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

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.

In the evidence

This study is part of the evidence base for a synthesis in the library. Here is how each one recorded it.

• State of the evidence: Ketamine ?Unclear

  Argues that ketamine's antidepressant efficacy likely arises from convergent multi-receptor and neuron-glia actions, that opioid effects are insufficient to explain its broader antidepressant action, and that many model components remain hypothetical.

  Synthesized October 25, 2026

Comparable studies

Other narrative reviews on ketamine, most cited first.