Potential molecular pathways and therapeutic implications of rapid-acting antidepressants on myelin biology: a scoping review.

Rapid-acting antidepressants, such as ketamine and serotonergic psychedelics, may affect myelin homeostasis. A systematic review of 41 studies (12 in humans, 21 in animals, 7 in vitro, and 1 computational) found that these drugs modulate myelination in a dose- and exposure-dependent manner: therapeutic doses generally promote myelin integrity and oligodendrocyte maturation, while high or repeated doses, or neonatal exposure, can disrupt myelin structure, impair oligodendrocyte viability, and produce cognitive, affective, and neurotoxic side effects. Myelin regulation may be a component of antidepressant action, but further research is needed to clarify mechanisms and implications for therapy.

Study at a glance

Abstract

Emerging evidence indicates that rapid-acting antidepressants (RAADs)-including ketamine and serotonergic psychedelics- may affect myelin homeostasis, aside from producing fast-onset, sustained improvements in several psychiatric disorders. A systematic search of PubMed (MEDLINE), Web of Science, Europe PMC, Directory of Open Access Journals (DOAJ), and Google Scholar was conducted up to October 2025 for studies examining the effects of RAADs on myelination and oligodendrocyte biology, as well as associated molecular and cellular mechanisms. Forty-one studies met the inclusion criteria: 12 in humans, 21 in animals, 7 in vitro, and one computational/theoretical. Thirty studies investigated ketamine and 11 serotonergic RAADs. Across models, RAADs modulate myelination in a dose- and exposure-dependent manner: therapeutic doses generally promote myelin integrity and oligodendrocyte maturation, while high or repeated doses, or neonatal exposure, can disrupt myelin structure and function, impair oligodendrocyte viability, and produce cognitive, affective, and neurotoxic side effects. Myelin regulation may represent a component of RAAD action, indicating that these agents could influence myelin biology. Further research is required to clarify the mechanisms underlying these effects, their potential implications for therapies aimed at preserving or restoring myelin integrity, and potential side effects. Their dose-dependent effects highlight the need for careful consideration of dosing and treatment duration.