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.
The reasoning for this requirement is that trial participants temporarily experienced sedation, visual disturbances, trouble speaking, confusion, numbness, and feelings of dizziness during immediately after. The approval of esketamine for TRD by the FDA was controversial due to limited and mixed evidence of efficacy and safety. In January 2020, esketamine was rejected by the National Health Service (NHS) of Great Britain. The NHS questioned the benefits of the medication for depression and claimed that it was too expensive. People who have been already using esketamine were allowed to complete treatment if their doctors considered this necessary.Spravato debuted to a cost of treatment of US$32,400 per year when it launched in the United States in March 2019. The Institute for Clinical and Economic Review (ICER), which evaluates cost effectiveness of drugs analogously to the National Institute for Health and Care Excellence (NICE) in the United Kingdom, declined to recommend esketamine for depression due to its steep cost and modest efficacy, deeming it not sufficiently cost-effective.Esketamine is the second drug to be approved for TRD by the FDA, following olanzapine/fluoxetine (Symbyax) in 2009. Other agents, like the atypical antipsychotics aripiprazole (Abilify) and quetiapine (Seroquel), have been approved for use in the adjunctive therapy of MDD in people with a partial response to treatment. In a meta-analysis conducted internally by the FDA during its evaluation of esketamine for TRD, the FDA reported a standardized mean difference (SMD) of esketamine for TRD of 0.28 using the three phase 3 short-term efficacy trials conducted by Janssen.