Neuron-Neuroglia Syncytial Constellations Proposed as New Framework for Mental Illness Pathophysiology

Current psychotropic drugs offer modest therapeutic indices with limited efficacy and significant adverse effects for mental illness. Traditional models, focused on small-molecule neurotransmitters at synapses, struggle to explain complex psychiatric disorders or the unexpected positive CNS effects of larger molecules like GLP-1 analogs. These observations, including reduced "food noise" and improved mood, compel a re-evaluation of prevailing neuron-centric paradigms. The field needs a framework that integrates the growing evidence for neuroglia, particularly astrocytes, in higher mental functions and their disruption in psychiatric diseases.

This comprehensive review synthesized existing literature to challenge the prevailing neuron-centric models of mental illness and propose an integrated framework. Researchers examined the historical development of psychiatric disease models, from Virchow and Cajal's neuron-centered paradigms to neurochemical discoveries. They specifically reviewed astrocyte phylogenetics across vertebrates, their regional specialization within the human brain, and their synthesis of diverse small and large molecules, integrating these findings to support a novel conceptual model.