"Look ON the Bright Side of Life"

Monty Python
The Holy Grail -- Witch Scene (1975)

Probably one of the things Monty Python did better than anyone else ---

• They took an irreverent historical sensibility
• And combined it with completely wrong and differing ideas and pitted them against each other -----
  • ​Whose right?  Nobody's right.
• There is the not so subtle implication that this also rings true in Modern Times.

For me, when I see debates about which flawed, scientifically invalid diagnostic category someone fits into ---

• ​OMG --- how effing stupid are you people --- don't answer I think I know.

On the other hand, someone could say that about me, if they hyper-focused on my flaws.

It doesn't mean those challenges don't exist --- but there are Strengths, too.

​RESEARCHERS vs. CLINICIANS

• Researchers Around the World understand the URGENCY to get to the underlying biology of psychiatric disorders.
  • By and large, Clinicians do not appreciate how shaky current diagnostic foundations actually are.
    • ​​There are exceptions and some Clinicians have spoken out.​​​​​

• On the other hand, Clinicians are playing a major role in trying to hold this society together under often less than ideal circumstances.

Rules of Evidence and the Mess in Mental Health

​Analysis of human neuronal cells carrying ASTN2 deletion associated with psychiatric disorders (2024)

*Japanese Researchers

​Schizophrenia (SCZ), autism spectrum disorder (ASD), and bipolar disorder (BP) are very common psychiatric disorders, with high lifetime prevalence rates of ~0.5% , 2.5%, and 1%, respectively.

They are characterized by their duration as chronic diseases, from childhood to the time of death. This results in a longer treatment period and extensive social and personal damage.

​However, the biological pathogenesis of these psychiatric disorders is not well understood.

Their understanding is urgently needed to develop novel therapies that significantly improve the functional outcomes of patients.

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, has established the diagnostic criteria for SCZ, ASD, and BP as independent and separate diseases.

​In contrast, in clinical settings, the comorbid diagnoses are also allowed, and in some patients, drawing the diagnose line is difficult, suggesting that these psychiatric disorders partially share clinical symptoms and phenotypes.

​[Val's Note:   The University of Colorado was one of the first to say -- we need the ability to make these diagnoses less by "the book" (meaning the DSM 5).

Further, handing out multiple co-morbid diagnoses is not particularly helpful to the patient --- we need PRECISION MEDICINE that is tailored to the individual and the underlying biology.]

​Indeed, studies reported that psychiatric disorders show common alterations, such as dysfunction in the white matter microstructure in the body of the corpus callosum and brain responses in the ventral striatum during reward anticipation.

Additionally, recent genetic studies have uncovered common risk genomic variants in these psychiatric disorders.

​These findings imply that there are common underlying mechanisms in these psychiatric disorders, prompting us to examine the molecular and cellular alterations caused by the common risk variants across these psychiatric disorders.

Recently, we identified the variants in ASTN2 as a candidate risk factor for psychiatric disorders by whole-genome copy number variation (CNV) analysis.

​Moreover, a study reported that deletions in ASTN2 that would disrupt almost all transcript isoforms . . . are significantly enriched in patients with neurodevelopmental disorders, such as ASD, attention-deficit/hyperactivity disorder, and intellectual disability.

In support of these results, ASTN2 is also listed in multiple databases, such as SFARI (https://gene.sfari.org/) and DBDGD (https://dbd.geisingeradmi.org/), which are centered on genes implicated in these psychiatric disorders.