|Trade names||Ketanest, Ketanest S, Spravato, others|
|Synonyms||Esketamine hydrochloride; (S)-Ketamine; S(+)-Ketamine; JNJ-54135419|
|AHFS/Drugs.com||International Drug Names|
|Intranasal; Intravenous infusion|
|Drug class||NMDA receptor antagonists; Antidepressants; General anesthetics; Dissociative hallucinogens; Analgesics|
|CompTox Dashboard (EPA)|
|Chemical and physical data|
|Molar mass||237.725 g/mol g·mol−1|
|3D model (JSmol)|
Esketamine, sold under the brand names Ketanest and Spravato, among others, is a medication used as a general anesthetic and for treatment-resistant depression. Esketamine is used as a nasal spray or by injection into a vein.
Esketamine acts primarily as a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist. It also acts to some extent as a dopamine reuptake inhibitor but, unlike ketamine, does not interact with the sigma receptors. The compound is the S(+) enantiomer of ketamine, which is an anesthetic and dissociative similarly. It is unknown whether its antidepressant action is superior, inferior or equal to racemic ketamine and its opposite enantiomer, arketamine, which are both being investigated for the treatment of depression.
Esketamine was introduced for medical use in 1997. In 2019, it was approved for use with other antidepressants, for the treatment of depression in adults in the United States. The cost of the nasal spray as of 2019 will be US$4,700 to $6,800 for the first month.
Esketamine is a general anesthetic and is used for similar indications as ketamine. Such uses include induction of anesthesia in high-risk patients such as those with hemorrhagic shock, anaphylactic shock, septic shock, severe bronchospasm, severe hepatic insufficiency, cardiac tamponade, and constrictive pericarditis; anesthesia in caesarian section; use of multiple anesthetics in burns; and as a supplement to regional anesthesia with incomplete nerve blocks.
Similarly to ketamine, esketamine appears to be a rapid-acting antidepressant. It received a breakthrough designation from the FDA for treatment-resistant depression (TRD) in 2013 and major depressive disorder (MDD) with accompanying suicidal ideation in 2016. The drug was studied specifically for use in combination with an oral antidepressant in people with TRD who had been unresponsive to treatment; six phase III clinical trials for this indication were conducted in 2017. It is available as a nasal spray.
In February 2019, an outside panel of experts recommended that the FDA approve the nasal spray version of esketamine, provided that it be administered in a clinical setting, with patients remaining on site for at least two hours after administration. The reasoning for this requirement is that drug trial participants temporarily experienced sedation, visual disturbances, trouble speaking, confusion, numbness, and feelings of dizziness/faintness during the period immediately after administration.
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 to 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.
Esketamine was introduced for medical use as an anesthetic in Germany in 1997, and was subsequently marketed in other countries. In addition to its anesthetic effects, the medication showed properties of being a rapid-acting antidepressant, and was subsequently investigated for use as such. In November 2017, it completed phase III clinical trials for treatment-resistant depression in the United States. Johnson & Johnson filed a Food and Drug Administration (FDA) New Drug Application (NDA) for approval on September 4, 2018; the application was endorsed by an FDA advisory panel on February 12, 2019, and on March 5, 2019, the FDA approved esketamine, in conjunction with an oral antidepressant, for the treatment of depression in adults.
Esketamine is the generic name of the drug and its INN and BAN, while esketamine hydrochloride is its BANM. It is also known as S(+)-ketamine, (S)-ketamine, or (–)-ketamine, as well as by its developmental code name JNJ-54135419.
Esketamine is marketed as an antidepressant in the United States; and as an anesthetic in Europe, including in Austria, Denmark, Estonia, Finland, Germany, the Netherlands, Norway, Slovenia, Sweden, and Switzerland.
Meeting, February 12, 2019. Agenda Topic: The committees will discuss the efficacy, safety, and risk-benefit profile of New Drug Application (NDA) 211243, esketamine 28 mg single-use nasal spray device, submitted by Janssen Pharmaceutica, for the treatment of treatment-resistant depression.