|Trade names||Ketanest, Ketanest S|
|Synonyms||Esketamine hydrochloride; (S)-Ketamine; S(+)-Ketamine; JNJ-54135419|
|AHFS/Drugs.com||Consumer Drug Information|
|Chemical and physical data|
|Molar mass||237.725 g/mol|
|3D model (JSmol)|
|(what is this?)|
Esketamine, sold under the brand names Ketanest and Ketanest S, also known as (S)-ketamine or S(+)-ketamine, is a general anesthetic and a dissociative hallucinogen. It is the S(+) enantiomer of the drug ketamine, which is an anesthetic and dissociative similarly. Esketamine acts primarily as a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist. In addition, the drug shows properties of being a rapid-acting antidepressant, and as of June 2017, it is in phase III clinical trials for treatment-resistant depression (TRD).
Esketamine is approximately twice as potent as an anesthetic as racemic ketamine. It is eliminated from the human body more quickly than arketamine (R(–)-ketamine) or racemic ketamine, although arketamine slows its elimination.
A number of studies have suggested that esketamine has a more medically useful pharmacological action than arketamine or racemic ketamine. However, in mice found that the rapid antidepressant effect of arketamine was greater and lasted longer than that of esketamine. As such, as an antidepressant, the contrary has been stated ("R ketamine appears to be a potent and safe antidepressant relative to S ketamine", "(2R,6R)-HNK (hydroxynorketamine), a major metabolite of (R)-ketamine", "R-ketamine as a longer-lasting antidepressant compared with rapastinel").
Esketamine inhibits dopamine transporters eight times more than arketamine. 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. 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. This is however in contradiction with R-ketamine being devoid of psychotomimetic side effects.
Esketamine has an affinity for the PCP binding site of the NMDA receptor 3–4 times higher than that of arketamine. Unlike arketamine, esketamine does not bind significantly to sigma receptors. Esketamine increases glucose metabolism in frontal cortex, while arketamine 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 arketamine is reportedly more relaxing. However, another study found no difference between racemic and (S)-ketamine on the patient's level of vigilance. Interpretation of this finding is complicated by the fact that racemic ketamine comprises 50% (S)-ketamine.
Similarly to ketamine, esketamine shows a profile of being a rapid-acting antidepressant. As such, it is currently under development by Johnson & Johnson in a nasal spray formulation under the developmental code name JNJ-54135419 for the treatment of major depressive disorder (MDD). The drug is being studied specifically for use in combination with an oral antidepressant in patients with TRD who have been unresponsive to treatment. As of June 2017, it is in phase III clinical trials for this indication, with six ongoing trials. Esketamine has received breakthrough designation from the FDA for depression twice, specifically for TRD in November 2013 and for MDD with accompanying suicidal ideation in August 2016. It has been said recently that esketamine seems to be the closest novel and rapid-acting antidepressant to approval for the treatment of depression.
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