Ketamine Pharmacology in Neuropsychiatric Treatment

Ketamine is a versatile agent originally developed as a dissociative anaesthetic and now repurposed at subanaesthetic doses for rapid relief of treatment-resistant depression, bipolar depression, post-traumatic stress disorder and certain chronic pain syndromes. Its primary mode of action involves non-competitive antagonism at N-methyl-D-aspartate (NMDA) receptors on GABAergic interneurones, leading to disinhibition of glutamatergic transmission. This transient surge in glutamate stimulates α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors, triggers downstream release of brain-derived neurotrophic factor (BDNF) and activates the mechanistic target of rapamycin (mTOR) pathway to promote synaptogenesis and restoration of dysfunctional neural circuits. Ketamine undergoes rapid hepatic N-demethylation to norketamine and then to hydroxynorketamine (HNK), which exerts complementary effects via distinct receptor systems. Clinically, the pharmacokinetic profile—characterised by high lipid solubility, stereoselective metabolism and active metabolites—supports diverse routes of administration including intravenous infusion, intranasal spray and oral formulations. Continued research seeks to refine dosing regimens to extend antidepressant durability, minimise psychotomimetic adverse effects and inform the design of next-generation analogues with reduced dissociative properties.

Research from Nature Portfolio

Recent studies have implemented advanced chemical biology tools to elucidate ketamine’s intracellular distribution. By engineering genetically encoded fluorescent biosensors targeted to the plasma membrane and endoplasmic reticulum, researchers have shown that S-ketamine permeates organellar membranes within seconds of extracellular exposure and equilibrates rapidly upon washout. These observations extend the pharmacological model beyond cell-surface NMDA receptor blockade, implicating potential organellar targets such as ion channels or transporters in the antidepressant and psychoactive actions of ketamine.

Ketamine Pharmacology in Neuropsychiatric Treatment publication trend

The graph below shows the total number of articles in ketamine pharmacology in neuropsychiatric treatment across all publications each year (not limited to Nature Index journals).

Technical terms

NMDA receptor: A subtype of ionotropic glutamate receptor that mediates calcium influx and is critical for synaptic plasticity and learning.

AMPA receptor: A fast-acting glutamate receptor that mediates excitatory synaptic transmission and promotes synaptic strengthening.

Hydroxynorketamine (HNK): An active ketamine metabolite formed by hepatic N-demethylation and hydroxylation, which exerts antidepressant effects via non-NMDA receptor mechanisms.

Synaptogenesis: The process of forming new synaptic connections between neurones, essential for neuroplasticity and functional recovery in mood disorders.

BDNF–TrkB signalling: A neurotrophic pathway activated by brain-derived neurotrophic factor binding to its receptor TrkB, promoting neuronal survival, growth and synaptic plasticity.

Neurexins: A family of presynaptic adhesion molecules that regulate synaptic organisation and stability through alternative splicing and interactions with postsynaptic partners.

References

1. Hydroxynorketamine, but not ketamine, acts via α7 nicotinic acetylcholine receptor to control presynaptic function and gene expression. Translational Psychiatry (2024).
2. New perspective on sustained antidepressant effect: focus on neurexins regulating synaptic plasticity. Cell Death Discovery (2024).
3. Comparative metabolomic analysis in plasma and cerebrospinal fluid of humans and in plasma and brain of mice following antidepressant-dose ketamine administration. Translational Psychiatry (2022).
4. Uncovering the Underlying Mechanisms of Ketamine as a Novel Antidepressant. Frontiers in Pharmacology (2022).
5. Biosensors Show the Pharmacokinetics of S-Ketamine in the Endoplasmic Reticulum. Frontiers in Cellular Neuroscience (2019).