They start hearing voices. They see things that aren’t there. They think someone planted ideas in their heads. To schizophrenics, it’s like a switch has flipped in their brains.

Scientists reported in Nature that they’ve found what helps flip that switch. In the past decade, rapid advances in the field of neuroscience, biochemistry and psychiatry has resulted in a dramatic paradigm shift in the way we understand the role of genes, hormones, childhood adverse events, environmental influences and function of anatomical parts like the glia in normal brain functions and brain disorder pathology. 

Schizophrenia is not a genetically defined static disorder, as what was confined in DSM-V’s criteria, but a dynamic process leading to dysregulation of multiple pathways. It is not simply defined by several major genes but rather evolves from addition or potentiation of a specific cluster of genes, which subsequently determines the genetic vulnerability of an individual.  Linkage and association studies suggest that a genetic vulnerability combined with triggering factors and environmental influences, i.e. birth complications, drug abuse, urban background or time of birth have been identified as multimodal causes of this complex disorder.

A growing body of evidence shows that diversified populations of astrocytes, microglia, oligodendrocyte precursors and mature oligodendrocytes play a critical role in the regulation of synaptic functions, blood-brain barrier, immune response regulation, myelination and axonal conduction, and in the synthesis of the extracellular matrix, a key regulator of neural plasticity. 

Building on this evidence, exciting new findings are beginning to emerge, shedding light on glia abnormalities and other molecular mechanisms in schizophrenia and their impact on these functions. 

A team led by geneticist Steven McCarroll of the Broad Institute, based in Cambridge, Mass., combed through genetic information from about 29,000 schizophrenia cases, 36,000 controls and 700 brain samples from deceased patients.

McCarroll found that patients who had certain variations of a gene called C4 were more likely to inherit the disease. In healthy brains, the gene helps prune unnecessary connections between cells. But when it runs amok, as it does in schizophrenia, the process destroys healthy brain tissue.

C4’s involvement might also explain why schizophrenia arises during the late teens into the 20s. “It’s a period in human development in which brain circuits change and reorganize and . . . vulnerabilities to many neuropsychiatric illnesses emerge,” McCarroll says.

There are several different hypothesis based on several facets of the disease, some of them due to the relatively well-known mechanisms of therapeutic agents. The most widely considered neurodevelopmental hypothesis of schizophrenia integrates environmental influences and causative genes. 

The dopamine hypothesis of schizophrenia is based on the fact that all common treatments involve antidopaminergic mechanisms and genes such as DRD2, DRD3, DARPP-32, BDNF or COMT are closely related to dopaminergic system functioning. 

The glutamatergic hypothesis of schizophrenia lead recently to a first successful mGlu2/3 receptor agonistic drug and is underpinned by significant findings in genes regulating the glutamatergic system (SLC1A6, SLC1A2 GRIN1, GRIN2A, GRIA1, NRG1, ErbB4, DTNBP1, DAAO, G72/30, GRM3). 

Correspondingly, GABA has been proposed to modulate the pathophysiology of the disease which is represented by the involvement of genes like GABRA1, GABRP, GABRA6 and Reelin. 

Moreover, several genes implicating immune, signaling and networking deficits have been reported to be involved in the disease, i.e. DISC1, RGS4, PRODH, DGCR6, ZDHHC8, DGCR2, Akt, CREB, IL-1B, IL-1RN, IL-10, IL-1B. However, molecular findings suggest that a complex interplay between receptors, kinases, proteins and hormones is involved in schizophrenia.

 In a unifying hypothesis, different cascades merge into another that ultimately lead to the development of symptoms adherent to schizophrenic disorders.Although treatments may be years away, identifying these potential molecular mechanisms in schizophrenia provides a starting point.

What’s important for all of us to understand is that there is no one causative mechanism for every Schizophrenia patient, not everyone’s switch is flipped in the exact same way. As clinician scientists, our goal would be to immerse ourselves into exploring and studying the various different facets of the disorder, and hope to scratch the surface in personalised medicine where we can offer more accurate, targeted therapy to individuals instead of referring our patients to Psych or simply filling up prescription bottles.

It’s high time we stop our current “trial-and-error” approach and shift towards a more informed targeted therapy that has transformative potential for how we deliver care. PM is already common parlance in other areas of Medicine. For schizophrenia, the promise is still some way off. The need is far too great for us to not raise our voices. 

Read, share, add links to other intriguing articles in the comments below and let’s be the change we want to see in the mental health ecosystem.



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