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New diagnostic framework, glutamate-mediated Excitotoxity in Neuro-Developmental & psychiatric disorDers

2/16/2025

Towards a consensus roadmap for a new diagnostic framework for mental disorders (2024)

"In general, the meeting indicated a crucial need for a biology-informed framework to establish more precise diagnosis and treatment for mental disorders to facilitate bringing the right treatment to the right patient at the right time."

Glutamate-Mediated Excitotoxicity in the Pathogenesis and Treatment of Neurodevelopmental and Adult Mental Disorders (2024)
Disruption of the mechanisms responsible for glutamate homeostasis may result in

the accumulation of excessive glutamate levels,
which in turn leads to increased calcium levels,
mitochondrial abnormalities,
oxidative stress, and
eventually cell atrophy and death.

This condition is known as glutamate-induced excitotoxicity and is considered as a pathogenic mechanism

in several diseases of the central nervous system,
including neurodevelopmental,
substance abuse, and
psychiatric disorders.

What is Excitotoxicity?

2/15/2025

Val's Take / Conjecture

"Excitotoxity" is actually associated with CELL DEATH across a wide range of diseases and disorders.
That wide range includes Neuro-Developmental & Psychiatric Disorders.
It does seem that dysregulated microglia that can result from Maternal Immune Activation, could promote inflammation and excess glutamate release and neurotoxity.

Further, there can be more overlap than we often appreciate.
Further, we talk so much about the lack of BIOMARKERS in Mental Health -- but that is a perennial battle in Medicine.
- Other areas of Medicine have more BIOMARKERS than Mental Health.
- But Mental Health is getting Metabolomic Biomarkers and others, and
- At least in the last few years, people have seen the Trifecta of Neuro-Developmental, Psychiatric and Neuro-Degenerative Disorders and researchers have been exploring the relationships among them to a greater and greater degree.
- More and more we're seeing relationships with other Disorders and Diseases as well.

RIPK1 activation in Mecp2-deficient microglia promotes inflammation and glutamate release in RTT (2024)

Glutamate-Mediated Excitotoxicity in the Pathogenesis and Treatment of Neurodevelopmental and Adult Mental Disorders (2024)

Discovery of the therapeutic potential of naltriben against glutamate-induced neurotoxicity (2025)

Editorial: Glutamate-Related Biomarkers for Neuropsychiatric Disorders (2019)

What Happens When You Have Too Much Glutamate?

What happens when you have too much glutamate?

Too much glutamate in the brain can cause nerve cells to become overexcited.

Overexcitement can lead to brain cell damage and/or death. In this case, glutamate is called an excitotoxin.

Having too much glutamate in the brain is associated with some conditions, including:

*Amyotrophic lateral sclerosis (Lou Gehrig’s disease).

*Multiple sclerosis.

*Alzheimer’s disease.

*Parkinson’s disease.

*Huntington’s disease.

*Stroke.

*Fibromyalgia.

*Chronic fatigue syndrome

Glutamate and microglia activation as a driver of dendritic apoptosis [a type of cell death]: a core pathophysiological mechanism to understand schizophrenia (2021)

The role of glutamate receptors in the regulation of the tumor microenvironment (2023)

Glutamate-induced excitotoxicity in Parkinson's disease: The role of glial cells (2020)

The Greatest Human diversity is in our immune systems

2/12/2025

Kendrick Lamar
DNA

University of Manchester Professor Dan Davis (UK)

The vast majority of Human DNA is the same.

The greatest human diversity is in our Immune Systems

Metabolomics, immuno-methylomics, Biomarkers And slowly moving to better diagnostics

2/7/2025

Val's Take/Conjecture

The New Insight that Neuro-Developmental and Psychiatric Disorders are not just disorders of the Brain -- is opening up new opportunities for biomarkers.
- Brain surgery is not required.
It is also profoundly re-conceptualizing what Neuro-Developmental & Psychiatric Disorders are and understanding relationships with:
- Auto-Immune Disease
- Cancer, and
- Neurodegenerative Disorders

Metabolomic Biomarker Signatures for Bipolar and Unipolar Depression (2024)

Infant microbes and metabolites point to childhood neurodevelopmental disorders (2024)

Association Between Human Blood Metabolome and the Risk of Psychiatric Disorders (2023)

The microRNA profile of brain-derived extracellular vesicles: A promising step forward in developing pharmacodynamic biomarkers for psychiatric disorders (2025)

"[A]nalyzing the miRNA expression profile of brain-derived EVs in blood may allow us to non-invasively assess miRNA dysregulation and thus to gain knowledge about the pathophysiology of psychiatric disorders and identify potential new predictive targets.

miRNA regulation of social and anxiety-related behaviour (2020)

"[O]verview of recent expression profiling and genetic association studies in human patient-derived samples in an attempt to highlight the most promising candidates for biomarker discovery and therapeutic intervention."

Dissecting depression symptoms: Multi-omics clustering uncovers immune-related subgroups and cell-type specific dysregulation (2025)

Exploring the use of immunomethylomics in the characterization of depressed patients: A proof-of-concept study (2025)

"DNA-methylation based cell-type profiles may be valuable in the immunological characterization and stratification of patients with MDD [Major Depressive Disorder].

"Future models should consider the inclusion of more cell-types and cytokines for better prediction of treatment outcomes."

Claudin-5 and occludin levels in patients with psychiatric disorders - A systematic review (2025)

"Recent research has underscored the critical role of blood-brain barrier (BBB) integrity in psychiatric disorders, highlighting disruptions in tight junction (TJ) proteins, specifically claudin-5 and occludin.

"These proteins are pivotal in maintaining the BBB's selective permeability, which is essential for brain homeostasis.

"Altered levels of the TJ proteins have been observed in various psychiatric conditions, suggesting potential as biomarkers for the pathophysiology of these disorders."

Large-scale metagenomic analysis of oral microbiomes reveals markers for autism spectrum disorders (2024)

MicroRNA-dependent control of neuroplasticity in affective disorders (2021)

Plasma and CSF neurofilament light chain distinguish neurodegenerative from primary psychiatric conditions in a clinical setting (2024)

Peripheral mitochondrial DNA as a neuroinflammatory biomarker for major depressive disorder (2025)

Towards a consensus roadmap for a new diagnostic framework for mental disorders (2024)

2/7/2025

Towards a consensus roadmap for a new diagnostic framework for mental disorders (2024)

Val's Take/Conjecture

It's been over a decade since the US National Institute of Mental Health said the DSM 5 lacked scientific validity.
Since then, researchers around the world have corroborated that concern and begun their own efforts to address it.
There are more and more entities and researchers around the world articulating the "crucial need" for a "biology-informed framework."
This has implications for Criminal Justice and State Disability Housing, Placement and Service provision.

Coming to Terms with the Criminal Justice System as the Disability Provider of Last Resort

Abstract

Current nosology claims to separate mental disorders into distinct categories that do not overlap with each other.

This nosological separation is not based on underlying pathophysiology but on convention-based clustering of qualitative symptoms of disorders which are typically measured subjectively.

Yet, clinical heterogeneity and diagnostic overlap in disease symptoms and dimensions within and across different diagnostic categories of mental disorders is huge.

While diagnostic categories provide the basis for general clinical management, they do not describe the underlying neurobiology that gives rise to individual symptomatic presentations.

The ability to incorporate neurobiology into the diagnostic framework and to stratify patients accordingly will be a critical step forward for the development of new treatments for mental disorders.

Furthermore, it will also allow physicians to provide patients with a better understanding of their illness's complexities and management.

To realize this ambition, a paradigm shift is needed to build an understanding of how neuropsychiatric conditions can be defined more precisely using quantitative (multimodal) biological processes and markers and thus to significantly improve treatment success.

The ECNP [European College of Neuropharmacology] New Frontiers Meeting 2024 set out to develop a consensus roadmap for building a new diagnostic framework for mental disorders by discussing its rationale, outlook, and consequences with all stakeholders involved.

This framework would instantiate a set of principles and procedures by which research could continuously improve precision diagnostics while moving away from traditional nosology. In this meeting report, the speakers' summaries from their presentations are combined to address three key elements for generating such a roadmap, namely:

* the application of innovative technologies,

*understanding the biology of mental illness, and

*translating biological understanding into new approaches.

In general, the meeting indicated a crucial need for a biology-informed framework to establish more precise diagnosis and treatment for mental disorders to facilitate bringing the right treatment to the right patient at the right time.

2025 Research: Neo-Natal Inflammation, Microglia, and Investigation of New Treatments

2/7/2025

2025 is bringing a continued focus on:

Neo-Natal Inflammation
Microglia (the Brain's Innate Immune Cells), and
More Investigation of New Treatments

Remimazolam attenuates lipopolysaccharide-induced neuroinflammation and cognitive dysfunction (2025)

Ginsenoside reprogramming microglia through the FGF/FGFR1 inhibits post traumatic stress disorder (2025)

Neonatal inflammation impairs developmentally-associated microglia and promotes a highly reactive microglial subset (2025)

Chronic Fatigue Syndrome & Neuro-developmental / Psychiatric Disorders

2/6/2025

Val's Take: IT TAKES A LOT OF TIME AND ENERGY to UNDERSTAND THESE DISORDERS, especially if they have not been easily resolved with current understandings.

What's left is pretty darn complicated --- Health Disorders such as:

Neuro-Developmental and Psychiatric Disorders
ME/CFS
Cancer
Autoimmune Diseases
Neuro-Degenerative Disorders
Neuro-Immune Disorders
Etc.

Most "Neuro-Developmental" and "Psychiatric" diagnoses at this point are conceptualized as NEURO-DEVELOPMENTAL, MULTI-SYSTEM DISORDERS in the Research.

How many People know that?
How many Clinicians know that?
How many Policymakers?

University of Michigan School of Medicine
Dr. Melvin McInnis

The Cells of People with Bipolar Disorder are Developmentally Different (2017)

Columbia Public Health
Dr. Mady Hornig

Scientists Discover Robust Evidence That Chronic Fatigue Syndrome (ME/CFS) Is a Biological Illness (2015)

Broken Battery

ME/CFS -- The Greatest Medical Scandal of the 21st Century (2024)

Many people with Neuro-Developmental & Psychiatric Disorders have issues with Burnout, Melt Downs & Shut Downs. BIO-ENERGETICS is turning out to be a big issue in Neuro-Developmental & Psychiatric Disorders.

In fact, some type of Mitochondrial Dysfunction and Fatigue is associated with many diseases and disorders.

A lot of people in the Homeless Population get tagged with being "LAZY" or "UNMOTIVATED," and I think what is going on is much more complicated.

Astrocytes in Depression and a complicated biological universe for criminal justice

2/5/2025

Various types of GLIAL CELLS in both the Central Nervous System (CNS) and the Peripheral Nervous System (PNS) seem critical in Neuro-Developmental Disorders, Psychiatric Disorders, Neuro-Degenerative Disorders as well as other Diseases and Disorders.

This is exceedingly complicated in 2025.

What happens if we have a Criminal Justice System that is unable to deal honestly and effectively with this COMPLEXITY?

Well, you might live in the most incarcerated country in the world that still has significant safety problems.

NeuroLingo

Liam Anuj O'Leary
McGill University (Canada)
McGill Group for Suicide Studies

Fewer astrocytes in depression

Astrocytic Neuroligin-3 influences gene expression and social behavior, but is dispensable for synapse number (2025)

Widespread Decrease of Cerebral Vimentin-Immunoreactive Astrocytes in Depressed Suicides (2021)

Microglia, Neuro-Degenerative Diseases & Neuro-Developmental Disorders

1/31/2025

Dr. Melanie Capasso
DZNE, Bonn, Germany

Overactive Microglia in the Aging Brain

"Not only neurons exist in the brain, but also immune cells, the microglia. These microglia form our 'brain security' and protect the brain from pathogens.

"But with increasing age, the microglia, which are supposed to protect the brain, permanently raise the alarm and become chronically active.

"Inflammation occurs: this is an excessive immune reaction. The microglia turn against the brain and then secrete pro-inflammatory substances themselves.

"This violent over-activation in turn contributes to the progression of a neurodegenerative disease such as Alzheimer's – because inflammatory processes in the brain accelerate neurodegeneration, i.e. the death of neurons."

Lior Brimberg
Feinstein Institute for Medical Research

Captopril Reduces Microglial Activation in Autism and Improves Social Behavior

"As the primary brain immune cells, microglia are critical for maintaining a healthy brain and are recognized as important sculptors of neuronal development.

"Exposure in utero to maternal brain reactive antibodies may perturb microglia programing leading to neurodevelopmental disorder."

MiCROGLIA & Substance Use

1/25/2025

Val's Take/Conjecture

Neuro-Developmental Disorders and Substance Use Issues are very prevalent in the Criminal Justice System and have challenged reform efforts.
My big mantra has been --- we need A PUBLIC HEALTH APPROACH to CRIMINAL JUSTICE.
We need the updated understandings and treatments to fully make that a reality.
That is what the researchers are giving us.
Further, many of our current treatments are helping people.

Microglia NLRP3 Inflammasome and Neuroimmune Signaling in Substance Use Disorders. (2023)

"During the last decade,
substance use disorders (SUDs) have been increasingly recognized as neuroinflammation-related brain diseases.

...Recently, inflammasome-mediated signaling has been identified as playing critical roles in the microglia activation …"

Glial mechanisms underlying substance use disorders.
(2019)

"Although there is an extensive body of literature examining the neuronal mechanisms of substance use disorders, effective therapies remain elusive.

"Glia, particularly microglia and astrocytes, have an emerging and meaningful role in a variety of proces …"

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Translational Medicine Friday

New diagnostic framework, glutamate-mediated Excitotoxity in Neuro-Developmental & psychiatric disorDers

What is Excitotoxicity?

The Greatest Human diversity is in our immune systems

Metabolomics, immuno-methylomics, Biomarkers And slowly moving to better diagnostics

Towards a consensus roadmap for a new diagnostic framework for mental disorders (2024)

2025 Research: Neo-Natal Inflammation, Microglia, and Investigation of New Treatments

Chronic Fatigue Syndrome & Neuro-developmental / Psychiatric Disorders

Astrocytes in Depression and a complicated biological universe for criminal justice

Microglia, Neuro-Degenerative Diseases & Neuro-Developmental Disorders

MiCROGLIA & Substance Use

Translational Medicine Friday

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