Decoding the molecular network communication mechanism of ketamine's antidepressant effects.

Rationale: Major Depressive Disorder (MDD) is a global public health burden, with traditional monoaminergic antidepressants facing critical limitations including slow onset, adverse side effects, and high rates of treatment resistance (TRD). Ketamine, a rapid-acting agent with sustained antidepressant effects, has revolutionized depression treatment paradigms but challenges conventional mechanistic understanding.

Objectives: This review proposes a “network communication” framework to systematically decipher ketamine’s antidepressant mechanism, integrating clinical and basic research evidence to clarify its multi-level regulatory roles.

Methods: A comprehensive review of recent high-quality studies was conducted, covering ketamine’s pharmacokinetics, pharmacodynamics, molecular signaling pathways, cellular targets, and neural circuit modulation.

Results: Ketamine (a racemic mixture of S/R-enantiomers) functions as a network-level regulator: it reverses medial prefrontal cortical excitatory-inhibitory imbalance via NMDAR blockade on GABAergic interneurons, activates AMPAR-dependent signaling, and triggers downstream cascades (BDNF-TrkB, mTORC1) to promote synaptic plasticity. It selectively targets glial cells (astrocytes, microglia) and specific neuron subtypes, while integrating key neural circuits (mPFC-DRN, LHb) and systemic mechanisms (epigenetics, brain-gut axis).

Conclusions: Ketamine’s antidepressant efficacy arises from synergistic network communication across molecular, cellular, circuit, and systemic levels, rather than isolated single targets. This framework offers critical insights for developing next-generation rapid-acting antidepressants with improved safety profiles.