Esketamine (also (S)-ketamine or S(+)-ketamine) (brand name Ketanest S) is a general anaesthetic and a dissociative. It is the S(+) enantiomer of the drug ketamine, a general anaesthetic. Esketamine acts primarily as a non-competitive NMDA receptor antagonist, but is also a dopamine reuptake inhibitor. As of July 2014, it is in phase II clinical trials for treatment-resistant depression (TRD).^[1]

Esketamine is approximately twice as potent as racemic ketamine.^[2] It is eliminated from the human body more quickly than R(−)-ketamine or racemic ketamine, although R(−)-ketamine slows its elimination.^[3]

A number of studies have suggested that esketamine has a more medically useful pharmacological action than R(−)-ketamine or racemic ketamine. Esketamine inhibits dopamine transporters eight times more than R(−)-ketamine.^[4] This increases dopamine activity in the brain. At doses causing the same intensity of effects, esketamine is generally considered to be more pleasant by patients.^[5][6] Patients also generally recover mental function more quickly after being treated with pure esketamine, which may be a result of the fact that it is cleared from their system more quickly.^[2][7]

Esketamine has an affinity for the PCP binding site of the NMDA receptor 3-4 times higher than that of R(−)-ketamine. Unlike R(−)-ketamine, esketamine does not bind significantly to sigma receptors. Esketamine increases glucose metabolism in frontal cortex, while R(−)-ketamine decreases glucose metabolism in the brain. This difference may be responsible for the fact that esketamine generally has a more dissociative or hallucinogenic effect while R(−)-ketamine is reportedly more relaxing.^[7] However, other studies have found no difference between the isomers in the patient’s level of vigilance.^[5]

Johnson & Johnson is developing a nasal spray formulation of esketamine as a treatment for depression in patients that have been unresponsive to other antidepressants in the United States.^[1] As of July 2014, phase II clinical trials of intranasal esketamine sponsored by the Johnson & Johnson subsidiary Janssen Pharmaceutica are underway.^[1][8] Other pharmaceutical companies are also developing new antidepressant drugs that act similarly to ketamine, including Naurex‘s rapastinel (GLYX-13) and NRX-1074, and Cerecor‘s CERC-301.^[1]

Although most studies suggest that esketamine is preferable for medical uses, a 2013 study found that the antidepressant effect of R(−)-ketamine lasted longer than those of S(+)-ketamine in mice.^[9]

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