

      Reply
  11. GramSci

    It was a depressing year when I was denied tenure, so I sought out a prescription for Prozac, which had just come on the market. The next morning I popped my first ‘zac and set off to work cursing the damned bastards who had sabotaged my career. Twenty minutes down the road I found myself singing ♬ damned bastards ♬, ♬ damned bastards ♬.

    So I can testify to the fact that SSRIs can have an anti-depressive effect, but I did not find Prozac to have an enduring effect. I liken my Singspiel phase shift to similar phase shifts that can occur when under the influence of various mostly-illegal indoles acting as mGlu2R agonists.

    If the resulting phase shift should invoke a constructive epiphany, the depressed patient might indeed be cured. However, if the patients’ problems result not from bad memories, but from the sick society in which they are forced to live, I can also see how the epiphanies might turn suicidal. Or homicidal.

    (FBOW I was allowed to appeal the tenure decision, and the following year the evil dean was defenestrated.)

    Reply
    1. JBird4049

      When a person is enjoying real depression, they often have no energy to do anything. For some, they cannot feel anything. I think that when someone is being treated, whatever that treatment is, there is an increased risk of suicide because the sufferer is likely to have more energy, or more energy, is able to do something with whatever that their now clearer thoughts and feelings are telling them; restated, while there are probably drugs that can make a person more suicidal, often it is being more capable before being more functional or well is what kills people. “Oh, I can feel something again. It’s agony. How do I make it stop!”

      Also, I am exaggerating here, but why do people insist that how a treatment works, or that it must be near universally effective, or else it is bogus nonsense peddled by grifters? Even something as “simple” as depression has different causes and treatments. It is like saying that someone has an infection. A description less than useful. Sometimes talk, sometimes drugs, sometimes exercise, and sometimes just time works. Even if Big Pharma is profitably pushing drugs like the local meth dealer that does not make the drugs always a mistake. It just makes the dealers scum.

      Reply
    1. JAC

      Pollan is a horrible hack who knows nothing about everything. You all will say serotonin plays no role ion depression and then tell people to take mushroom who’s main action is to act on the serotonin receptor HTR2A!

      Reply
    2. lambert strether

      I read this book and found it curiously slack and undisciplined. Pollan’s earlier works are great, this not so much.

      Reply
  12. Val

    Why is the antidote the antidote? Why is the plantidote the plantidote? It is not because of a pharma sales plan, profit nodes or hand-wavy narratives and researches.

    Maybe we are not depressed but physically and mentally enslaved by an ecocidal death cult fronted by cretinous mincing ghouls?

    Practice being in Nature with gratitude. Mushrooms really can help. The side-effects are only political.

    Reply
    1. Amfortas the hippie

      “The side-effects are only political.”
      amen, hallelujah and pass the psilocybin popsicle.
      (koolaide, fun guys, ice trays, thick toothpicks and a decent blender)

      but again, it should be taken seriously, prepared for, and not expected to be a fixall miracle(one cannot search for serendipitous boons, after all…it defeats the magic)

      Reply
    2. steve2241

      Mushrooms may very well help, but I wouldn’t ascribe that to “serotonin”. Everything beneficial under the sun has been associated with the act of manipulating serotonin levels. Nothing but Big Pharma marketing.

      Reply
  13. paul

    I had four serious psychotic bipolar breakdowns in fifteen years, resulting in my being sectioned in mental hospitals for months at a time. Happily, I now take lithium carbonate, and haven’t had an attack in twenty-two years. I have no intention of stopping taking lithium, for the efficacy of which there is abundant evidence. During the depressive phases of breakdowns I was given SSRIs to raise my mood three times; the first time I was left to get better without them. I did get better, after nine months and two suicide attempts. The other three times I got better after three months with no suicide attempts. Should I ever have another depressive breakdown, I shall certainly ask to be prescribed SSRIs. Anyone who hasn’t suffered clinical depression will probably find it hard to understand how painful it is. It isn’t feeling blue, it’s thinking about suicide and nothing but suicide all day and much of the night. It’s excruciating. Even if SSRIs have no efficacy at all, they would be worth taking for the tiny amount of hope they give.

    Reply
    1. Matthew

      Late capitalist angst is no doubt a contributor but anyone with a close acquaintance with real mental illness cannot seriously assert that there isn’t something deeper than that going on.

      Reply
  14. rettiwt

    @Yves:

    By KLG, who has held research and academic positions…

    I would like to send this article’s link to a relative of mine who is a doctor and practicing therapist but I’m afraid I would be asked: who is KLG?

    Would it be possible do disclose that info? Thanks a lot for all this enlightment.

    Reply
    1. Yves Smith Post author

      The only additional information I can provide is that he is an associate professor of biochemistry and an assistant dean at a medical school.

      Reply
  15. Mark Gisleson

    Given how much processed food average Americans eat, I do not understand how any drug can receive meaningful trials in this country. I’ve taken various antidepressants and some have had an impact, some haven’t. Some good, some bad (sorry Paxil but I missed my uh, what Amafortas said).

    But I’ve also done exercise and cleaned up my diet and that helped more than any pills but still I can’t help but notice that the new regimen started with a small inheritance that took away my financial stress.

    My cure for everything remains increasing the minimum wage, effectively raising wages for the bottom half which will not cure cancer but I’m betting cancer rates would drop, happiness indexes would soar, depression would be less widespread, deaths of despair would decrease, and overall health would improve. Prove me wrong : )

    Reply
    1. CanCyn

      Chiming belatedly on this one….
      Indeed financial woes are stressors for many, and no doubt other stress contributes to mental and physical health problems. For many, I can’t help but wonder about diet…I think Hippocrates was on to something when he said “Let food be your medicine…” From the article, this raised my eyebrows, “Back to serotonin, also called 5-hydroxy tryptamine (5HT), which is active in platelets and the cardiovascular and gastrointestinal systems.“ I am beginning to think poor gut health is the source for many of our mental and physical ills. Antibiotic fed animals, pesticide treated plants that our food eats and that we eat, highly processed food, too much sugar… it all has to take a toll on our gut biome. I have friends who suffer from either autoimmune disease or depression. They each had some kind of childhood illness for which they were given high doses of antibiotics. Many of them had parents who jumped on the convenient processed food wagon when they were kids. I know, anecdotal, but some correlation? My parents stuck to ‘real’ whole food for us. I didn’t know what Kraft dinner looked like until I was an adult, and I was not amused when I did finally taste it. Yuck. I digress, all this to say that if autoimmune disease and mental health problems are more frequent in the population these days, then perhaps, along with the obesity epidemic, our food system could be considered somewhat to blame? When I worked, I had an employee with depression and anxiety whose dr was on an endless quest to help her find the ‘right’ drug cocktail. She was forever switching meds. She was off sick more than anyone else on staff. Took more than one short term disability leave in the 3 years we worked together. She was overweight and often ate fries or chips and pop for lunch. Never took a walk or got any outdoor exercise. I get that the darkness of depression makes motivation to move a problem and inertia is a real thing. But one of my friends with depression has a dr who prescribes exercise in the form of outdoor walking along with her meds and checks in with her about her walking during talk therapy sessions.
      Last, for the folks here who are benefitting from their meds, that’s great, carry on, Just know that suggesting that there are alternatives for some is not a personal attack.

      Reply
  16. Lexx

    There’s your genes and the circumstances of your birth; there’s what you eat/drink/do and the environment you live in, and the stresses you’re under. Then there’s what bearing all that had as nutrients/waste wound through your tubing and came out the other end. I’m pretty sure it’s the last one we have the most to learn from.

    While wastewater analysis will tell us about the health of our community, our individual poop reports will tell us how our bodies are processing the outside world… to our benefit or our detriment. This is ‘functional’ medicine still in its early stages. We’re not all built to handle to our satisfaction (or that of others) everything life has to offer (or throw at us) over the course of a human lifetime. We are a long lived species. As a culture heavy on individualism*, we’re not good to recognizing our own weaknesses, sharing them with others (or even having someone to share them with), and/or asking for help. Getting through it all with one’s body whole and sanity intact is a challenge.

    If SSRI’s work for some, the reasons don’t much matter until some better understanding of humans becomes available. For the pharma industry though, the answer will always be drugs. All they have is a hammer – a very profitable hammer – and we’re the nails.

    *And what I think of as a kinda nasty version of ‘tribalism’… maybe tribalism was always nasty and I didn’t notice till I got into my 60’s.

    Reply
  17. Questa Nota

    My concerns about SSRIs fit into a subcategory of mistrust of the pharmaceutical industry and regulatory apparatus.
    Briefly, I break down the issues into a few categories.

    1. What provides people real relief?
    What incentives are there to over- or mis-diagnose, either to avoid litigation and/or to get paid more, without seeming regard for patient welfare?
    What are the side effects and are they potentially fatal?
    What are alternatives, like outdoor exercise and other items noted by other commenters?

    2. Why is the business model based on getting people of all ages hooked on dubious meds?
    Will there ever be any exposé of drug excesses on major media, given what and how long it took to get at Purdue?

    Reply
  18. Cesar Jeopardy

    Serotonergic medications never worked well for me. Way too sedating, so I can’t comment on heir effectiveness. Still, they keep trying to prescribe them for me. “Your mileage may vary” applies to these medications. For me, the MAOI Nardil worked best.

    Reply
  19. berit

    Thank you, Yves and Lamberth, for yet another informative, most valuable article! and comments!
    I recognize the overarching theme of trying to understand and come to terms with – or not – the tribulations life throws at us, the disgust and/or terror and/or grief and possible enlightenment from living out our days in this weird and beautiful and truly terrible world with warlords like Jens, Joe, Vlad, Volodymyr and ladies (Gro, Hillary, Nancy, Madeleine-500 000 dead Iraqi children-was worth it), take center stage. It’s sickening. Yet we keep going as best we can, watching the powers that be, hoping for survival and our world to go on spinning.
    The blog Mad in America, Mad in Norway etc covers the topics in this article. I recommend it! and its knowledgeable and wise writers, scientists, doctors, psychologists, survivors, family members … https://www.madinamerica.com/2022/08/psychiatry-textbooks-propaganda/

    Reply

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