Chemical Imbalance Theory - Meme, Trope or Metaphor?

 

A while back I posted about how the “chemical imbalance theory” was a meme that originated in pharmaceutical advertising and all of the evidence to support that observation. This post is about whether that was really a trope and also why psychiatrists should not do too deep of a dive into the neurobiology of medications as a reaction. My concern about the deep dive came from something I saw on LinkedIn, that made the mistake of taking chemical imbalance quite literally rather than the rhetoric commonly used by the detractors of psychiatry.  The suggested strategy was outlining the known neurobiology of antidepressants – a strategy I do not favor.

First things first.  The difference between a meme and a trope has always seemed poorly delineated.  Richard Dawkins is credited with defining a meme as a unit of cultural transmission for evolutionary purposes.  Common modern usage is that it is an image, piece of text, or video that spreads rapidly on the internet and is adapted by various users.  A famous example is the Bernie Sanders mitten meme. A trope is a recurring theme or literary device used in storytelling that audiences immediately recognize.  It is a figure of speech.  In advertising the tropes may be less explicit.  Some examples include a white coat expert speaking authoritatively about a product, the suggestion that a product either directly or indirectly makes you more attractive or successful, or the suggestion that a product makes you more savvy or competent.

Here is a direct comparison between memes and tropes across key cultural and linguistic dimensions (1).

Considering all of the dimensions and definitions the chemical imbalance theory is possibly one of the most effective advertising tropes ever used.  At the time that the first SSRIs and SNRIs were approved by the FDA, all of the companies involved were focused on this trope.  From my original post - the chemical imbalance theory was also referred to when bupropion was marketed in the negative sense that it was “non-serotonergic” and had “minimal risk of sexual dysfunction”.  Some of the ads included a rough scorecard of receptor activity.  These medications were being marketed like potential customers were neurochemists and the mechanism of action of the medications were known.  As noted in the core definition in the above table, the figurative language of chemical imbalance is a shortcut to bypass a very complex process.

An additional consideration of an advertising trope is that it can also be turned into a meme and I think this occurred. In those pre-Internet days, early SSRI advertising overlapped with National Depression Screening Day.  Exposure of attendees and physicians at that screening was thorough and people in the community were being exposed to the same trope in TV and magazine ads.  It was not long before I started to encounter patients in the late 1990s that wanted to know if they had a chemical imbalance.

The academic literature at the time did not reflect the term and has not ever since.  The originators of the monoamine hypothesis of depression were much more circumspect – considering depression to be a complex multifactorial disorder that could not be explained by a simple change in monoamines. Since that era there have been over 100 hypotheses about depression with many carried forward to current times.  The serotonin based theories of depression have faded rapidly over the past 2 decades even though serotonergic systems are important for brain function and sophisticated in vivo monitoring has shown that antidepressants of several classes all increase extraneuronal serotonin levels.  As noted in the above link, Charney and Nestler’s text currently aggregates depression hypotheses under neurotrophic, immune, and neuroendocrine headings.  The specifics at this point are lacking and since depression is a heterogenous condition with multiple known medical and substance induced etiologies it will take subtypes that are clearly defined by more than written criteria.  At some point I hope to provide a more detailed map, but for now I will get back to the trope rather than the science.

The detractors of psychiatry can always be counted upon to throw a trope at the wall and see what sticks.  What better trope to use than a wildly successful one from Pharma marketing?  Just add that psychiatrists are intellectually dishonest and are just selling pharmaceuticals like drug companies and pretending to know the cause of depression and the mechanism of action of antidepressants. You might even extend that rhetoric to suggest that psychiatrists need to cling to that certainty in order to legitimize themselves in medicine.

Is any of that rhetoric legitimate? First, all FDA approved package inserts have a Mechanism of Action section.  For many medications that section has a complete or provisional statement about the mechanism of action being unknown (14-18).  In the case of antidepressants, the mechanism of action is generally listed as involving monoaminergic transporters or receptors at some level.  Second, in reviews of drug targets in general antidepressant and antipsychotic medications are listed with respective targets like most other medications in clinical use (19).  Third, and most importantly – there is a tendency to think of rhetoric, memes, tropes, and metaphor as being limited to arts and literature.  Cognitive scientists and linguists view these dimensions as the foundational mechanics of human communication and there is ample evidence that they are used in every discipline – including medicine and science.

At least part of the issue is that tropes, memes, and metaphors are not really part of the mainstream of medical or scientific literature. Nothing will be found in neurology, psychiatry, or even neuroscience texts.  It is generally covered by linguists or researchers who identify as both linguists and cognitive psychologists. That literature is useful to read because of the overlap with cognitive psychology and also how these foundational mechanics of language are used on a daily basis.  It provides an additional dimension for analysis of the literature in your primary field. It goes beyond language disorders and aphasias noted in medical practice.

The following table is a compilation of the current theories of metaphor – since that is the basis for many (but not all) tropes.  It shows how metaphors are theoretically more or less efficient and the main mechanism of action.  Interestingly the suggested mechanisms are basically processing metaphors.  In reading about modern theories of metaphors, it is clear that the landscape has changed to one that sees much human communication as being dependent on metaphors and the line between literal and figurative language as being much less clear.  Beyond that metaphors are seen as foundational cognitive mechanisms rather than just linguistic or literary devices.

In Conceptual Metaphor Theory (CMT) the mapping is a simplified or mechanistic view of the brain is mapped onto a complex (multifactorial/multidimensional) emotional state.  Once that is established the result is reasoning from that state suggests that correcting the imbalance with correct the associated stated. The cognitive load is decreased because thinking about all of the real neuroanatomy and neurophysiology is not necessary.  The reasoning is more like keeping your car full of gas or oil to keep it running.

Categorization Theory (CT) states that two unlike categories are not mapped but instead a new superordinate category is created.  The example in this case would be the category of things with mechanical or material deficiencies. This category includes things that are depleted and in need of repair like broken automobiles or vitamin deficiencies.  The brain and the car both do not work because of a material deficiency and once that is identified they can be repaired.

Career of Metaphor Theory (COMT) says that metaphors shift over time as they become more familiar.  They start out as active comparisons as suggested in the first two theories but eventually become their own categorizations as dead metaphors.  A dead metaphor no longer requires the active comparison. For example, early in the course chemical imbalance could be compared with another deficiency diseases like diabetes, but as time goes on and it is more accepted chemical imbalance is accepted as equivalent to depression without any imagination of the chemistry involved.

Deliberate Metaphor Theory (DMT) draws a distinction between metaphors that are used unconsciously and those that are introduced deliberately. The intentional metaphors are more often used rhetorically.  In this case, chemical imbalance was used intentionally as a marketing device to explain or legitimize the use of antidepressants.  It also shifts explanatory power away from environmental or psychological causes to biological ones.

As I read about these theories, I recalled the first time I was confronted with the chemical imbalance theory back in the 1980s.  It was presented to me by two pharmaceutical representatives.  As a guy with considerable biochemistry and chemistry experience my reaction was: “It sounds like you are saying the brain is just a bag of chemicals.”  They were not very happy with me.  But this approach and the theory did not have any traction with me.  There is concern within the science community about the use of metaphor and the possible inadequacies.  With chemical imbalance theory there are several including: it does not adequately describe the level of complexity involved, it does not accurately reflect the scientific literature, it creates a level of certainty that does not exist, and it has led to a trope where it is accepted at a political rather than a scientific level.

For all of these reasons, no psychiatrist should be using this trope clinically.  In the general population it is pervasive to the point that I have talked with patients who tell me how they are trying to correct their chemical imbalance.  The people I am referring to have never seen a psychiatrist and are trying to correct that imbalance by using street drugs.  They often have an elaborate scheme about how they can selectively increase various neurotransmitters to get certain effects. They were shocked when I advised them that things don’t work that way.

Returning to the reason for this post, what is necessary to say to most people for adequate and ethical informed consent?  I have reviewed this in several posts on this blog (20-26). Informed consent about both the diagnosis and treatment intervention is critical and it needs to be adapted for the abilities and preferences of every patient.  When I saw the reaction to the problems of the chemical imbalance trope being countered by the suggestion that psychiatrist present more detailed neurobiological information – I thought it reflected a lack of understanding of clinical reality and here is why:

1:  It does not reflect what most people want.  People come in to see psychiatrists at the last possible moment. The people I saw over the course of my career had already seen primary care physicians and therapists.  They were seeing me because nothing has worked.  In some cases, they had specific concerns about treatments or medications and wanted those concerns addressed initially.  That is often the easiest unasked question.

2:  Discussing alternate treatments and a no treatment option.  In the process I clarify my role as providing the best possible advice based on current science.

3:  In the case of medications – discussing my experience with the recommended medication including time course of response, typical side effects, rare but serious side effects, and indications to call me.  I also included a statement that most people wait too long to call or decide that they might “get used to” a side effect but that I prefer they call me about it.  

4:  A discussion of the therapeutic alliance, how that works, and the informed consent aspects.  This is often referred to as “shared decision-making” these days.  I will always prefer the models of therapeutic alliance and informed consent as a better fit for psychiatric practice.

5:  A discussion of other metaphors and tropes.  There are many more out there today due to the internet and popular science sites promoting them.  Just a few examples – “rewiring your brain”, “neuroplasticity”, “cleaning/cleansing your brain”, “reprogramming your brain”, brain as a "switchboard", brain regions as an "orchestra", need for brain "reset", brain as "hardware" and mind as "software", etc.  They are often used as a reason for diet, exercise, branded psychotherapies, self help, even a walk in the outdoors.  As far as I know none are used rhetorically and repeatedly by antipsychiatry despite the fact that many of the claims overblown.

Effective treatment should be what the informed consent decision is based on and that does not require that everyone become a neuroscientist any more than receiving dental care requires everyone to become an expert in teeth.       

This post has been an interesting excursion into linguistics, cognitive psychology, and rhetoric.  I discovered an entire field of metaphorical linguistics that I was unaware of.  Metaphor and simile are concepts right out of freshman English composition – but the idea that metaphor is a cognitive process is much more current.  The progression of metaphors over time is consistent with the conversion of episodic memory into semantic memory.  I have not been able to confirm whether any of the metaphor theorists believe that at this point or whether it has been written down anywhere.  I do encourage caution in using metaphors in psychiatry and agree with Kendler’s thesis that we do not need to avoid biological reality in discussions with patients. At the same time Kendler saw the need for metaphorical brain talk as arising out of the need for a brain focus combined with an explanatory gap, status anxiety over a clear underlying pathology, and a wish that we may eventually get to the deeper understanding of the brain that we all seek.  This missing piece is from linguistic theory that metaphor is a basic cognitive mechanism that we all use and the evidence is all of the depression tropes well beyond chemical imbalance at this point.     

In conclusion, meme, trope or metaphor - chemical imbalance has utility from a linguistic perspective and that may be why it persists at a rhetorical level today.  There is also overlap with the goals of that rhetoric as pejorative and I would argue it has attained dead metaphor status in that regard and therefore is not a term any psychiatrist should use.  

George Dawson, MD, DFAPA

 

Supplementary 1:

If you are a cognitive psychologist or linguist - I am interested in references that you would consider state of the art about the role of metaphor in cognition.

Supplementary 2:

This post reminded me that as a senior psychiatry resident, I was fortunate enough to have an office down the hall from two excellent speech and language pathologists. We had many great discussions about language, speech, and cognition.  That happened at the William S. Middleton Memorial Veterans Hospital in Madison, Wisconsin.

References:

1:  Animétudes.  Postmodern Media : Memes and Database Consumption.  May 3, 2020:  https://animetudes.com/2020/05/03/postmodern-media-memes-and-database-consumption/

2:  Kole M. Science fiction tropes: a guide for writers.  Good Story Company.  October 2019:  https://www.goodstorycompany.com/science-fiction-tropes

3:  Everywriter R.  100 science fiction tropes. Everywriter May4, 2024:  https://www.everywritersresource.com/100-science-fiction-tropes/

4:  TV Tropes.  Science fiction:  https://tvtropes.org/pmwiki/pmwiki.php/Main/ScienceFiction

5:  Taylor C, Dewsbury BM. On the problem and promise of metaphor use in science and science communication. Journal of microbiology & biology education. 2018 Mar;19(1):10-128.

6:  Bradie M. Science and metaphor. Biology and Philosophy. 1999 Apr;14(2):159-66.

7:  Reynolds AS. Understanding metaphors in the life sciences. Cambridge University Press; 2022 Apr 28.

8:  Mahootian F. Metaphor in chemistry: An examination of chemical metaphor. In: Philosophy of Chemistry: Growth of a New Discipline 2014 Oct 19 (pp. 121-139). Dordrecht: Springer Netherlands.

9:  Muller CH, Rau MA. Instructional analogies dominate, domain-inherent metaphors are overlooked: A systematic review of metaphorical mappings in chemistry education. Journal of Chemical Education. 2025 Jun 6;102(7):2576-91.

10:  Rodriguez X, Arroyo-Santos A. The function of scientific metaphors: An example of the creative power of metaphors in biological theories. InThe paths of creation. Creativity in science and art 2011 Jan (Vol. 9, pp. 81-96). Peter Lang Publishing Group Bern.

11:  Swiatczak B. Understanding life through metaphors: Andrew S. Reynolds: Understanding metaphors in the life sciences. Cambridge: Cambridge University Press, 2022, xx+ 200 pp,£ 11.99 PB.

12:  Veit W, Ney M. Metaphors in arts and science. European Journal for Philosophy of Science. 2021 Jun;11(2):44.

CT doesn’t mean all metaphors in science are legitimate. Just like some metaphors in artistic works are bad in various ways – bland, tasteless, confusing,etc. – some in science might be bad. Neither does it imply that the same criteria need to be used in evaluating metaphors in science as in the arts.

13:  Fernyhough C.  Metaphors of the mind.  British Psychological Society.  The Psychologist.  June 18, 2006:  https://www.bps.org.uk/psychologist/metaphors-mind

14:  FDA Package Insert: nortriptyline.

The mechanism of mood elevation by tricyclic antidepressants is at present unknown. Pamelor is not a monoamine oxidase inhibitor. It inhibits the activity of such diverse agents as histamine, 5-hydroxytryptamine, and acetylcholine. It increases the pressor effect of norepinephrine but blocks the pressor response of phenethylamine. Studies suggest that Pamelor interferes with the transport, release, and storage of catecholamines.

15:  FDA Package Insert: fluoxetine.

Although the exact mechanism of PROZAC is unknown, it is presumed to be linked to its inhibition of CNS neuronal uptake of serotonin.

16:  FDA Package Insert: venlafaxine.

The exact mechanism of the antidepressant action of venlafaxine in humans is unknown, but is thought to be related to the potentiation of serotonin and norepinephrine in the central nervous system, through inhibition of their reuptake. Non- clinical studies have demonstrated that venlafaxine and its active metabolite, ODV, are potent and selective inhibitors of neuronal serotonin and norepinephrine reuptake and weak inhibitors of dopamine reuptake.

17:  FDA Package Insert: bupropion.

The exact mechanism of the antidepressant action of bupropion is not known, but is presumed to be related to noradrenergic and/or dopaminergic mechanisms. Bupropion is a relatively weak inhibitor of the neuronal reuptake of norepinephrine and dopamine, and does not inhibit the reuptake of serotonin. Bupropion does not inhibit monoamine oxidase.

18:  FDA Package Insert: vortioxetine.

The mechanism of the antidepressant effect of vortioxetine is not fully understood, but is thought to be related to its enhancement of serotonergic activity in the CNS through inhibition of the reuptake of serotonin (5-HT). It also has several other activities including 5-HT3 receptor antagonism and 5-HT1A receptor agonism. The contribution of these activities to vortioxetine’s antidepressant effect has not been established.

19:  Santos R, Ursu O, Gaulton A, Bento AP, Donadi RS, Bologa CG, Karlsson A, Al-Lazikani B, Hersey A, Oprea TI, Overington JP. A comprehensive map of molecular drug targets. Nat Rev Drug Discov. 2017 Jan;16(1):19-34. doi: 10.1038/nrd.2016.230. Epub 2016 Dec 2. PMID: 27910877; PMCID: PMC6314433.

20:  The Spectrum of Caring About Medication Information:  https://real-psychiatry.blogspot.com/2014/05/the-spectrum-of-caring-about-medication.html

21:  Vigilance Is Required for Adequate Informed Consent:  https://real-psychiatry.blogspot.com/2019/04/vigilance-is-required-for-adequate.html

22:  The New Black Box Warning on Benzodiazepines:  https://real-psychiatry.blogspot.com/2021/03/the-new-black-box-warnings-on.html

23:  The Problem of Antidepressant Discontinuation:  https://real-psychiatry.blogspot.com/2018/06/the-problem-of-antidepressant.html

24:  2000 Words About the Last Ten Minutes of a Psychiatric Evaluation:  https://real-psychiatry.blogspot.com/2019/07/2000-words-about-last-ten-minutes-of.html

25:  Therapeutic Alliance - A Better Diagram:  https://real-psychiatry.blogspot.com/2017/09/therapeutic-alliance-better-diagram.html

26:  Components of Patient Outcome:  https://real-psychiatry.blogspot.com/2018/10/components-of-patient-outcome.html

Depression Is Not A Proton and Other Nosological Musings....

 

I have been thinking about protons a lot lately. Probably not too unusual for an old science guy.  After all we used them in chemistry and physics.  I have been doing some reading about stellar evolution lately and how the elements were formed. In that reading I came across the fact that a proton has a life of 10^32 years. Some estimates say 10^34 years.  And proton decay doesn’t happen slowly over time. At some point it is just instantaneous.  A proton is a composite particle rather than an elementary particle – composed of three valence quarks resulting in a net positive charge. But in chemistry and biochemistry they are generally written as a simple H⁺.  When protons decay – it happens instantaneously to a positron and a pion.  The positron is antimatter so it collides with an electron and is annihilated and gives off gamma photons.  The pion explodes doing the same.  The proton is converted to energy. This process is so rare it has never been directly observed although there is a massive experiment in progress to see if it can be done.

Practically all the protons in the universe today, were made during the Big Bang about 13.8 billion years ago.  Some protons are made in the universe today but it is a very small process compared with the original source. That means that all of the protons in my body (and yours) are recycled and will be for the next 10^23 years.  That’s nearly a trillion trillion (10^24) years.  The various estimates for the death of the universe range from tens of billions of years to 10^100 years.  And of course, life on Earth and Earth as a habitable planet is much shorter.

All of these thoughts about protons brings to mind Carl Sagan’s various quotes about how we are all made of stardust.  His thoughts go far beyond protons to every element in our bodies and how they were synthesized in stars and temporarily borrowed by us. Each one of us is an aggregate of this star dust maintained by energy input and localization. Part of Sagan’s intent was to point out how this can be reassuring and spiritual.  I do find it that way.

There is something else about protons. The verbal description of protons may vary slightly between disciplines (physics, particle physics, chemistry, biochemistry) but everyone is in agreement that protons exist and can see the logic of all of the notations and definitions.  Everyone agrees that there is one type of proton and it will be around forever.

A lot of people will say species are qualitatively different from disease and protons are qualitatively different from organisms and diseases.  Without using any philosophical words – species, protons, and diseases have different rules of existence, boundaries, and causal mechanisms.  To cite one example – no biological organism or disease originated in the Big Bang and is expected to last forever. The rules of existence are much different for a proton. It also does not adapt, process information, or experience or feel anything.  An organism has emergent rather than summed properties, is subject to evolutionary pressure, complex organization, and a finite lifespan. At the basic level the proton is a thing and an organism is a process over time – a qualitative difference.

The comparison of species to disease shows that species are generally individuals and diseases are abstract classes.  The individuals are organized in an evolutionary or phylogenic classification and diseases are organized as a disruption of normal physiological or mental function in an individual.  The species move through time and the disease happens to an individual at one point in time. As the appreciation of disease complexity has increased over time there is now an understanding that the lines that blur the distinction between species can also occur with diseases. 

That obviously is the case in biology and medicine. From taxonomy, we can find rare cases of organisms that are the only match to their phenotype – there is one description of a single genus and species.  We can also find identical phenotypes that can be separated into genus and species only by genetic subtyping. We can find monogenic diseases that produce several phenotypes and polygenic diseases that produce many more. In other words – the match between description and consensus-based reality is far from perfect.

I attempted to capture this phenomenon in the diagram at the top of this post.  I eschew the idea of a spectrum or continuum, the categories are presented here just to give estimates of possible numbers of subtypes in each category and the associated uncertainty. Some may take issue with including speciation with diseases.  In that case I will defer to Linnaeus who classified both and invented the predominant classification nomenclature still used in taxonomy.  

To be clear – this graphic is literally an apple to oranges comparison.  The first issue is the physical wave-particle compared to biological entities.  The second is the different levels within biology.  Species occur at the population level over time defined by properties such as reproductive isolation, morphological distinguishability, and monophyly.  The boundaries between species reflect evolutionary divergence rather than trait variation.  

To cite few examples moving from left to right. The proton is off the chart because there is no discrepancy between description and there is only one agreed upon type.  The first three organisms (Gingko biloba, Balaeniceps rex, and Thermus aquaticus) all have just one species through evolutionary mechanisms.  I did not equate them to a proton because being trained in biology (and without looking it up) – I am sure there are various descriptions but common recognition they are the same species.

Things get interesting with the Bornean Fanged Frog.  In this case all of the frogs look exactly alike and can only be separated into 18 different species by molecular genetics (1).  The authors specific quote “single species has been split into 18 genetically divergent yet morphologically indistinguishable species.”  This is the definition of a cryptic species but they also point out controversy about that definition and say that cryptic species are common in the Tree of Life and understanding them is critical to understanding biodiversity. 

Moving on to monogenic diseases, most of which can be identified by molecular tests there are also limited number of phenotypes that do not add much to classification but can be important in terms of treatment. Infection and toxic agents are generally thought of as being defined by the agent involved but there are a number of possible phenotypes based on host susceptibility, organ system involved, disease state, lethality of the infection agent or toxin, and in the case of the latter – toxidromes. 

That brings me to major depression – one of the most maligned diagnostic criteria in the DSM.  When I read the critiques, it seems like some people believe there will be a magical verbal description of depression and all of our worries will be over.  The sun will shine and we will never have to worry about actually treating the vagaries of depression on a clinical basis. The new pure description will be perfect enough to lead to an improvement in biological research and therapeutics.  The other more insidious part of that criticism is “I know more about depression than anybody and this is how it should be classified and diagnosed.” 

I don’t buy that criticism.  And here is why – I have seen tens of thousands of people with severe depression and bipolar disorder successfully treated during the eras of the DSM-III, DSM-IV, and DSM-5 and have worked with the thoughtful experts involved.  I don’t think for a second that it matters what was in those manuals or what turns up in the DSM-6.  Assessing and treating depression and differentiating it from other conditions doesn’t depend on what is in the DSM or the ICD.  It depends on what is in the mind of the psychiatrist, how that mind was trained, and what that mind experienced. 

As far as the classification goes – I can show the table of contents of Kraepelin’s text Clinical Psychiatry (2) to any practicing psychiatrist today and they will recognize what he is talking about over a hundred years ago.  It seems that we have to deny the validity of previous observations or label them as “pragmatic” but otherwise meaningless. The newer hierarchical or network-based schemes don’t mention the circularity of being based on descriptions pulled directly out of the DSM and all previous observations.

The diagram shows that based on the DSM criteria there are 227 possible phenotypes of varying frequency and a recent study showed that only 170 were observed in a large clinical sample.  Genomic studies often use a compromised phenotype by using the PHQ-9 or PHQ-2.  Nobody ever suggests that is a “practical” research compromise when you are analyzing the genomes of many more people than several psychiatrists would see in their lifetime.  But that is one reason some people think we need better criteria. How will better criteria be useful in rapidly characterizing 100,000 people for a genomics study?  Let me go out on a limb here and say there will be no better verbal or written criteria.  There is a limit of what you can classify with just words – especially in biology.

The proof is evident in the next three categories.  Everyone can recognize a domestic dog. There is tremendous phenotypic diversity in dogs based on morphology and behavior.  And they are all the same genus and species. Atopic dermatitis or eczema is one of the most common dermatological conditions and based on IgE status, age at onset, course, endotype, molecular endotype, chronicity, fillagrin mutation status, and severity there are 6,144 combinations although there is clinical overlap and there has been no clinical investigation into how many of those variants exist. From a morphological standpoint - many different rashes from eczema can exist on the same person at the same time and specialists in dermatology are the best people to diagnose that.  The same analysis can be done for systemic lupus erythematosus (SLE) using formal criteria and that produces 27,648 combinations of signs, symptoms, and lab findings.        

There is a range to the limits of verbal classification in biology and medicine.  In the case of cryptic species, we have a phenotype that presents very little perceptual or verbal information for classification and that classification depends on molecular biology.  In some cases, there is a one-to-one mapping of classification onto species.  That rarely if ever works in medicine and examples abound. I would not expect it to happen at high rates in biological organisms with stochastic processes, genetic mechanisms like incomplete penetrance, variable expressivity, polygenic modification of monogenic risk, epistasis, pleiotropy, allelic heterogeneity, epigenetic variability, and compound inheritance all increasing the gap between genotypes and expected phenotypes.  Approximate classifications are not a deterrent to science or clinical practice even though that is a common critical opinion. 

Stay tuned for an even deeper dive into biological classification of diseases based on some of these concepts. 

 

George Dawson, MD, DFAPA

 

References:

1:  Kin Onn Chan, Dario N Neokleous, Shahrul Anuar, Rafe M Brown, Carl R Hutter, Indraneil Das, Stefan T Hertwig, A Genomic Perspective on Cryptic Species Reveals Complex Evolutionary Dynamics in the Gray Zone of the Speciation Continuum, Systematic Biology, 2026;, syag001, https://doi.org/10.1093/sysbio/syag001 (open access).

2:  Kraepelin E.  Clinical Psychiatry.  The MacMillan Company/Norwood Press, Norwood,MA 1902, 1907. 628 p.

3:  Kendler KS. The Phenomenology of Major Depression and the Representativeness and Nature of DSM Criteria. Am J Psychiatry. 2016 Aug 1;173(8):771-80. doi: 10.1176/appi.ajp.2016.15121509. Epub 2016 May 3. PMID: 27138588.

4:  Zachar P, Kendler KS. The Philosophy of Nosology. Annu Rev Clin Psychol. 2017 May 8;13:49-71. doi: 10.1146/annurev-clinpsy-032816-045020. PMID: 28482691.

Graphics Credit:

An original from me - generated with MS Visio.

Waste, Fraud, and Fish...

 

The high point of summers when I was a kid was fishing with my grandfather.  It was only about 4 or 5 hours but it was an adventure.  He had a 1933 Diamond-T flatbed truck that he used for his business that I have highlighted in a couple of places on this blog.  He also had a 14 ft. wooden boat built by the Peshtigo Boat Factory that he kept in immaculate condition.  He shellacked the interior and repainted the exterior every three years.  It always looked new.  He powered it with a 15 hp Johnson outboard motor.

Every fishing trip started the same way.  We put the boat and motor into the back of the Diamond-T, headed to the local bakery and picked up a dozen plain donuts or “fry cakes” as he would call them, and then drove out to Bad River where we put the boat in.  He knew several people with boat landings and occasionally we would just drop it in down a steep river bank from a dirt road.  We were always within a few miles on the upstream or downstream side of the U.S. Hwy 2 bridge.

Our fish of choice was walleye (Sander vitreus).  My grandfather’s preferred bait was June Bug spinners with nightcrawlers.  He and I usually used those with bait casting setups and 40 lb test nylon line.  The third person in the boat was a guest who in some cases would use exotic spin casting or spinning setups with many different artificial lures.  Bad River has a lot of snags and brush on the banks and that caused trouble for exotic lures cast great distances with monofilament line. 

We did not catch a lot of our preferred fish but there were plenty of other species to keep things interesting.   We typically caught and released them all except for the occasional walleye.  Between the fish biting we ate donuts and drank coffee.  There was always some kind of explanation for why we did not catch fish.  The water was too muddy or warm.  The river had been fished out with commercial gill nets. At one point there was talk of electrified nets and poison applied to catch or kill the sea lamprey (Petromyzon marinus). Sea lamprey are cartilaginous ancient parasitic fish that have been around for 340M years and survived all of the extinction events.  Before the advent of shipping canals in the mid-19^th century, Niagara Falls was a natural barrier to sea lamprey migration into the Great Lakes.  The first sea lamprey was discovered in Lake Superior in 1938 and in other Great Lakes earlier.  Sea lamprey have a devastating effect on the commercial and game fishery of the Great Lakes because of their reproductive success and success as a parasite.  Each lamprey can kill up to 40 lbs of game fish per year and reduce the fishing harvest to a fraction of what it should be.  The program to control sea lamprey is highly successful largely by controlling the larval forms that develop and migrate in various tributaries off the Great Lakes like Bad River.

What got me thinking about the sea lamprey again?  Over the past two days I was staying at a hotel on Lake Superior and noticed the parking lot had a small fleet of trucks from the US Fish and Wildlife Service (USFWS). Each pickup truck had SeaLampreyControl.org painted on the rear quarter panel.  When I saw all of these trucks, I was actively looking for the personnel driving them.  I was interested in how this program was able to survive the cuts of the Trump administration.   It seemed like an easy target.  Most people don’t know anything about the Great Lakes ecosystem or how it is scientifically monitored and managed.  Most people have no clue that as they are driving across Michigan’s upper peninsula and across northern Wisconsin into Minnesota that there are fishery biologists all along the way focused on that habitat and trying to keep it healthy.  The Trump administration has made it very clear that they don’t care about the environment or any of the associated science and in fact have open contempt for it.  But I was not able to find any of the staff driving those trucks so I decided to do my own research.  I have done limnology and freshwater biology and chemistry courses and research as an undergraduate – but this research was more straightforward.  I wanted to know if this program was a target of the Trump administration’s cuts.

The Department of Government Efficiency (DOGE) did target the U.S. Fish and Wildlife Service’s (USFWS) Sea Lamprey Control Program. In early 2025, 14 critical personnel (12 from USFWS and two from the U.S. Geological Survey(USGS)) were terminated right before the spring treatment cycle.  The Resolution highlights the fact that terminations and hiring freezes would reduce the lamprey control program by 1/3, leaving insufficient staff to implement the program and putting the Great Lakes fishery at great risk.  At least one reference states that the Trump administration was “ordered” to reinstate the fired workers (2).  Other sources suggest the cuts were potentially much larger and that Trump reversed them in January of 2026 by a bill. There is also supposed to be a paper trail of what happened in Congressional Committees and within the Department of the Interior / USFWS Memos.  But I can’t find any details about this.  I was eventually able to locate a press release about the firings and how they were reversed by court order.  The specific USFWS employees were mentioned (4).

My overall analysis based on limited information highlights the obvious lack of rational thinking. Before I had located any of the references, it seemed like the usual bad administrative exercise of just cutting an arbitrary number of people for the sake of making numbers. We know from DOGE headlines that this effort saved nowhere near the amount that they claimed and fired critical workers who had to be immediately rehired because the firings created a safety threat to the American people.  At first glance it seems like that is what happened to sea lamprey control. After the initial workforce reduction, the economic details presented in reference 1 were considered and the staff were rehired in order to prevent massive losses to the Great Lakes Fishery.  

But that is not what appears to have happened.  There was no rational thinking by the administration, only a legal technicality noted by a judge who said the administration does not have the power to fire staff from agencies outside the Executive Branch.  A Supreme Court decision eventually blocked reinstatement of probationary employees on a technicality.  So, no rational reversal of an irrational decision. To be clear, I am not sure that anyone knows the status of the fired employees from the USFWS and USGS.  I have sent an email to the USFWS to clarify what happened and I asked them specifically about whether sea lamprey control was at full strength.

My intent in writing this post is to focus squarely on the shortcomings of ideological decision making.  First, it short circuits rational decision making. Just looking at the economics – it makes no sense to stop a cost-effective government initiative that benefits a multibillion-dollar fishing and tourist industry.  That alone has value even without comparisons to how the current administration has squandered billions in tax dollars and continues to do so.  Second, the ethical dimension exists in the form of: “Is it ethical to stand by and watch the Great Lakes ecosystem destroyed and overrun by millions of parasitic fish?”  According to the numbers the sea lamprey is capable of this level of destruction.  The sea lamprey would not even be in the Great Lakes if it were not for government canal building initiatives bypassing Niagara Falls allowing the initial migrations.  At that level sea lamprey and other invasive species are a manmade problem and it seems like a serious ethical lapse to not want to prevent that catastrophic outcome.

This is one small example of what happens when you have ideological myopia. Allowing the destruction of the Great Lakes ecosystem would be consistent with this administration's approach to climate science, medical care, scientific and medical research, and international aid all based on an alleged financial gain. It is essentially running a government that should have benefits for the people - like running a business to produce benefits for only the favored few.  

It is hard to imagine a Great Lakes without Grandfathers and Grandchildren fishing.... 

 

George Dawson, MD, DFAPA

 

References:

1:  United States Committee of Advisors to the Great Lakes Fishery Commission. Resolution 25-01: A Resolution Calling for Full Support of the Great Lakes Sea Lamprey Control Program Including Full Restoration of Staff and an Exception to the Hiring Freeze in the United States to Implement the Critical Bi-National Control Program.  https://www.glfc.org/pubs/pdfs/resol2025_1.pdf

2:  Greco F.  U.S. firings reversed, yet Great Lakes Sea lamprey fight faces uphill battle.  CBC Lite April 4, 2025.  https://www.cbc.ca/lite/story/1.7501665

3:  Krumme M.  The invasive sea lamprey is poised for comeback in the Great Lakes.  Wisconsin Public Radio.  December 8, 2025. https://www.wpr.org/news/invasive-sea-lamprey-comeback-great-lakes-federal-funding

4:  Jenkins D.  Judge adds U.S. Fish and Wildlife to order curbing DOGE firings.  Capital Press.  March 3, 2025.  https://capitalpress.com/2025/03/03/judge-adds-u-s-fish-and-wildlife-to-order-curbing-doge-firings/

5:  Totenberg N, Gatti C.  Supreme Court lets Trump move forward with firing thousands of federal workers.  NPR News April 8, 2025.  https://www.npr.org/2025/04/08/nx-s1-5351799/scotus-probationary-workers

6:  Fritze J, Cole D Sneed T.  Supreme Court backs Trump for now on fired probationary federal employees.  CNN.  April 8, 2025.  https://www.cnn.com/2025/04/08/politics/probationary-fired-employees-supreme-court-trump

7:  Bijman V. The Sea Lamprey (Petromyzon marinus) Invasion: The Construction of an Invasive Animal Threatening a "Healthy" Great Lakes Ecosystem. J Hist Med Allied Sci. 2025 Oct 8;80(4):363-383. doi: 10.1093/jhmas/jrae046. PMID: 39889225; PMCID: PMC12504013.

“Although sea lamprey research, localized control practices, and environmental discourses considerably changed, the sea lamprey continued to be regarded as an invasive fish that was not allowed to exist in the Great Lakes.”

8:  Siefkes MJ. Use of physiological knowledge to control the invasive sea lamprey (Petromyzon marinus) in the Laurentian Great Lakes. Conserv Physiol. 2017 May 30;5(1):cox031. doi: 10.1093/conphys/cox031. PMID: 28580146; PMCID: PMC5448140.

9:  Dale P. Burkett, Jessica M. Barber, Todd B. Steeves, Michael J. Siefkes, Sea lamprey control 2020 – 2040: Charting a course through dynamic waters, Journal of Great Lakes Research, Volume 47, Supplement 1, 2021, Pages S809-S814,

“Delivery of a successful Sea Lamprey Control Program depends upon bi-national, government-funded operations and research and is contingent upon public understanding of the need for the Program and its ecosystem and economic benefits. Changing social, political, regulatory, and climatological environments present a host of strengths, weaknesses, opportunities, and threats requiring an array of responses.”

10:  F.B. Neave, R.M.W. Booth, R.R. Philipps, D.A. Keffer, G.A. Bravener, N. Coombs,  Changes in native lamprey populations in the Great Lakes since the onset of sea lamprey (Petromyzon marinus) control, Journal of Great Lakes Research, Volume 47, Supplement 1, 2021, Pages S378-S387,

The control of invasive sea lamprey in the Great Lakes basin has been highly successful, but has deleteriously affected native lamprey species. American brook, northern brook, silver and chestnut lampreys are all susceptible to lampricide treatments.

 

Supplementary 1:  It is widely known that Freud studied eels as a young biologist and in that process also studied the nervous system of the sea lamprey.  Here are some of Freud's original drawings:  https://chsi.harvard.edu/freud-riddle-eel

Supplementary 2:  The sea lamprey pesticides:  Are they toxic to dopaminergic neurons? 

TFM and Bayluscide, are specialized pesticides called lampricides. These are applied by agencies like the Great Lakes Fishery Commission to targeted streams and tributaries where young lamprey larvae hatch and develop.

 

• TFM (3-trifluoromethyl-4'-nitrophenol): This is the most widely used lampricide. It is a selective poison that disrupts the energy metabolism (mitochondrial decoupling) of sea lampreys at concentrations that leave most other native fish and organisms unharmed. Lampreys have a reduced capacity to detoxify the chemical.

 

• Bayluscide (niclosamide): Highly toxic lampricide that is often used in combination with TFM. By adding a small amount of Bayluscide to TFM, agencies can reduce the overall amount of chemical needed, keeping treatment methods highly effective and lowering costs. A granular time-release form is also used to treat deep, slow-moving waters or estuaries where TFM is less effective.

 

Both chemicals are regulated restricted-use pesticides that break down naturally in the environment and do not bioaccumulate.  Niclosamide has been suggested as a treatment for neurodegenerative disorders including Parkinsons and it a potential neuroprotectant:

 

Apolloni S, D'Ambrosi N. Repurposing niclosamide for the treatment of neurological disorders. Neural Regen Res. 2023 Dec;18(12):2705-2706. doi: 10.4103/1673-5374.373705. PMID: 37449632; PMCID: PMC10358648.

 

Disenrollment And Payment Suspension To Minnesota Health Care Providers MHCPs)...

 

Inspection of the above timeline shows how the second wave of Operation Metro Surge in the Twin Cities was coordinated with a crackdown on suspected health care benefits fraud that was attributed to undocumented communities.  The threat to withhold funding was based on that unsubstantiated hypothesis.  The Trump administration used a coordinated threat narrative tying “open border” immigration policy to fraud exploiting public systems.  It is a familiar “the unworthy are stealing your tax dollars” political rhetoric.   The coordinated threat narrative—which claimed that local "open-border" policies directly enabled massive Medicaid and pandemic welfare fraud rings—collapsed under legal and factual scrutiny.  The vast majority of an estimated 3,000-4,000 immigration arrests were not linked to health care fraud.  The people charged were US citizens. The Metro Surge itself caused $700M in economic damage and lost economic activity.  It also cost taxpayers an estimated $18M per week.  In other words the financial cost of the operation was much more than the fraud detected but far beyond that there were the lives lost in the process.    

There was a recent massive disenrollment of Minnesota Health Care providers (MHCPs).  By definition these are health care providers funded by Medicaid (Medical Assistance, or MA) and MinnesotaCare.  Each one of these providers has a portal to the state that enables direct payment for services.  The Minnesota Department of Human Services (DHS) has disenrolled 3,411 out of nearly 5,600 reviewed "high-risk" Medicaid providers. These providers have had their Minnesota Health Care Programs (MHCP) payments immediately cut off. Disenrolled entities have 60 days to appeal their removal (1).  Unless they have a successful appeal they can no longer bill Medicaid.

Minnesota identifies “high risk providers” as belonging to the following 14 categories (2):

1. Early Intensive Developmental and Behavioral Intervention (EIDBI): Autism therapy and developmental services for children.
2. Adult Companion Services: Non-medical care, socialization, and supervision for adults.
3. Adult Day Services: Structured community-based programs offering health and social services.
4. Adult Rehabilitative Mental Health Services (ARMHS): Mental health services focused on instructing and supporting independent living skills.
5. Assertive Community Treatment (ACT): Intensive, comprehensive community-based outreach and treatment for severe mental illness.
6. Community First Services and Supports (CFSS): Assistance with activities of daily living and health-related tasks.
7. Individualized Home Supports (IHS): Support provided in a person’s own home or community to build independent living skills.
8. Integrated Community Supports (ICS): Multi-tenant housing support services for individuals with disabilities.
9. Intensive Residential Treatment Services (IRTS): Time-limited, 24/7 mental health treatment in a residential setting.
10. Night Supervision Services: Overnight monitoring and assistance in a person's home.
11. Nonemergency Medical Transportation Services (NEMT): Transportation for medical appointments and services.
12. Peer Recovery Support Services: Substance use disorder support provided by individuals with lived recovery experience.
13. Recuperative Care: Medical care and support for individuals experiencing homelessness who are too ill to live on the street.
14. Housing Stabilization Services:  Consult and develop a housing plan for individuals without a case manager and support transition and stabilization in that setting.

 

  As a former acute care and inpatient psychiatrist at least 4 of these services (3,4,5, and 9) were critical in discharge planning for hospitalized patients.  That could mean the difference between a timely discharge and either no discharge or a suboptimal plan.  These resources are clearly in place for assisting disabled persons with few resources.  The Trump administration has already prioritized tax cuts for the wealthy over health care for the disabled and low-income adults most notably by cutting an estimated $1 trillion in Medicaid spending over the next 10 years. Much of those cuts are backloaded into the last 5 years of the bill.  As estimated 10 million people will lose healthcare coverage.  

The threatened cuts to Minnesota apparently occurred on the basis that the Trump administration Centers for Medicare and Medicaid Services (CMS) demanded the state implement a corrective action plan and they threatened to withhold up to $2 billion in Medicaid funding and froze over $200 million in payments. There are clear problems with that idea at the both the local and federal levels. 

The first problem is the determination of waste, fraud, and abuse in Minnesota.  How is it measured and are there any problems with the metrics?   CMS does keep ongoing records for Improper Payment Rates by year.  From the CMS page for the 2025 report just released:

“The Medicaid estimated improper average payment rate (comprised of the past three cycles of approximately 17 states per cycle from reviews in 2023, 2024, and 2025) was 6.12%, or $37.39 billion, compared to the FY 2024 reported rate of 5.09%, or $31.10 billion. Of the FY 2025 Medicaid improper payments, 77.17% were the result of insufficient documentation, which is generally not indicative of fraud or abuse.”

The improper payment rates for Medicaid/CHIPS in Minnesota was 2.2% in both 2022 and 2025 – the most recent years surveyed.  That compares to a nationwide average improper payment rate of 15.62% and 6.12% respectively.  It is also below a national threshold established in H.R. 1 of 3% for financial penalties that will apply to all states starting in 2030.  The author of this article (dated January 30, 2026) clearly states that this indicates the action against Minnesota is partisan (1).

All of this occurs in the context of unprecedented personal and political attacks by President Trump and his cabinet.  Waste, fraud, and abuse is one of their common attacks.  It was the basis for the initial DOGE purges of 300,000 federal employees, that saved no money, eliminated considerable expertise and institutional knowledge and impacted the safety of the American people to the point that 25,000 had to be called back immediately.  The firings include 40,000 VA employees including 3,000 nurses and 1,000 physicians.  Part of those firings included 17 Inspector Generals whose job it is to determine waste, fraud, and abuse.  A subsequent report showed that the effects of the Inspectors General on waste, fraud, and abuse dwarfed the impact of DOGE. It is remarkable that the main selling points of DOGE were gross exaggerations of waste, fraud, and abuse. The goal of 1-2 trillion in savings was unrealistic from the outset.  At one point the White House spokesperson and Elon Musk both claimed that $2.7 trillion in Medicaid and Medicare benefits had been diverted to foreign nationals overseas.  In actual fact this was an estimate of improper payments by numerous government agencies since 2003. 

Apart from the lack of government savings and efficiency, destruction of government infrastructure, and destruction of federal employee morale – there has been a massive human cost that is hardly mentioned in the United States. Defunding USAID and PEPFAR will result in an estimated 500,000 to 1,000,000 deaths annually, 4.2 million deaths due to AIDS, and as many as 14.1 million deaths by 2030.  The excess mortality will primarily be from AIDS, malaria, tuberculosis, nutritional deficiencies, and diarrheal diseases (4).  

To be clear, fraud is always occurring at some level whether it is government programs or internet schemes designed to steal money from citizens. There are no fraud free zones in the United States and the protections for private citizens are minimal. Medicaid Fraud Control Units under the Inspector General are charged with investigating fraud and recovering money if possible.  Since Medicaid is a joint federal and state program each state also has an Inspector General or Medicaid Fraud Control Unit (MFCU).

It should be clear to any objective observer that rage and faux rage are all part of the Trump and MAGA ethos.  It is more commonly referred to as bullying and intimidation directed at anyone Trump dislikes.  Waste, fraud, and abuse is their war cry despite the fact that Trump has granted clemency to persons who have been convicted of fraud and in many cases ordered to pay penalties and restitution for a total of $2 billion. That is over $2 billion just excused by an administration who claims to be concerned with fraud.

That is what is really going on in Minnesota.  It is the only explanation for the great precipitous disenrollment of MHCP providers and Vance’s latest demand to investigate the Governor and Attorney General for “fraud”.  This pattern will continue until this contentious government is either voted out or shut down by Congress or the Judicial branch.      

 

George Dawson, MD, DFAPA

 

References:

1:  Schneider A.  CMS Quietly Releases Medicaid State Improper Payment Rates for 2025: How Did Minnesota Do?.  January 30, 2026  https://ccf.georgetown.edu/2026/01/30/cms-quietly-releases-medicaid-state-improper-payment-rates-for-2025-how-did-minnesota-do/

2:  Clemency Grants by President Donald J. Trump (2025-Present).  Office of the Pardon Attorney:  https://www.justice.gov/pardon/clemency-grants-president-donald-j-trump-2025-present

3:  Minnesota Litigation Tracker (Attorney General Web Site).  Minnesota is currently or was a party in 61 lawsuits against the federal government. https://www.ag.state.mn.us/Rule-Of-Law/Litigation/

4:  Cavalcanti D, de Oliveira Ferreira de Sales L, da Silva A et al.  Evaluating the impact of two decades of USAID interventions and projecting the effects of defunding on mortality up to 2030: a retrospective impact evaluation and forecasting analysis.  The Lancet, 2025; 406, 283-29  https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(25)01186-9/fulltext

 5:  Karcher-Ramos M.  Housing, Jobs and the Local Economy: Operation Metro Surge’s Long-term Impacts to People and Prosperity in Minnesota.  McKnight Foundation News. https://www.mcknight.org/news-ideas/economic-impact-operation-metro-surge/

6:  Ellie Roth.  DHS disenrolls 3,400 Medicaid providers while flagging small fraction for further fraud review.  MPR.  June 4, 2026.  https://www.mprnews.org/story/2026/06/04/dhs-disenrolls-3400-medicaid-providers-while-flagging-small-fraction-for-further-fraud-review

7:  Medicaid Program Integrity.  Minnesota Department of Human Services.  https://mn.gov/dhs/program-integrity/

 

 

Supplementary 1:  Lawsuits between states and the federal government under each administration

Presidential Administration	Total Multistate Lawsuits Filed by States
Ronald Reagan (1981–1989)	15 lawsuits
George H.W. Bush (1989–1993)	8 lawsuits
Bill Clinton (1993–2001)	18 lawsuits
George W. Bush (2001–2009)	76 lawsuits
Barack Obama (2009–2017)	78 lawsuits
Donald Trump (First Term) (2017–2021)	138 lawsuits
Joe Biden (2021–2025)	Approximately 100 lawsuits
Donald Trump (Second Term) (2025–Present)	100 in the first 18 months

 

Supplementary 2:  I received the following notice by email today from the Minnesota Department of Human Services.  My interpretation of it is that they are seeking to provide relief to providers by lifting the payment suspension based on an appeal.  This is obviously one small part of a massive and unnecessary drama initiated by the Trump administration.