A January 2021 meta-analysis reported that ketamine was similarly effective to esketamine in terms of antidepressant effect size (SMD for depression score of –1.1 vs. –1.2) but more effective than esketamine in terms of response and remission rates (RR = 3.01 vs. RR = 1.38 for response and RR = 3.70 vs. RR = 1.47 for remission). A September 2021 Cochrane review found that ketamine had an effect size (SMD) for depression at 24 hours of –0.87, with very low certainty, and that esketamine had an effect size (SMD) at 24 hours of –0.31, based on moderate-certainty evidence. However, these meta-analyses have involved largely non-directly-comparative studies with dissimilar research designs and patient populations. Only a single clinical trial has directly compared ketamine and esketamine for depression as of May 2021. This study reported similar antidepressant efficacy as well as tolerability and psychotomimetic effects between the two agents. However, the study was small and underpowered, and more research is still needed to better-characterize the comparative antidepressant effects of ketamine and esketamine. Preliminary research suggests that arketamine, the R(−) enantiomer of ketamine, may also have its own independent antidepressant effects and may contribute to the antidepressant efficacy of racemic ketamine, but more research likewise is needed to evaluate this possibility.In February 2019, an outside panel of experts recommended in a 14–2 vote that the FDA approve the nasal spray version of esketamine for TRD, provided that it be given in a clinical setting, with people remaining on site for at least two hours after.
This was similar to an SMD of 0.26 for olanzapine/fluoxetine for TRD and lower than SMDs of 0.35 for aripiprazole and 0.40 for quetiapine as adjuncts for MDD. These drugs are less expensive than esketamine and may serve as more affordable alternatives to it for depression with similar effectiveness. Adverse effects
The most common adverse effects of esketamine for depression (≥5% incidence) include dissociation, dizziness, sedation, nausea, vomiting, vertigo, numbness, anxiety, lethargy, increased blood pressure, and feelings of drunkenness. Long-term use of esketamine has been associated with bladder disease. Pharmacology
Pharmacodynamics
Esketamine is approximately twice as potent an anesthetic as racemic ketamine.In mice, the rapid antidepressant effect of arketamine was greater and lasted longer than that of esketamine. The usefulness of arketamine over esketamine has been supported by other researchers.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 arketamine being devoid of psychotomimetic side effects.Unlike arketamine, esketamine does not bind significantly to sigma receptors. Esketamine increases glucose metabolism in the 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.