Kendler Keeping It Real…..

 

Kenneth Kendler, MD needs no introduction to anyone even vaguely familiar with the psychiatric literature.  If you need to do your own research his accomplishments and scientific papers are widely available on the Internet. This post is to focus on his recent commentary in JAMA psychiatry (1) over the issue of psychiatric diseases and whether or not they are brain diseases.  He starts out with a 1867 quote from Griesinger stating that the brain is the only logical origin for symptoms of insanity. His analysis is at the level of “pathological and physiological” factors.

He briefly reviews two common arguments about whether psychiatric disorders are brain diseases.  The first Cartesian dualism that a mind emerges from the brain and is not the same as a brain. Since a brain is necessary for all mental phenomenon there is no specific answer to the question about whether the phenomenon observed with psychiatric disorders are diseases.  The second common argument is that grossly detectable brain diseases (lesions at autopsy and sophisticated imaging)  eventually became the purview of neurology.  To complement Kendler’s commentary, I would add that this has never been strictly true since both overt lesions and physiological brain dysfunction has always been studied by psychiatrists.  It has been a common antipsychiatry argument advanced by Szasz and others based on 19^th century concepts.  Ron Pies (2) has recently commented that it involved a misunderstanding of Virchow’s work on pathophysiology.   

An indirect way this problem has been handled is to suggest that it has to do with the vague definitions of disease (3).  Without a clear definition, anyone can use their own to declare that psychiatric disorders are not diseases. That has been a common tactic used to declare that not only that mental illnesses are not diseases – because of the lack of clear gross pathology they do not exist.  Dealing with the problem at this rhetorical level has not been very successful largely due to the lack of interest in rhetoric on the part of medical professionals and constant repetition by the rhetoricians.

More practical philosophical attempts at disease definition like loss of function models seem to not have much traction. Munson and Resnick (4) proposed one of these models and also suggested that the loss of function is related to programming errors in biological processes.    

Kendler suggests a clear path that has appeal to anyone who has studied pathophysiology and treated illnesses without clear lesions or with lesions that had to be the end product of some unknown pathophysiology.  That group of people would be anyone who has done an internship or residency in any medical field.  Anyone with that experience has seen a wide array of medical conditions that are polygenic in nature and have either an unknown or highly speculative pathophysiology.

The suggested path is genetics-> pathophysiology or more broadly “genetics -> brain -> schizophrenia.”  Rather than bemoaning all of the failed GWAS studies and Decade of the Brain, Kendler cites “the most robust empirical findings in all of psychiatry—that genetic risk factors impact causally and substantially on liability to all major psychiatric disorders.”  More specifically he cites a 2022 report that shows that gene expression (as mRNA levels) of risk variants for schizophrenia were noted in the brain and no other tissue.  That brings the brain expression in his causal link into clear focus. 

At that point he hedges and suggests that this may not be robust enough to suggest that a brain disease is occurring. For me it is plenty.  He goes on to suggest that there are 5 advantages of this approach including data driven rather than metaphysical, bypasses the 19^th century need for gross lesions, fits with pluralism or multiple possible etiologies, can potentially provide information about other diseases affecting the brain, and avoids a hard line of demarcation between normal and disease at the physiological level.  The last point has been elaborated in the more recent past as quantitative versus qualitative diseases and the associated variants. 

On the limitation side – a genetics only approach is the main consideration.  The antipsychiatrists that he has alluded to may be realizing that they need to finally modify their 19^th century rhetoric and I have seen the equally absurd claims that there are no genetic effects for psychiatric disorders.  The difference is that Kendler is an expert in the area – so only the most dedicated post modernists will claim that they did their own research and came to a different conclusion.  He does see the innovation of being able to detect tissue levels effects of genetic variants as a good starting point.  The goal is to elaborate the functional networks affected by these variants, describe mechanisms at the molecular level, and how those mechanisms are affected by variants (5).

This is really an inspiring commentary at a time when it is getting more fashionable to attack basic science research in psychiatry. I saw a comment just last week about how biological psychiatry was a drain on mental health research.  And there are frequent comments about how there should be more psychosocial research, even though there is no clear evidence that is necessary.

As a clinical psychiatrist and a physician first, my observations have been that most people go to medical school to gain knowledge about the human body and how to treat, prevent and where possible cure diseases. Speculative pathophysiology and mechanisms are all part of that starting in the first two years of basic science course and extending to clinical rounds at bedside during residency.  Philosophy and endless arguments about the nature of disease or psyche is not.  Psychiatry has lost its way many times due to an inability to recognize and respond to rhetoric. Kendler’s solution to the question of whether mental disorders are brain diseases is an elegant one and it is consistent with the way physicians are trained.  It also establishes a boundary that some questions in psychiatry are not answerable by philosophy.

Finally, what is still lacking?  I think that ultimately, we want medicine and psychiatry to be part of a comprehensive view of human biology. We need more comprehensive theories about human biology and how things really work at the physiological and molecular level.  That knowledge is currently spotty across all specialties. Biology theory rather than biological psychiatry is really the goal here and we can use more input from theoretical biologists of all specialties.

George Dawson, MD, DFAPA

References:

1:  Kendler KS. Are Psychiatric Disorders Brain Diseases?-A New Look at an Old Question. JAMA Psychiatry. 2024 Feb 28. doi: 10.1001/jamapsychiatry.2024.0036. Epub ahead of print.

2:  Pies R.  Did Szasz Misunderstand Virchow’s Concept of disease? Psychiatric Times. Feb 21, 2024.  https://www.psychiatrictimes.com/view/did-szasz-misunderstand-virchow-s-concept-of-disease

3:  Pies RW, Dawson G.  Epistemic Humility in Psychiatry: Why We Need More Montaigne and Less Savonarola.  Psychiatric Times.  Oct 19, 2023.  https://www.psychiatrictimes.com/view/epistemic-humility-in-psychiatry

4:  Albert DA, Munson R, Resnik MD.  Reasoning in Medicine: An Introduction to Clinical Inference.  Baltimore, Maryland: The Johns Hopkins University Press, 1988: 150-180.

5:  van Dongen J, Slagboom PE, Draisma HH, Martin NG, Boomsma DI. The continuing value of twin studies in the omics era. Nat Rev Genet. 2012 Sep;13(9):640-53. https://doi:10.1038/nrg3243

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