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.

The First 25 Pages….

 

I was minding my own business on Twitter last week and noticed a slide posted with the image of the DSM-5.  It did not take too long the realize that it was not posted by anyone who had read the DSM – at least not the first 25 pages.  These pages are technically the introduction to the diagnostic section of the manual.  Important words because they summarize the process, orient the reader to the manual, and describe several important qualifiers.  That is how I was able to tell that the slide on Twitter had nothing to do with the DSM.  The statements made about it were essentially false.

The first problem is the characterization that diagnoses are “operational criteria” and that therefore it is a “fallible tool”. These are common mistakes by anyone who has not been trained in medicine and the understanding of disease states.  For simplicity, consider the definition from my physical diagnosis text from medical school:

"For several thousand years physicians have recorded observations and studies about their patients.  In the accumulating facts they have recognized patterns of disordered bodily functions and structures as well as forms of mental aberration.  When such categories were sufficiently distinctive, they were termed diseases and given specific names. “ 

 

DeGowin and DeGowin, Bedside Diagnostic Examination. 1976, p 1

 

The introduction notes that the precursor to the American Psychiatric Association (APA) published the precursor to the DSM back in 1844.  Even before that, the description of psychiatric disorders stretches back for thousands of years. The above definition notes the importance of patterns that are consistent over time.  A detailed description of these patterns and those evolved descriptions is how all of medicine has advanced.  The other important aspect of these descriptions is that they are sufficiently descriptive.  In the most basic analysis, the DSM is the standard way that physicians have indexed diseases and medical problems from the beginning.  The idea that it is merely “operational criteria” as in arbitrary routine measurement is far from accurate. The introduction is very clear that a diagnosis is not a checklist of symptoms and that a formulation is required.

The fact that the DSM inconveniently contains a Neurocognitive Disorders chapter and qualifiers about ruling out all other medical illnesses as causes of the presenting disorder is typically not mentioned by the discrete pathological lesion crowd.  If it is, the standard rhetoric that is applied goes something like this: "Well it is a disease it's just no longer a psychiatric disease. When real diseases are discovered they are no longer in the purview of psychiatry."  Even though psychiatrists have been diagnosing and studying these diseases for over a hundred years.

 One of the frequent mischaracterizations of medicine and psychiatry is that it operates from a biomedical model. This is confusing to a lot of people because physicians are certainly trained and interested in the molecular biology of both normal human function and all of the associated pathophysiological functions. Psychiatrists are interested in brain function in particular but also other systems that directly affect psychiatric care. Every psychiatrist has performed physical and neurological examinations at some point in their career.  Every psychiatrist has done a detailed neurological examination. Every psychiatrist has seen and read ECGs and brain imaging studies. That does not mean that psychiatrists don’t know the limitations of standard medicine when it comes to analyzing problems generated by both the brain and its associated conscious state.  If fact, psychiatrists have some of the best analyses and criticisms of these approaches. The standard biomedical model criticism is used to suggest an absurd degree of reductionism.  That is a model that no psychiatrist adheres to and the evidence is the statement in the DSM about multiple underlying causes of mental disorders.  Interestingly many of these same critiques often advocate for specific psychosocial causes of mental disorders on a global scale – a form of psychosocial reductionism.

 

There are often philosophical digressions on the nature of mental illness and whether mental illness is a disease or not.  I have written fairly extensively about that in other areas of this blog.  For the purpose of addressing the slides I will say that the lesion basis for both mental illnesses and physical illnesses was addressed from within the field in response to the pathological theories by Virchow and Koch. Interestingly, the answer to that theory was a study of hypertension:

“It was in fact the example of hypertension which finally discredited the nineteenth-century assumption that there was always a qualitative distinction between sickness and health. The demonstration by Pickering and his colleagues twenty years ago (5) that such a major cause of death and disability as this was a graded characteristic, dependent, like height and intelligence, on polygenic inheritance and shading insensibly into normality, was greeted with shock and disbelief by most of their contemporaries, and the prolonged resistance to their findings showed how deeply rooted the assumptions of Koch and Virchow had become.” (2)

Sixty years later, some academics apparently still have a hard time realizing that mental illnesses are polygenic illnesses of varying severity and a source of significant death and disability and yet there is no clear qualitative difference between illness and disease demarcated by a lesion.  We are well past the time that they should be ignored.

Conflict of interest is also a favorite tactic of those who seek to discredit psychiatry.  The suggestion in the original slide was that both committee approaches and pharmaceutical influence were sources of corruption.  The first 25 pages describes why this is not true.  The financial limitations of committee members were significant. In the intervening 6 years since the DSM-5 was released there has been no evidence of pharmaceutical influence.  Why would there be?  Pharmaceutical companies can come up with any indication they need for medication indications. They don’t need a manual to develop a symptom list and initiate a clinical trial for that purpose.  Anyone who has actually read the manual notices that the highlights under each category stress a pluralistic approach to mental illness and no actual treatment approaches are described.  The vast majority of new pharmaceuticals are prescribed by non-psychiatrists like primary care physicians and physician extenders. In my experience, many of these prescriptions are for transient conditions that a psychiatrist would not prescribe a medication for.

 

The current reality is this.  The DSM consider mental disorders to be disorders. They don’t address the issue of what is a disease and what is not. The manual is very clear about their process and the fact that it is a work in progress. That is nothing unique to psychiatry. Diagnoses are always in a state of flux across all of medicine and that even includes diagnoses that are defined by particular lesions.  As the science of medicine advances, expect more diagnoses and large diagnostic categories like asthma, diabetes mellitus Type II, and depression to be broken up into smaller and smaller categories that will probably correlate with physiological findings.  The authors of DSM-5 are very clear that the manual is designed to be a cooperative document with both NIMH Research Domain Criteria (RDoC) for research purposes and International Classification of Diseases 11th revision (ICD-11) for administrative an epidemiological purposes.  The good news is that if you are not a psychiatrist or mental health clinician the details contained in the manual are probably not useful for you to know.  On my blog, I pointed out that even primary care physicians don’t read it, so why would anyone else?

 Psychiatrists have obvious theoretical and historical interest in the manual, but on a day to day basis it is safe to say that nobody is closely reading it except for researchers. It is very apparent that the so-called critics of psychiatry rarely do or they would not be adhering to premises that are clearly wrong at the outset. Equally disappointing is the endless stream of philosophical arguments that make similar errors. I read a paper by Jefferson (6) less than a month ago where she posits three different ways that mental disorders can be considered brain diseases. And of course the first one is Szasz’s – specifically:

 

“If Szasz is right, the very idea that mental illness is an illness depends on the idea that there is independent brain pathology causing mental distress.”

 

She goes on to say that Szasz ”drew a skeptical conclusion” from his own definition of brain disease and concluded that most mental disorders were not brain diseases. I seem to be the only one that recognizes that Szasz has been wrong about a lot of things for a long time, most notably the restricted pathologically based view of any or all diseases. 

 

That doesn’t seem to prevent it from being dragged out time and time again. The realm of philosophers and antipsychiatrists is apparently the only place Szasz is never wrong. And people can say whatever they want about the DSM-5 – even if they clearly have not read the first 25 pages.

 

 

 

 

George Dawson, MD, DFAPA

 

 

 

References:

 

1:  Leonard A. The theories of Thomas Sydenham (1624-1689). J R Coll Physicians Lond. 1990 Apr;24(2):141-3. PMID: 2191117; PMCID: PMC5387565.

 

2:  Kendell RE. The concept of disease and its implications for psychiatry. Br J Psychiatry. 1975 Oct;127:305-15. doi: 10.1192/bjp.127.4.305. PMID: 1182384.

 

3:  Smith R. In search of "non-disease". BMJ. 2002 Apr 13;324(7342):883-5. doi: 10.1136/bmj.324.7342.883. PMID: 11950739; PMCID: PMC1122831.

4:  Meador CK. The art and science of nondisease. N Engl J Med. 1965 Jan 14;272:92-5. doi: 10.1056/NEJM196501142720208. PMID: 14223129.

5:  Oldham PD, Pickering G, Fraser Roberts JA, Sowry GS. The nature of essential hypertension. Lancet. 1960 May 21;1(7134):1085-93. doi: 10.1016/s0140-6736(60)90982-x. PMID: 14428616.

6:  Jefferson, A. (2021). On Mental Illness and Broken Brains. Think, 20(58), 103-112. doi:10.1017/S1477175621000099

Graphics Credit:

Slides are all made by me with appropriate referencing.  Click on any slide to enlarge.