Demyelination in psychiatric and neurological disorders: Mechanisms, clinical impact, and novel therapeutic strategies.
Rumi Murayama, Yi Cai, Hiroyuki Nakamura, Kenji Hashimoto
Neuroscience & Biobehavioral Reviews July 1, 2025 DOI: 10.1016/j.neubiorev.2025.106209 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Topics | Ketamine |
| Keywords | Demyelination Gut-brain axis Oligodendrocyte Transforming growth factor-β1 Vagus nerve White matter |
| Key findings | Demyelination is a key factor in multiple psychiatric and neurological disorders, and emerging therapeutic strategies include sphingosine 1-phosphate receptor modulators, muscarinic acetylcholine receptor antagonists, arketamine, and gut-brain axis interventions. |
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.
Comparable studies
Other narrative reviews on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms | 2018 | Review | |
| Mechanisms of Ketamine Action as an Antidepressant | 2018 | Review | |
| Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation Adults with treatment-resistant depression | 2021 | Review | |
| Ketamine Pharmacology: An Update (Pharmacodynamics and Molecular Aspects, Recent Findings) | 2013 | Review | |
| A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders | 2017 | Review and consensus statement |
Citations in the library
Cites 16
- R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Translational Psychiatry September 1, 2015
- Rapid‐acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective Psychiatry and Clinical Neurosciences June 19, 2019
- Pharmacological and behavioral divergence of ketamine enantiomers: implications for abuse liability Molecular Psychiatry April 15, 2021
- Molecular mechanisms underlying the antidepressant actions of arketamine: beyond the NMDA receptor Molecular Psychiatry May 7, 2021
- Molecular mechanisms of the rapid-acting and long-lasting antidepressant actions of (R)-ketamine. Biochemical Pharmacology July 1, 2020
and 11 more in the library