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.  I

magine 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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