Work

Integrating multi-receptor and neuron–glia mechanisms of ketamine's antidepressant action: a convergence framework for understanding efficacy

Year: 2026

Type: review

Abstract: Ketamine has revolutionized psych iatric treatment, challenging monoamine-based paradigms through its capacity for rapid antidepressant action. While N-methyl-D-aspartate receptor (NMDAR) antagonism remains the canonical mechanism, this integrative review proposes a multi-receptor, neuron–glia convergence model to help account for ketamine's therapeutic efficacy. We outline the well-established disinhibition cascade, whereby preferential NMDAR blockade on GABAergic interneurons induces cortical disinhibition, triggering a transient glutamate surge and subsequent α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor activation. Furthermore, we discuss emerging, albeit indirect reports suggesting that ketamine and its metabolites may interact with the tropomyosin receptor kinase B (TrkB) transmembrane domain and modulate TrkB-related signaling. Beyond neurons, we consider the contributions of glial cells, particularly astrocytes, microglia, and oligodendrocyte lineage cells, as players in ketamine response in antidepressant effects. We further discuss evidence for opioid context-dependent effects that, at present, are insufficient to account for ketamine's broader antidepressant effects. Finally, we highlighted the sigma-1 receptor (S1R) as a chaperone modulator of ketamine-induced sustained neuroplasticity and intercellular neuron-glia communication. Collectively, the available data suggest that ketamine's efficacy likely arises from convergent actions across multiple molecular targets and both neuronal and glial cell types. Importantly, many components of this model remain hypothetical and require rigorous in vivo functional verification. By delineating testable mechanisms and distinguishing putative pro-plasticity effects from dissociative liabilities, this framework may inform precision psychiatry, biomarker-guided patient stratification, and the rational design of safer, next-generation rapid-acting antidepressants.

Source: Frontiers in Molecular Neuroscience

DOI: 10.3389/fnmol.2026.1950244

Authors: Zuzanna Sulej, Magdalena Zielińska

Institution: Mossakowski Medical Research Institute, Polish Academy of Sciences

Language: English

Topic: Treatment of Major Depression

Subfield: Pharmacology (medical)

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,801