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Rationale <p>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.</p> Objectives <p>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.</p> Methods <p>A comprehensive review of recent high-quality studies was conducted, covering ketamine’s pharmacokinetics, pharmacodynamics, molecular signaling pathways, cellular targets, and neural circuit modulation.</p> Results <p>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).</p> Conclusions <p>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.</p>

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Decoding the molecular network communication mechanism of ketamine’s antidepressant effects

  • 期刊论文

  • 发表日期：

    2026年3月16日

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  • Ye Li,
  • Qilong Cheng,
  • Guoxin Lin,
  • Kaiming Duan,
  • Saiying Wang

摘要

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.