Demyelination in psychiatric and neurological disorders: Mechanisms, clinical impact, and novel therapeutic strategies
Rumi Murayama, Yi Cai, Hiroyuki Nakamura, Kenji Hashimoto
Abstract
Demyelination, defined as the loss of myelin sheaths around neuronal axons, is increasingly recognized as a key factor in a broad range of psychiatric and neurological disorders, including schizophrenia, major depressive disorder, bipolar disorder, post-traumatic stress disorder, autism spectrum disorder, substance use disorders, Alzheimer's disease, Parkinson's disease, and multiple sclerosis. This review investigates the core mechanisms driving demyelination, its clinical impact, and emerging therapeutic strategies aimed at maintaining or restoring myelin integrity. Disruption of myelin impairs crucial neural communication pathways, resulting in cognitive, motor, and behavioral deficits that substantially reduce quality of life and create significant economic and social challenges. Key contributors to demyelination include genetic predisposition, environmental triggers, immune dysregulation, neuroinflammation, and alterations in the gut-brain axis mediated by the vagus nerve. Promising therapies include sphingosine 1-phosphate receptor modulators and muscarinic acetylcholine receptor antagonists, both of which diminish immune-related myelin damage and may enhance neuroprotection. In addition, the novel antidepressant arketamine appears to boost myelination through transforming growth factor-β1 signaling pathways. Approaches targeting the gut-brain axis, such as noninvasive transcutaneous auricular vagus nerve stimulation and fecal microbiota transplantation, may also help reduce inflammation and support myelin repair. Future research should center on clarifying the precise molecular mechanisms of demyelination, developing targeted therapies, and leveraging advanced neuroimaging for earlier detection and personalized treatment. By combining immunomodulatory and neuroprotective strategies, there is potential to significantly improve outcomes for individuals affected by demyelinating psychiatric and neurological disorders.