Two cellular hypotheses explaining the initiation of ketamine's antidepressant actions: Direct inhibition and disinhibition

Neuropharmacology. 2016 Jan;100:17-26. doi: 10.1016/j.neuropharm.2015.07.028. Epub 2015 Jul 26.


A single, low dose of ketamine evokes antidepressant actions in depressed patients and in patients with treatment-resistant depression (TRD). Unlike classic antidepressants, which regulate monoamine neurotransmitter systems, ketamine is an antagonist of the N-methyl-D-aspartate (NMDA) family of glutamate receptors. The effectiveness of NMDAR antagonists in TRD unveils a new set of targets for therapeutic intervention in major depressive disorder (MDD) and TRD. However, a better understanding of the cellular mechanisms underlying these effects is required for guiding future therapeutic strategies, in order to minimize side effects and prolong duration of efficacy. Here we review the evidence for and against two hypotheses that have been proposed to explain how NMDAR antagonism initiates protein synthesis and increases excitatory synaptic drive in corticolimbic brain regions, either through selective antagonism of inhibitory interneurons and cortical disinhibition, or by direct inhibition of cortical pyramidal neurons. This article is part of the Special Issue entitled 'Synaptopathy--from Biology to Therapy'.

Keywords: AMPA receptor; AMPAR; Ambient glutamate; Cortex; Depression; Disinhibition; Folimycin (PubChem CID: 6438151); GluN2B; Glutamate (PubChem CID: 33032); Homeostatic synaptic plasticity; Inhibition; Ketamine; Ketamine (PubChem CID: 3821); MK-801 (PubChem CID: 180081); Memantine (PubChem CID: 4054); NBQX (PubChem CID: 3272524); NMDA receptor; NMDAR; Picrotoxin (PubChem CID: 5360688); Protein synthesis; Rapamycin (PubChem CID: 5284616); Riluzole (PubChem CID: 5070); Ro 25-6981 (PubChem CID: 6604887).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antidepressive Agents / pharmacology*
  • Antidepressive Agents / therapeutic use
  • Brain / drug effects*
  • Brain / metabolism
  • Depressive Disorder, Major / metabolism*
  • Depressive Disorder, Major / therapy
  • Depressive Disorder, Treatment-Resistant / metabolism*
  • Depressive Disorder, Treatment-Resistant / therapy
  • Electroconvulsive Therapy
  • Excitatory Amino Acid Antagonists / pharmacology*
  • Excitatory Amino Acid Antagonists / therapeutic use
  • Glutamic Acid / metabolism
  • Humans
  • Interneurons / drug effects
  • Interneurons / metabolism
  • Ketamine / pharmacology*
  • Ketamine / therapeutic use
  • Models, Neurological
  • Neural Inhibition*
  • Neuronal Plasticity
  • Neurons / drug effects*
  • Neurons / metabolism
  • Protein Subunits / metabolism
  • Receptors, AMPA / metabolism
  • Receptors, N-Methyl-D-Aspartate / metabolism


  • Antidepressive Agents
  • Excitatory Amino Acid Antagonists
  • Protein Subunits
  • Receptors, AMPA
  • Receptors, N-Methyl-D-Aspartate
  • Glutamic Acid
  • Ketamine