Esketamine

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, 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.